leptin and Obesity

Mammalian puberty and Drosophila metamorphosis, despite their evolutionary distance, exhibit similar design principles and conservation of molecular components. In this Viewpoint, we review recent advances in this area and the similarities between both processes in terms of the signaling pathways and neuroendocrine circuits involved. We argue that the detection and uptake of peripheral fat by Drosophila prothoracic endocrine cells induces endomembrane remodeling and ribosomal maturation, leading to the acquisition of high biosynthetic and secretory capacity. The absence of this fat-neuroendocrine interorgan communication leads to giant, obese, non-pupating larvae. Importantly, human leptin is capable of signaling the pupariation process in Drosophila, and its expression prevents obesity and triggers maturation in mutants that do not pupate. This implies that insect metamorphosis can be used to address issues related to the biology of leptin and puberty.

Topics: Animals; Drosophila; Humans; Leptin; Mammals; Obesity; Puberty; Sexual Maturation; Signal Transduction

Leptin polymorphism (LEP) has been associated with coronary heart disease (CAD), obesity, and high body mass index (BMI). However, we performed a systematic review and meta-analysis to discover the association because previous studies reached different conclusions.. Review Manager, version 5.3.5, and Stata, version 15.0, were used for statistical analysis. We calculated the effect size of the studies using the OR with the corresponding 95% CI, and two-sided (bilateral) p-values of 0.05 were considered significant. To determine heterogeneity among the selected studies, the Q test and I2 statistics were used. Meta-regression was used to examine the disease (heart disease, obesity, and high BMI) and heterogeneity between these subgroups.. Eleven studies with 18,984 subjects were included in this study. The G-2548A (rs12112075), rs7799039, and A19G (rs2167270) polymorphisms of the leptin gene (but not the Lys656Asn (rs1805094) polymorphism) are associated with an increased risk of cardiovascular disease. Our pooled analysis revealed an association between the G-2548A (rs12112075) polymorphism and heart disease, high BMI, and obesity. This indicates that individuals carrying the AA allele are at an increased risk for heart disease, high BMI, and obesity. People with heart failure and coronary artery disease did not have the rs7799039 polymorphism or its alleles linked to them.. Combined analysis of data from current and published research suggests that the leptin gene polymorphisms G-2548A (rs12112075), rs7799039, and A19G (rs2167270) (but not the Lys656Asn (rs1805094) polymorphism) are associated with an increased risk of cardiovascular disease. Further research is needed to understand this association.

Topics: Adult; Body Mass Index; Cardiovascular Diseases; Coronary Artery Disease; Humans; Leptin; Obesity; Polymorphism, Genetic; Receptors, Leptin

Cardiac fibrosis is a hallmark of various cardiovascular diseases, which is quite commonly found in obesity, and may contribute to the increased incidence of heart failure arrhythmias, and sudden cardiac death in obese populations. As an endogenous regulator of adiposity metabolism, body mass, and energy balance, obesity, characterized by increased circulating levels of the adipocyte-derived hormone leptin, is a critical contributor to the pathogenesis of cardiac fibrosis. Although there are some gaps in our knowledge linking leptin and cardiac fibrosis, this review will focus on the interplay between leptin and major effectors involved in the pathogenesis underlying cardiac fibrosis at both cellular and molecular levels based on the current reports. The profibrotic effect of leptin is predominantly mediated by activated cardiac fibroblasts but may also involve cardiomyocytes, endothelial cells, and immune cells. Moreover, a series of molecular signals with a known profibrotic property is closely involved in leptin-induced fibrotic events. A more comprehensive understanding of the underlying mechanisms through which leptin contributes to the pathogenesis of cardiac fibrosis may open up a new avenue for the rapid emergence of a novel therapy for preventing or even reversing obesity-associated cardiac fibrosis.

Topics: Cardiomyopathies; Endothelial Cells; Fibrosis; Humans; Leptin; Obesity

Polycystic ovarian syndrome (PCOS) affects 5-20% of females and is the most common cause of anovulatory infertility. Leptin seems to have an important role in reproduction. Many reproductive pathologies such as preeclampsia, PCOS, and endometriosis are associated to plasma adiponectin levels. Kisspeptin levels are increased in PCOS women.. A review of the literature was completed through the PubMed database aiming to find articles regarding leptin, adiponectin and kisspeptin and if they are related to PCOS pathogenesis.. Even today it is not clear what is the role of leptin in women with PCOS, although most of the researchers found increased levels of leptin as well as leptin resistance in PCOS (both obese and lean individuals). Many more longitudinal studies should be done to discover the usefulness of measuring adiponectin in prepubertal women who apparently have a possibility to develop PCOS to find out if they finally develop PCOS. Most of the researchers found that PCOS women have decreased levels of adiponectin unrelated to BMI levels. Nevertheless, not all studies had the same result. Moreover, it is necessary more studies to be made to investigate the connection between kisspeptin and other metabolic factors such as LH and insulin resistance.. In general, it remains inconclusive whether leptin, adiponectin, and kisspeptin can be used as clinical and/or biochemical markers of PCOS. Therefore, it is essential to review the current data with regards to the association between PCOS and circulating leptin, adiponectin, and kisspeptin in women with PCOS.

Topics: Adiponectin; Female; Humans; Kisspeptins; Leptin; Obesity; Polycystic Ovary Syndrome

Obesity may create a mitogenic microenvironment that influences tumor initiation and progression. The obesity-associated adipokine, leptin regulates energy metabolism and has been implicated in cancer development. It has been shown that some cell types other than adipocytes can express leptin and leptin receptors in tumor microenvironments. It has been shown that peroxisome proliferator-activated receptors (PPAR) agonists can affect leptin levels and vice versa leptin can affect PPARs. Activation of PPARs affects the expression of several genes involved in aspects of lipid metabolism. In addition, PPARs regulate cancer cell progression through their action on the tumor cell proliferation, metabolism, and cellular environment. Some studies have shown an association between obesity and several types of cancer, including breast cancer. There is some evidence that suggests that there is crosstalk between PPARs and leptin during the development of breast cancer. Through a systematic review of previous studies, we have reviewed the published relevant articles regarding leptin signaling in breast cancer and its crosstalk with peroxisome proliferator-activated receptors α and γ.

Topics: Breast Neoplasms; Female; Humans; Leptin; Obesity; Peroxisome Proliferator-Activated Receptors; PPAR alpha; Signal Transduction; Tumor Microenvironment

Abdominal obesity has been associated with an increased risk of insulin resistance, metabolic syndrome, and diabetes. Central fat removal procedures such as liposuction, lipectomy, and abdominoplasty are among the most common surgical procedures. The impact of the latter on the former is controversial and understudied. The authors aimed to explore the effect of subcutaneous fat elimination procedures on insulin resistance measures and adipokine levels.. Relevant studies regarding the effects of surgical subcutaneous fat removal on glucose, insulin, adipokines, and lipid metabolism, as well as blood pressure, were identified by searching PubMed and Ovid-Cochrane without limits in date, type of publication, or language. After the selection process, 24 studies were obtained. The results of the articles were summarized using descriptive statistics. For the final analysis, a randomized effects model was used to evaluate heterogeneity; averages and meta-analytic differences were expressed with a confidence interval of 95%.. All studies reported a reduction in weight (-2.64 kg; 95% CI, -4.32 to -0.96; P = 0.002; I 2 = 36%; P of I 2 < 0.001) and body mass index after liposuction. A significant improvement in triglycerides (-10.06 mg/dL; 95% CI, -14.03 to -6.09; P < 0.001; I 2 = 48%; P of I 2 = 0.05), serum glucose concentration (-4.25 mg/dL; 95% CI, -5.93 to -2.56; P < 0.001; I 2 = 68%; P of I 2 < 0.001), serum insulin concentration (-2.86 μIU/mL; 95% CI, -3.75 to -1.97; P < 0.001; I 2 = 59%; P of I 2 = 0.003), and serum leptin concentration (-7.70 ng/mL; 95% CI, -11.49 to -3.92; P = 0.0001; I 2 = 96%; P of I 2 < 0.001) was consistently observed.. In addition to weight loss, there is a significant decrease in leptin, triglyceride, glucose, and insulin serum concentrations after liposuction, a fact that should be considered in future discussions.

Topics: Blood Glucose; Body Mass Index; Body Weight; Glucose; Humans; Insulin; Insulin Resistance; Leptin; Lipectomy; Lipids; Obesity

Alzheimer's disease (AD) is the most common type of dementia characterized by the deposition of amyloid beta (Aβ) plaques and tau-neurofibrillary tangles in the brain. Visceral obesity (VO) is usually associated with low-grade inflammation due to higher expression of pro-inflammatory cytokines by adipose tissue. The objective of the present review was to evaluate the potential link between VO and the development of AD. Tissue hypoxia in obesity promotes tissue injury, production of adipocytokines, and release of pro-inflammatory cytokines leading to an oxidative-inflammatory loop with induction of insulin resistance. Importantly, brain insulin signaling is involved in the pathogenesis of AD and lower cognitive function. Obesity and enlargement of visceral adipose tissue are associated with the deposition of Aβ. All of this is consonant with VO increasing the risk of AD through the dysregulation of adipocytokines which affect the development of AD. The activated nuclear factor kappa B (NF-κB) pathway in VO might be a potential link in the development of AD. Likewise, the higher concentration of advanced glycation end-products in VO could be implicated in the pathogenesis of AD. Taken together, different inflammatory signaling pathways are activated in VO that all have a negative impact on the cognitive function and progression of AD except hypoxia-inducible factor 1 which has beneficial and neuroprotective effects in mitigating the progression of AD. In addition, VO-mediated hypoadiponectinemia and leptin resistance may promote the progression of Aβ formation and tau phosphorylation with the development of AD. In conclusion, VO-induced AD is mainly mediated through the induction of oxidative stress, inflammatory changes, leptin resistance, and hypoadiponectinemia that collectively trigger Aβ formation and neuroinflammation. Thus, early recognition of VO by visceral adiposity index with appropriate management could be a preventive measure against the development of AD in patients with VO.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Cytokines; Humans; Leptin; Obesity; Obesity, Abdominal

Topics: Adiponectin; Biomarkers; C-Reactive Protein; Carbon; Chorionic Gonadotropin; Female; Humans; Infant, Newborn; Insulin; Leptin; Obesity; Obesity, Maternal; Pregnancy; Progesterone

Endothelial dysfunction is a major risk factor for many cardiovascular diseases, notably hypertension. Obesity increases the risk of endothelial dysfunction in association with increasing production of the adipokine leptin. Preclinical studies have begun to unravel the mechanisms whereby leptin leads to the development of endothelial dysfunction, which are sex-specific. This review will summarize recent findings of mechanisms of leptin-induced endothelial impairment in both male and females and in pregnancy.. Leptin receptors are found in high concentrations in the central nervous system (CNS), via which leptin promotes appetite suppression and upregulates sympathetic nervous system activation. However, leptin receptors are expressed in many other tissues, including the vascular endothelial cells and smooth muscle cells. Recent studies in mice with vascular endothelial or smooth muscle-specific knockdown demonstrate that endothelial leptin receptor activation plays a protective role against endothelial dysfunction in male animals, but not necessarily in females. Clinical studies indicate that women may be more sensitive to obesity-associated vascular endothelial dysfunction. Emerging preclinical data indicates that leptin and progesterone increase aldosterone production and endothelial mineralocorticoid receptor activation, respectively. Furthermore, decades of clinical studies indicate that leptin levels increase in the hypertensive pregnancy disorder preeclampsia, which is characterized by systemic endothelial dysfunction. Leptin infusion in mice induces the clinical characteristics of preeclampsia, including endothelial dysfunction.. Novel preclinical data indicate that the mechanisms whereby leptin promotes endothelial dysfunction are sex-specific. Leptin-induced endothelial dysfunction may also play a role in hypertensive pregnancy as well.

Topics: Animals; Endothelial Cells; Female; Humans; Hypertension; Leptin; Male; Mice; Obesity; Pre-Eclampsia; Receptors, Leptin

Hidradenitis suppurativa (HS) is a chronic, recurrent, debilitating disorder of the pilosebaceous unit. Although its pathophysiology is not fully explained, inflammation seems to play an essential role in the development of HS. A link between obesity - often considered a state of chronic inflammation - and a higher prevalence of HS has been described. Nevertheless, the exact association is not well understood. Adipose tissue is a highly active endocrine organ that produces and secretes a variety of metabolically and immunologically active molecules called adipokines. The imbalances in concentrations of several adipokines in patients with HS have already been described. A shift towards the overproduction of proinflammatory adipokines (including leptin, resistin and visfatin) with the suppression of anti-inflammatory ones (adiponectin) has been noted. We conducted a review of the available data on adipokines in HS, concentrating on the described imbalances in adipokine concentrations, as well as possible implications in HS pathogenesis. Moreover, new, unstudied adipokines with possible implications in the development of HS are proposed.

Topics: Adipokines; Adiponectin; Hidradenitis Suppurativa; Humans; Inflammation; Leptin; Obesity

Excess body weight is frequently associated with low-grade inflammation. Evidence indicates a relationship between obesity and cancer, as well as with other diseases, such as diabetes and non-alcoholic fatty liver disease, in which inflammation and the actions of various adipokines play a role in the pathological mechanisms involved in these disorders. Leptin is mainly produced by adipose tissue in proportion to fat stores, but it is also synthesized in other organs, where leptin receptors are expressed. This hormone performs numerous actions in the brain, mainly related to the control of energy homeostasis. It is also involved in neurogenesis and neuroprotection, and central leptin resistance is related to some neurological disorders, e.g., Parkinson's and Alzheimer's diseases. In peripheral tissues, leptin is implicated in the regulation of metabolism, as well as of bone density and muscle mass. All these actions can be affected by changes in leptin levels and the mechanisms associated with resistance to this hormone. This review will present recent advances in the molecular mechanisms of leptin action and their underlying roles in pathological situations, which may be of interest for revealing new approaches for the treatment of diseases where the actions of this adipokine might be compromised.

Topics: Adipokines; Adipose Tissue; Humans; Inflammation; Leptin; Obesity

Obesity has recently emerged as one of the most severe health concerns. Obesity is a key autonomous risk factor for heart failure and contributes to cardiovascular disease (CVD) risk factors such as hypertension, type 2 diabetes, and metabolic abnormalities. Obesity is caused by a metabolic imbalance, which occurs when calories burnt are fewer than the number of calories consumed. There are several pathways accountable for the adverse impacts of obesity on the cardiovascular system. Inflammatory cell infiltration develops in the adipose tissue, the pancreas, and other issues similar to the progression of obesity. Inflammation is triggered by immune cells that invade dysfunctional adipose tissue. The atherosclerotic inflammation phase, related to obesity, induces coronary calcification. Obesity is linked to elevated levels of leptin and high blood pressure. Leptin causes systemic vasoconstriction, sodium retention, and increased blood pressure by influencing the synthesis of nitric oxide and activating the sympathetic nervous system. Obesity is a well-known risk factor for CVD and is one of the leading causes of the greater risk of diseases, including dyslipidemia, hypertension, depression, metabolic syndrome, atrial fibrillation, and heart failure in adults and children. When used with dietary improvements, antiobesity drugs improve the probability of experiencing clinically healthy (5%) weight loss. This review aimed to address the consequences of obesity on cardiac structure and function, risk factors, the impact of the obesity paradox, pharmacological treatment strategies for managing and recommended exercise and diet.

Topics: Adult; Cardiovascular Diseases; Child; Diabetes Mellitus, Type 2; Heart Failure; Humans; Hypertension; Inflammation; Leptin; Obesity

Determining whether changes in leptin signaling plays a role in the improvement of cognitive function post-bariatric surgery may aid in the understanding and development of novel therapeutic approaches targeting cognitive dysfunction through the greater understanding of processes connecting obesity and brain health. Several studies have explored the effects of cognition post bariatric surgery, and others have studied leptin and its changes post surgery. However the amalgamation of the effects of leptin signaling in relation to cognition post bariatric surgery have yet to be considered as key tools in the understanding of cognitive dysfunction in obese subjects with leptin resistance or insensitivity. This review serves to highlight the potential correlations, to further elucidate the effect of improved leptin signaling on cognition post bariatric surgery, and to propose a direct cause for the improvement of cognitive function via the amelioration of the leptin Janus kinase/Signal transducer and activator of transcription (JAK/STAT) signaling pathway as a result of the reversal of inflammatory processes involved in diseased individuals.

Topics: Bariatric Surgery; Cognition; Humans; Leptin; Obesity; Signal Transduction

It is well established that decreases in plasma leptin levels, as with fasting, signal starvation and elicit appropriate physiological responses, such as increasing the drive to eat and decreasing energy expenditure. These responses are mediated largely by suppression of the actions of leptin in the hypothalamus, most notably on arcuate nucleus (ArcN) orexigenic neuropeptide Y neurons and anorexic pro-opiomelanocortin neurons. However, the question addressed in this review is whether the effects of increased leptin levels are also significant on the long-term control of energy balance, despite conventional wisdom to the contrary. We focus on leptin's actions (in both lean and obese individuals) to decrease food intake, increase sympathetic nerve activity, and support the hypothalamic-pituitary-thyroid axis, with particular attention to sex differences. We also elaborate on obesity-induced inflammation and its role in the altered actions of leptin during obesity.

Topics: Energy Metabolism; Female; Humans; Hypothalamus; Leptin; Male; Obesity; Pituitary Gland; Thyroid Gland

Obesity is a global epidemic disease representing the fifth leading cause of death in the world. It was shown that it is caused by the interaction between environmental factors and genes including leptin gene (LEP). This paper aimed to analyze the association between the LEP gene polymorphisms rs7799039 and rs11761556 with obesity in Moroccan individuals as well as to perform an update meta-analysis of this genetic association. Both polymorphisms were genotyped in 146 obesity patients and 104 controls using real-time PCR technique. The genetic association analysis and the comparison of quantitative parameters were carried out using the R language. Moreover, a meta-analysis including 20 genetic association studies was performed using Review Manager 5.3 software. No significant association was found between the polymorphisms rs7799039 and rs11761556 and the risk of obesity. The comparison of biochemical and clinical parameters between the genotypes of the rs7799039 polymorphism, showed a significant increased triglycerides levels in carriers of AA or GA genotypes (P value = 0.040). The meta-analysis showed no significant association between the rs7799039 polymorphism and obesity under all genetic models. In conclusion, the case-control study and meta-analysis demonstrated that the LEP gene polymorphisms rs7799039 and rs11761556 cannot be considered as genetic risk factors for obesity.

Topics: Case-Control Studies; Genetic Predisposition to Disease; Genotype; Humans; Leptin; Obesity; Polymorphism, Single Nucleotide; Receptors, Leptin

The effects of exercise training (Ex), dietary interventions (DIs), and a combination of Ex and DI (Ex + DI) on leptin and adiponectin have been established. However, less is known regarding the comparisons of Ex with DI and of Ex + DI with either Ex or DI alone. The aim of the present meta-analysis is to compare the effects of Ex with those of DI and those of Ex + DI with those of either Ex or DI alone on circulating leptin and adiponectin in individuals who are overweight and those with obesity. PubMed, Web of Science, and MEDLINE were searched to identify original articles, published through June 2022, that compared the effects of Ex with those of DI and/or the effects of Ex + DI with those of Ex and/or DI on leptin and adiponectin in individuals with BMIs (in kg/m

Topics: Adiponectin; Exercise; Humans; Leptin; Obesity; Overweight

Topics: Adipokines; Adiponectin; Adult; Curcuma; Curcumin; Dietary Supplements; Humans; Leptin; Obesity; Randomized Controlled Trials as Topic

As a multi-potency cytokine, leptin not only plays a crucial role in controlling weight and energy homeostasis but also participates in the metabolic balance in the human body. Leptin is a small helical protein with a molecular weight of 16 kDa. It can interact with multiple subtypes of its receptors to initiate intracellular signal transduction and exerts physiological effects. Disturbances in leptin signaling may lead to obesity and a variety of metabolic diseases. Leptin was also found to be a critical factor in many diseases of the elderly. In this review, we focus on recent advances in the structural and molecular mechanisms of leptin signaling through its receptors with the aim of a deeper understanding of leptin-related diseases.

Topics: Aged; Energy Metabolism; Humans; Leptin; Obesity; Receptors, Leptin; Signal Transduction

Midlife obesity and late-life weight loss confer a greater risk for developing dementia and Alzheimer's disease (AD), but the exact mechanisms behind this phenomenon are currently unknown. The answer could lie on the involvement of gastrointestinal factors, such as adipokines (e.g., leptin, adiponectin, and resistin) and ghrelin. In this context, we conducted a pre-registered systematic review and meta-analysis of 42 cross-sectional and 13 longitudinal studies targeting the associations between leptin, adiponectin, resistin, and ghrelin and the prevalence of general dementia, AD, and mild cognitive impairment (MCI). We also examined the relationship between the four gastrointestinal factors and neurocognitive outcomes and AD-related cerebrospinal fluid biomarkers. Patients with AD had lower blood leptin and higher resistin levels than cognitively normal participants. Lower leptin and higher resistin were associated with higher degree of cognitive impairment. Additionally, lower late-life leptin levels might be associated with higher prospective risk of dementia and AD, although more studies are needed to corroborate this. Results in ghrelin and adiponectin were not conclusive, with age, sex distribution, obesity, and severity of dementia seemingly acting as moderators across several analyses. Our work might contribute to the identification of new preclinical blood markers of MCI and AD.

Topics: Adipokines; Adiponectin; Alzheimer Disease; Biomarkers; Cognitive Dysfunction; Cross-Sectional Studies; Ghrelin; Humans; Leptin; Obesity; Prospective Studies; Resistin

Despite its important role in numerous physiological functions, including regulation of appetite and body weight, immune function and normal sexual maturation, raised leptin levels could result in significant damaging effects on sperm. The adverse effects of leptin on the male reproductive system result from its direct actions on the reproductive organs and cells instead of the hypothalamus-pituitary-gonadal axis. Binding of leptin to the receptors in the seminiferous tubular cells of the testes increases free radical production and decreases the gene expression and activity of endogenous enzymatic antioxidants. These effects are mediated via the PI3K pathway. The resultant oxidative stress causes significant damage to the seminiferous tubular cells, germ cells and sperm DNA leading to apoptosis, increased sperm DNA fragmentation, decreased sperm count, increased fraction of sperm with abnormal morphology, and decreased seminiferous tubular height and diameter. This review summarises the evidence in the literature on the adverse effects of leptin on sperm, which could underlie the often-reported sperm abnormalities in obese hyperleptinaemic infertile males. Although leptin is necessary for normal reproductive function, its raised levels could be pathologic. There is, therefore, a need to identify the cut-off level in the serum and seminal fluid above which leptin becomes pathological for better management of leptin associated adverse effects on male reproductive function.

Topics: Antioxidants; Humans; Infertility, Male; Leptin; Male; Obesity; Phosphatidylinositol 3-Kinases; Semen; Sperm Count; Sperm Motility; Spermatozoa

Over the past decades, obesity has grown to epidemic proportions worldwide. It has been associated with an increased risk for different types of cancer. In addition, obesity has been associated with a poor prognosis, an increased risk of metastasis and mortality, and resistance to anti-cancer therapies. The pathophysiological mechanisms underlying the obesity-cancer connection have not yet been fully elucidated. However, this connection could result, at least in part, from the action of adipokines, whose levels are increased in obesity. Among these adipokines, evidence suggests leptin's critical role in linking obesity to cancer. In this review, we first summarize the current state of the literature regarding the implication of leptin in tumorigenic processes. Next, we focus on the effects of leptin on the anti-tumor immune response. Then, we discuss the influence of leptin on the efficiency of antineoplastic treatments and the development of tumor resistance. Finally, we highlight the use of leptin as a potential target for the prevention and treatment of cancer.

Topics: Adipokines; Antineoplastic Agents; Humans; Leptin; Neoplasms; Obesity

By 2030, it is expected that a billion people will have suffer from obesity. Adipose tissue synthesizes leptin, an adipokine that affects cardiovascular risk. Leptin intensifies the synthesis of vascular endothelial growth factor (VEGF). Our study reviews recent reports on leptin-VEGF crosstalk in obesity and related disorders. PubMed, Web of Science, Scopus, and Google Scholar were searched. One hundred and one articles involving human, animal, and in vitro research were included. In vitro studies show the crucial role of interaction between endothelial cells and adipocytes and hypoxia as a factor that intensifies leptin's effects on VEGF. Leptin-VEGF crosstalk promotes the progression of cancer. The animal research reveal that a high-fat diet enhances leptin and VEGF crosstalk. Genetic and epigenetic mechanisms and procreator-offspring programming may be involved in leptin-VEGF crosstalk. Some female-specific characteristics of leptin-VEGF relation in obesity were observed. The human studies have shown that increased leptin and VEGF synthesis and leptin-VEGF crosstalk are factors linking obesity with elevated cardiovascular risk. The studies of the last 10 years documented a range of significant aspects of leptin-VEGF crosstalk specific for obesity and related disorders, shedding new light on the link between obesity and increased cardiovascular risk.

Topics: Animals; Endothelial Cells; Female; Humans; Leptin; Obesity; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors

Obesity is one of the risk factors for gallstone disease (GD). Leptin hormone is known to regulate central obesity. Thus, hyperleptinemia may also be involved in gallstone disease pathogenesis. In the present study, a meta-analysis was performed to compare the leptin levels in GD and controls.. The authors reviewed studies till April 12, 2021, which reported the serum leptin levels in gallstone patients and healthy controls. The online search involved ScienceDirect and PubMed databases. The data obtained from the research articles was scrutinized for selection criteria. Only those articles which fulfilled the inclusion criteria were subjected to meta-analysis.. Of 2047 articles, a total of eight studies met the inclusion and exclusion criteria and were considered for the meta-analysis. After meta-analysis, it was observed that the patients with GD  had high leptin levels as compared to healthy controls. A significant level of heterogeneity was observed in the included studies (I. High leptin levels might be involved in GD pathogenesis.

Topics: Gallstones; Humans; Leptin; Obesity; Risk Factors

Obesity, defined as the abnormal or excessive expansion of white adipose tissue, has reached pandemic proportions and is recognized as an important health concern since it is a common root for several comorbidities, including malignancies. Indeed, the current knowledge of the white adipose tissue, which shifts its role from an energy storage tissue to an important endocrine and metabolic organ, has opened up new avenues for the discovery of obesity's effects on tumor biology. In this review, we will report the epidemiological studies concerning the strong impact of obesity in several types of cancer and describe the mechanisms underlying the heterotypic signals between cancer cell lines and adipocytes, with particular emphasis on inflammation, the insulin/IGF-1 axis, and adipokines. Among the adipokines, we will further describe the in vitro, in vivo, and clinical data concerning the role of leptin, recognized as one of the most important mediators of obesity-associated cancers. In fact, leptin physiologically regulates energy metabolism, appetite, and reproduction, and several studies have also described the role of leptin in affecting cancer development and progression. Finally, we will summarize the newest pharmacological strategies aimed at mitigating the protumorigenic effects of leptin, underlining their mechanisms of action.

Topics: Adipokines; Adipose Tissue; Humans; Leptin; Neoplasms; Obesity

Organismal energy balance is controlled by inter-tissue communication mediated by the nervous system and hormones, the disruption of which causes metabolic syndrome exemplified by diabetes and obesity. Fat-storing adipose tissue, especially those located in subcutaneous white adipose tissue, secretes leptin in a proportion of fat mass, inhibiting the accumulation of organismal fat by suppressing appetite and promoting energy expenditure. With a prevalence of obesity that exhibits hyperleptinemia, most of the investigation on leptin has been focused on how it works and how it does not, which is expected to be a clue for treating obesity. In contrast, how it is synthesized, transported, and excreted, all of which are relevant to the homeostasis of blood leptin concentration, are not much understood. Of note, acute leptin reduction after hyperleptinemia in the context of obesity exhibited a beneficial effect on obesity and insulin sensitivity, indicating that manipulation of circulating leptin level may provide a therapeutic strategy. Technological advances such as "omics" analysis combined with sophisticated gene-engineered mice studies in the past decade enabled a deeper understanding of leptin's action in more detail. Here, we summarize the updated understanding of the action as well as regulation of leptin and point out the emerging direction of research on leptin.

Topics: Adipokines; Adipose Tissue; Animals; Diabetes Mellitus; Leptin; Mice; Obesity

Genetic disruption of key molecular components of the hypothalamic leptin-melanocortin pathway causes severe obesity in mice and humans. Physiological studies in people who carry these mutations have shown that the adipose tissue-derived hormone leptin primarily acts to defend against starvation. A lack of leptin causes an intense drive to eat and increases the rewarding properties of food, demonstrating that human appetite has a strong biological basis. Genetic studies in clinical- and population-based cohorts of people with obesity or thinness continue to provide new insights into the physiological mechanisms involved in weight regulation and identify molecular targets for weight loss therapy. This article is part of a discussion meeting issue 'Causes of obesity: theories, conjectures and evidence (Part II)'.

Topics: Adipose Tissue; Animals; Humans; Leptin; Mice; Mutation; Obesity; Thinness

Body weight is tightly regulated when outside the normal range. It has been proposed that there are individual-specific lower and upper intervention points for when the homeostatic regulation of body weight is initiated. The nature of the homeostatic mechanisms regulating body weight at the lower and upper ends of the body weight spectrum might differ. Previous studies demonstrate that leptin is the main regulator of body weight at the lower end of the body weight spectrum. We have proposed that land-living animals use gravity to regulate their body weight. We named this homeostatic system the

Topics: Animals; Body Weight; Energy Metabolism; Homeostasis; Leptin; Mice; Obesity

Cardiovascular and metabolic complications associated with excess adiposity are linked to chronic activation of the sympathetic nervous system, resulting in a high risk of mortality among obese individuals. Obesity-related positive energy balance underlies the progression of hypertension, end-organ damage, and insulin resistance, driven by increased sympathetic tone throughout the body. It is, therefore, important to understand the central network that drives and maintains sustained activation of the sympathetic nervous system in the obese state. Experimental and clinical studies have identified structural changes and altered dynamics in both grey and white matter regions in obesity. Aberrant activation in certain brain regions has been associated with altered reward circuitry and metabolic pathways including leptin and insulin signaling along with adiposity-driven systemic and central inflammation. The impact of these pathways on the brain via overactivity of the sympathetic nervous system has gained interest in the past decade. Primarily, the brainstem, hypothalamus, amygdala, hippocampus, and cortical structures including the insular, orbitofrontal, temporal, cingulate, and prefrontal cortices have been identified in this context. Although the central network involving these structures is much more intricate, this review highlights recent evidence identifying these regions in sympathetic overactivity in obesity.

Topics: Brain; Humans; Hypertension; Insulin Resistance; Leptin; Obesity; Sympathetic Nervous System

Similar to the general population, lifestyle interventions focused on nutrition and physical activity form the foundation for treating obesity caused by rare genetic disorders. Additional therapies, including metreleptin and setmelanotide, that target defects within the leptin signaling pathway can effectively synergize with lifestyle efforts to treat monogenic disorders of leptin, leptin receptor, proopiomelanocortin (POMC), and proprotein convertase subtilisin/kexin type 1 (PCSK1) and syndromic conditions, such as the ciliopathies Bardet-Biedl and Alström syndromes, whose pathophysiological mechanisms also converge on the leptin pathway. Investigational treatments for Prader-Willi syndrome target specific defects caused by reduced expression of paternally derived genes within the chromosome 15q region.

Topics: Humans; Leptin; Obesity; Prader-Willi Syndrome

Leptin is a hormone secreted primarily by adipose tissue. It regulates an organism's metabolism, energy balance, and body weight through a negative feedback mechanism. When a person or animal has low body fat and little energy, the leptin level in the body decreases, and conversely, when there is an excess of nutrients, the leptin level increases, giving a feeling of satiety. However, when leptin levels are abnormal (too high or too low) for a number of reasons, it can negatively affect your health, inducing inflammatory responses, obesity, and other problems. Many studies have shown that abnormal leptin levels, such as hyperleptinemia, are closely associated with common risk factors for atherosclerosis (AS). This review systematically states the relationship between leptin and common risk factors for AS (inflammation, obesity, diabetes mellitus, hypertension, and sleep disorders) and provides some new thoughts on the future direction of research on both. Because the abnormal level of leptin will have adverse effects on multiple atherosclerotic risk factors, how to regulate the leptin level of patients with AS, and whether we can treat and prevent AS by intervening the leptin level, these may be our new research directions in the future.

Topics: Adipose Tissue; Animals; Atherosclerosis; Humans; Leptin; Obesity; Risk Factors

The central nervous system (CNS) receives information from afferent neurons, circulating hormones, and absorbed nutrients and integrates this information to orchestrate the actions of the neuroendocrine and autonomic nervous systems in maintaining systemic metabolic homeostasis. Particularly the arcuate nucleus of the hypothalamus (ARC) is of pivotal importance for primary sensing of adiposity signals, such as leptin and insulin, and circulating nutrients, such as glucose. Importantly, energy state-sensing neurons in the ARC not only regulate feeding but at the same time control multiple physiological functions, such as glucose homeostasis, blood pressure, and innate immune responses. These findings have defined them as master regulators, which adapt integrative physiology to the energy state of the organism. The disruption of this fine-tuned control leads to an imbalance between energy intake and expenditure as well as deregulation of peripheral metabolism. Improving our understanding of the cellular, molecular, and functional basis of this regulatory principle in the CNS could set the stage for developing novel therapeutic strategies for the treatment of obesity and metabolic syndrome. In this review, we summarize novel insights with a particular emphasis on ARC neurocircuitries regulating food intake and glucose homeostasis and sensing factors that inform the brain of the organismal energy status.

Topics: Arcuate Nucleus of Hypothalamus; Diabetes Mellitus; Energy Metabolism; Glucose; Humans; Hypothalamus; Leptin; Obesity

Leptin is a hormone primarily produced by the adipose tissue in proportion to the size of fat stores, with a primary function in the control of lipid reserves. Besides adipose tissue, leptin is also produced by other tissues, such as the stomach, placenta, and mammary gland. Altogether, leptin exerts a broad spectrum of short, medium, and long-term regulatory actions at the central and peripheral levels, including metabolic programming effects that condition the proper development and function of the adipose organ, which are relevant for its main role in energy homeostasis. Comprehending how leptin regulates adipose tissue may provide important clues to understand the pathophysiology of obesity and related diseases, such as type 2 diabetes, as well as its prevention and treatment. This review focuses on the physiological and long-lasting regulatory effects of leptin on adipose tissue, the mechanisms and pathways involved, its main outcomes on whole-body physiological homeostasis, and its consequences on chronic diseases.

Topics: Adipose Tissue; Diabetes Mellitus, Type 2; Homeostasis; Humans; Leptin; Obesity

Consumption of an exceedingly high-fat diet with irregular eating and sleeping habits is typical in the current sedentary lifestyle, leading to chronic diseases like obesity and diabetes mellitus. Leptin is a primary appetite-regulating hormone that binds to its receptors in the hypothalamic cell membrane and regulates downstream appetite-regulating neurons NPY/AgRp and POMC in the hypothalamus. Based on the fat content of the adipose tissue, leptin is secreted, and excess accumulation of fat in adipose tissue stimulates the abnormal secretion of leptin. The secreted leptin circulating in the bloodstream uses its transporters to cross the blood-brain barrier (BBB) and reach the CSF. There is a saturation limit for leptin bound to its transporters to cross the BBB, and increased leptin secretion in adipose tissue has a defect in its transport across the BBB. Leptin resistance is due to excess leptin, a saturation of its transporters, and deficiency in either the receptor level or signalling in the hypothalamus. Leptin resistance leads to obesity due to excess food intake and less energy expenditure. Normal leptin secretion follows a rhythm, and alteration in the lifestyle leads to hormonal imbalances and increases ROS generation leading to oxidative stress. The sleep disturbance causes obesity with increased lipid accumulation in adipose tissue. Melatonin is the master regulator of the sleep-wake cycle secreted by the pineal gland during the night. It is a potent antioxidant with anti-inflammatory properties. Melatonin is secreted in a pattern called the circadian rhythm in humans as well. Research indicates that melatonin plays a vital role in hormonal regulation and energy metabolism, including leptin signalling and secretion. Studying the role of melatonin in leptin regulation will help us combat the pathologies of obesity caused by leptin resistance.

Topics: Appetite; Circadian Rhythm; Humans; Hypothalamus; Leptin; Melatonin; Obesity

Rare genetic forms of obesity are linked to impaired energy balance (i.e., eating behaviour and energy expenditure) involving hypothalamic pathways. More than 60 genes coding for proteins located in the hypothalamic leptin/melanocortin pathway contribute to the development of these rare forms of obesity. The ambition of the French National Protocol for the Diagnosis and Care (PNDS) of Obesity of Rare Causes was to establish practical recommendations for assessment and management at all ages. This report is available on the website of the French Health Authority (HAS). In addition to severe obesity, patients often display obesity-related comorbidities and neuropsychological/psychiatric disorders. These complex conditions make clinical management particularly challenging. Early diagnosis is critical for the organization of coordinated specialized multidisciplinary care, with mandatory interaction between caregivers, social partners and families. Strategies to prevent aggravation of obesity consist in limiting access to food, establishing a reassuring daily eating environment, and the practice of sustained adapted supervised daily physical activity. The implementation of genetic diagnosis in clinical practice now enables a personalized medicine approach with access to new drug therapies, and improves the analysis of the risk/benefit ratio of bariatric surgery.

Topics: Bariatric Surgery; Energy Metabolism; Humans; Hypothalamus; Leptin; Obesity; Obesity, Morbid

Obesity is a medical condition associated with metabolic disorders and low-grade systemic inflammation. Another characterizing feature of obesity is high circulating levels of leptin (a hormone predominantly made by adipose cells and enterocytes in the small intestine that helps to regulate energy balance), a phenomenon termed hyperleptinemia. Hyperleptinemia is associated with both low-grade systemic inflammation and metabolic dysfunction in obese human beings. Moreover, obesity is associated with low testosterone in men, which correlates with high body fat. The association between leptin and low testosterone could potentially be explained via the imbalanced leptin levels that results in higher estrogen levels, which further increases the aromatase activity. The increase in aromatase activity in turn reciprocally inhibits the testosterone levels and hypothalamic pituitary gonadal axis. Novel strategies are being used to treat obesity, including leptin and testosterone therapy. However, the efficacy and adverse effects of these strategies need further validation through preclinical and clinical studies. Additionally, further studies are needed to establish the molecular mechanism behind leptin-modulated changes to testosterone in obese men. This review summarizes the available literature on the role of leptin and low testosterone during obesity.

Topics: Aromatase; Humans; Inflammation; Leptin; Male; Obesity; Testosterone

Multiple sclerosis (MS) is a chronic autoimmune neurodegenerative disease of the central nervous system (CNS) characterized by demyelination, neuronal loss, and permanent neurological impairments. The etiology of MS is not clearly understood, but genetics and environmental factors can affect the susceptibility of individuals. Obesity or a body mass index of (BMI) > 30 kg/m2 is associated with serious health consequences such as lipid profile abnormalities, hypertension, type 2 diabetes mellitus, reduced levels of vitamin D, and a systemic lowgrade inflammatory state. The inflammatory milieu can negatively affect the CNS and promote MS pathogenesis due in part to the increased blood-brain barrier permeability by the actions of adipose tissue-derived cytokines or adipokines. By crossing the blood-brain barrier, the pro-inflammatory adipokines such as leptin, resistin, and visfatin activate the CNS-resident immune cells, and promote the inflammatory responses; subsequently, demyelinating lesions occur in the white matter of the brain and spinal cord. Therefore, better knowledge of the adipokines' role in the induction of obesity-related chronic inflammation and subsequent events leading to the dysfunctional blood-brain barrier is essential. In this review, recent evidence regarding the possible roles of obesity and its related systemic low-grade inflammation, and the roles of adipokines and their genetic variants in the modulation of immune responses and altered blood-brain barrier permeability in MS patients, has been elucidated. Besides, the results of the current studies regarding the potential use of adipokines in predicting MS disease severity and response to treatment have been explored.

Topics: Adipokines; Adipose Tissue; Cytokines; Diabetes Mellitus, Type 2; Humans; Inflammation; Leptin; Lipids; Multiple Sclerosis; Neurodegenerative Diseases; Nicotinamide Phosphoribosyltransferase; Obesity; Resistin; Vitamin D

Obesity disease results from a dysfunctional modulation of the energy balance whose master regulator is the central nervous system. The neural circuitries involved in such function complete their maturation during early postnatal periods, when the brain is highly plastic and profoundly influenced by the environment. This phenomenon is considered as an evolutionary strategy, whereby metabolic functions are adjusted to environmental cues, such as food availability and maternal care. In this timeframe, adverse stimuli may program the body metabolism to maximize energy storage abilities to cope with hostile conditions. Consistently, the prevalence of obesity is higher among individuals who experienced early life stress (ELS). Oxytocin, a hypothalamic neurohormone, regulates the energy balance and modulates social, emotional, and eating behaviors, exerting both central and peripheral actions. Oxytocin closely cooperates with leptin in regulating energy homeostasis. Both oxytocin and leptin impact the neurodevelopment during critical periods and are affected by ELS and obesity. In this review article, we report evidence from the literature describing the effect of postnatal ELS (specifically, disorganized/inconstant maternal care) on the vulnerability to obesity with a focus on the role of oxytocin. We emphasize the existing research gaps and highlight promising directions worthy of exploration. Based on the available data, alterations in the oxytocin system may in part mediate the ELS-induced susceptibility to obesity.

Topics: Adverse Childhood Experiences; Eating; Humans; Hypothalamus; Leptin; Obesity; Oxytocin

Respiratory viruses are associated with significant global morbidity and mortality, as well as socioeconomic factors. Certain conditions and patient groups are more susceptible to develop severe viral respiratory tract infections (RTIs).. To summarise the data on deregulated immune pathways that have been associated with increased susceptibility to severe viral RTIs in certain populations. We also describe the commonalities of the defective immune pathways across these susceptible populations that may represent possible targets for future therapeutic or preventative approaches.. We conducted free searches in Medline, Scopus, and Google Scholar for studies focusing on potential mechanisms of immune dysfunction that may be associated with severe viral RTIs in susceptible populations with conditions including pregnancy, obesity, diabetes mellitus, hypertension, cardiovascular disease, asthma, chronic obstructive pulmonary disease (COPD), chronic kidney disease, and extremes of age. We considered preclinical/animal data, original human studies, and reviews.. Innate and adaptive immune responses become quantitatively and qualitatively compromised in aging, obesity, and diabetes mellitus, with the most pronounced changes affecting T cells. Moreover, immune dysregulation by the so-called inflamm-aging results in chronic low-grade inflammation in such conditions. Increased leptin levels affect the immune system particularly in obesity, while leptin dysregulation plays a role in asthma and COPD pathogenesis. Deficient production of interferon (IFN) type I and III in response to rhinovirus contributes to asthma exacerbations. Similar attenuation of IFN production in response to influenza and rhinovirus has been documented in pregnancy. Dampened type I IFN responses have also been found in diet-induced obese mice and in obese individuals.. Immunosenescence and chronic low-grade inflammation accompanying aging and a variety of chronic conditions, such as diabetes, obesity, asthma, COPD, chronic renal disease, and hypertension, contribute to the poor outcomes observed following viral respiratory infections. Commonly affected pathways may represent potential future therapeutic targets.

Topics: Animals; Asthma; Disease Susceptibility; Enterovirus Infections; Humans; Hypertension; Immunity; Inflammation; Interferons; Leptin; Mice; Obesity; Pneumonia; Pulmonary Disease, Chronic Obstructive; Respiratory Tract Infections; Rhinovirus

Neuronal circuits within the hypothalamus play a critical role in the homeostatic regulation of body weight. By disrupting the development or function of these circuits, human monogenic disorders cause hyperphagia (increased food intake), neuroendocrine abnormalities, impaired sympathetic nervous system activation, and obesity. Some genetic disorders also cause maladaptive behaviors such as anxiety, autism, emotional lability, and aggression, highlighting the role of the specific molecules expressed by these hypothalamic neurons in the regulation of innate behaviors that are essential to survival. These findings inform understanding of a wide range of clinical disorders and highlight the challenges associated with targeting these hypothalamic pathways for weight loss therapy.

Topics: Appetite; Body Weight; Humans; Hypothalamus; Leptin; Obesity; Syndrome

A primary cilium, a hair-like protrusion of the plasma membrane, is a pivotal organelle for sensing external environmental signals and transducing intracellular signaling. An interesting linkage between cilia and obesity has been revealed by studies of the human genetic ciliopathies Bardet-Biedl syndrome and Alström syndrome, in which obesity is a principal manifestation. Mouse models of cell type-specific cilia dysgenesis have subsequently demonstrated that ciliary defects restricted to specific hypothalamic neurons are sufficient to induce obesity and hyperphagia. A potential mechanism underlying hypothalamic neuron cilia-related obesity is impaired ciliary localization of G protein-coupled receptors involved in the regulation of appetite and energy metabolism. A well-studied example of this is melanocortin 4 receptor (MC4R), mutations in which are the most common cause of human monogenic obesity. In the paraventricular hypothalamus neurons, a blockade of ciliary trafficking of MC4R as well as its downstream ciliary signaling leads to hyperphagia and weight gain. Another potential mechanism is reduced leptin signaling in hypothalamic neurons with defective cilia. Leptin receptors traffic to the periciliary area upon leptin stimulation. Moreover, defects in cilia formation hamper leptin signaling and actions in both developing and differentiated hypothalamic neurons. The list of obesity-linked ciliary proteins is expending and this supports a tight association between cilia and obesity. This article provides a brief review on the mechanism of how ciliary defects in hypothalamic neurons facilitate obesity.

Topics: Animals; Cilia; Humans; Hyperphagia; Hypothalamus; Leptin; Mice; Obesity

Obesity is a chronic, relapsing condition characterized by excess body fat. Its prevalence has increased globally since the 1970s, and the number of obese and overweight people is now greater than those underweight. Obesity is a multifactorial condition, and as such, many components contribute to its development and pathogenesis. This is the first of three companion reviews that consider obesity. This review focuses on the genetics, viruses, insulin resistance, inflammation, gut microbiome, and circadian rhythms that promote obesity, along with hormones, growth factors, and organs and tissues that control its development. It shows that the regulation of energy balance (intake vs. expenditure) relies on the interplay of a variety of hormones from adipose tissue, gastrointestinal tract, pancreas, liver, and brain. It details how integrating central neurotransmitters and peripheral metabolic signals (e.g., leptin, insulin, ghrelin, peptide YY

Topics: Adipocytes; Adipose Tissue; Energy Metabolism; Humans; Insulin; Leptin; Obesity

Obesity, and obesity-associated conditions such as hypertension, chronic kidney disease, type 2 diabetes, and cardiovascular disease, are important risk factors for severe Coronavirus disease-2019 (COVID-19). The common denominator is metaflammation, a portmanteau of metabolism and inflammation, which is characterized by chronically elevated levels of leptin and pro-inflammatory cytokines. These induce the "Suppressor Of Cytokine Signaling 1 and 3" (SOCS1/3), which deactivates the leptin receptor and also other SOCS1/3 sensitive cytokine receptors in immune cells, impairing the type I and III interferon early responses. By also upregulating SOCS1/3, Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV)-2 adds a significant boost to this. The ensuing consequence is a delayed but over-reactive immune response, characterized by high-grade inflammation (e.g., cytokine storm), endothelial damage, and hypercoagulation, thus leading to severe COVID-19. Superimposing an acute disturbance, such as a SARS-CoV-2 infection, on metaflammation severely tests resilience. In the long run, metaflammation causes the "typical western" conditions associated with metabolic syndrome. Severe COVID-19 and other serious infectious diseases can be added to the list of its short-term consequences. Therefore, preventive measures should include not only vaccination and the well-established actions intended to avoid infection, but also dietary and lifestyle interventions aimed at improving body composition and preventing or reversing metaflammation.

Topics: COVID-19; Humans; Inflammation; Interferon Type I; Leptin; Obesity; SARS-CoV-2

Characterized by a surplus of whole-body adiposity, obesity is strongly associated with the prognosis of atherosclerosis, a hallmark of coronary artery disease (CAD) and the major contributor to cardiovascular disease (CVD) mortality. Adipose tissue serves a primary role as a lipid-storage organ, secreting cytokines known as adipokines that affect whole-body metabolism, inflammation, and endocrine functions. Emerging evidence suggests that adipokines can play important roles in atherosclerosis development, progression, as well as regression. Here, we review the versatile functions of various adipokines in atherosclerosis and divide these respective functions into three major groups: protective, deteriorative, and undefined. The protective adipokines represented here are adiponectin, fibroblast growth factor 21 (FGF-21), C1q tumor necrosis factor-related protein 9 (CTRP9), and progranulin, while the deteriorative adipokines listed include leptin, chemerin, resistin, Interleukin- 6 (IL-6), and more, with additional adipokines that have unclear roles denoted as undefined adipokines. Comprehensively categorizing adipokines in the context of atherosclerosis can help elucidate the various pathways involved and potentially pave novel therapeutic approaches to treat CVDs.

Topics: Adipokines; Adiponectin; Adiposity; Atherosclerosis; Cardiovascular Diseases; Humans; Interleukin-6; Leptin; Obesity

Obesity and colorectal cancer (CRC) are among the leading diseases causing deaths in the world, showing a complex multifactorial pathology. Obesity is considered a risk factor in CRC development through inflammation, metabolic, and signaling processes. Leptin is one of the most important adipokines related to obesity and an important proinflammatory marker, mainly expressed in adipose tissue, with many genetic variation profiles, many related influencing factors, and various functions that have been ascribed but not yet fully understood and elucidated, the most important ones being related to energy metabolism, as well as endocrine and immune systems. Aberrant signaling and genetic variations of leptin are correlated with obesity and CRC, with the genetic causality showing both inherited and acquired events, in addition to lifestyle and environmental risk factors; these might also be related to specific pathogenic pathways at different time points. Moreover, mutation gain is a crucial factor enabling the genetic process of CRC. Currently, the inconsistent and insufficient data related to leptin's relationship with obesity and CRC indicate the necessity of further related studies. This review summarizes the current knowledge on leptin genetics and its potential relationship with the main pathogenic pathways of obesity and CRC, in an attempt to understand the molecular mechanisms of these associations, in the context of inconsistent and contradictory data. The understanding of these mechanisms linking obesity and CRC could help to develop novel therapeutic targets and prevention strategies, resulting in a better prognosis and management of these diseases.

Topics: Adipokines; Adipose Tissue; Colorectal Neoplasms; Humans; Leptin; Obesity; Receptors, Leptin

Obesity is a growing worldwide health problem, affecting many people due to excessive saturated fat consumption, lack of exercise, or a sedentary lifestyle. Leptin is an adipokine secreted by adipose tissue that increases in obesity and has central actions not only at the hypothalamic level but also in other regions and nuclei of the central nervous system (CNS) such as the cerebral cortex and hippocampus. These regions express the long form of leptin receptor LepRb, which is the unique leptin receptor capable of transmitting complete leptin signaling, and are the first regions to be affected by chronic neurocognitive deficits, such as mild cognitive impairment (MCI) and Alzheimer's Disease (AD). In this review, we discuss different leptin resistance mechanisms that could be implicated in increasing the risk of developing AD, as leptin resistance is frequently associated with obesity, which is a chronic low-grade inflammatory state, and obesity is considered a risk factor for AD. Key players of leptin resistance are SOCS3, PTP1B, and TCPTP whose signalling is related to inflammation and could be worsened in AD. However, some data are controversial, and it is necessary to further investigate the underlying mechanisms of the AD-causing pathological processes and how altered leptin signalling affects such processes.

Topics: Alzheimer Disease; Humans; Leptin; Obesity; Receptors, Leptin; Risk Factors

Cardiac fibrosis is a pathogenic factor of many cardiovascular diseases (CVD), which seriously affects people's life and health, causing huge economic losses.Therefore, it is very significant to find an effective treatment for myocardial fibrosis. Adipokines are mainly derived from adipose tissue and have an prominent regulatory effect on glucose and lipid metabolism, inflammation, immune response and cardiovascular function. Adipose tissue is composed of a variety of cell types, including adipocytes, endothelial cells, macrophages and smooth muscle cells. Adipokines mainly include adiponectin, leptin, resistin, visfatin and omentin, which are synthesized and secreted by adipocytes. More and more evidence shows that adipokines can regulate the progress of cardiac fibrosis. This scientific review provides new ideas for targeting adipokines in the treatment of myocardial fibrosis and provides strategies for the development of new, safe, and effective pharmacological antagonists against myocardial fibrosis based on adipokines activity.

Topics: Adipokines; Adiponectin; Adipose Tissue; Endothelial Cells; Fibrosis; Humans; Leptin; Obesity

Integration of genomic and other data has begun to stratify type 2 diabetes in prognostically meaningful ways, but this has yet to impact on mainstream diabetes practice. The subgroup of diabetes caused by single gene defects thus provides the best example to date of the vision of 'precision diabetes'. Monogenic diabetes may be divided into primary pancreatic beta cell failure, and primary insulin resistance. In both groups, clear examples of genotype-selective responses to therapy have been advanced. The benign trajectory of diabetes due to pathogenic GCK mutations, and the sulfonylurea-hyperresponsiveness conferred by activating KCNJ11 or ABCC8 mutations, or loss-of-function HNF1A or HNF4A mutations, often decisively guide clinical management. In monogenic insulin-resistant diabetes, subcutaneous leptin therapy is beneficial in some severe lipodystrophy. Increasing evidence also supports use of 'obesity therapies' in lipodystrophic people even without obesity. In beta cell diabetes the main challenge is now implementation of the precision diabetes vision at scale. In monogenic insulin-resistant diabetes genotype-specific benefits are proven in far fewer patients to date, although further genotype-targeted therapies are being evaluated. The conceptual paradigm established by the insulin-resistant subgroup with 'adipose failure' may have a wider influence on precision therapy for common type 2 diabetes, however. For all forms of monogenic diabetes, population-wide genome sequencing is currently forcing reappraisal of the importance assigned to pathogenic mutations when gene sequencing is uncoupled from prior suspicion of monogenic diabetes.

Topics: Diabetes Mellitus, Type 2; Humans; Insulin; Insulin Resistance; Leptin; Mutation; Obesity

Leptin is a well-known hunger-sensing peptide hormone. The role of leptin in weight gain and metabolic homeostasis has been explored for the past two decades. In this review, we have tried to shed light upon the impact of leptin signaling on health and diseases. At low or moderate levels, this peptide hormone supports physiological roles, but at chronically higher doses exhibits detrimental effects on various systems. The untoward effects we observe with chronically higher levels of leptin are due to their receptor-mediated effect or due to leptin resistance and are not well studied. This review will help us in understanding the non-anorexic roles of leptin, including their contribution to the metabolism of various systems and inflammation. We will be able to get an alternative perspective regarding the physiological and pathological roles of this mysterious peptide hormone.

Topics: Homeostasis; Humans; Leptin; Obesity; Signal Transduction

Consumption of a high calorie diet with irregular eating and sedentary behavior habits is typical of the current suboptimal lifestyle, contributing to the development of metabolic diseases such as obesity and type 2 diabetes mellitus. Most notably, the disorder of adipokine secretion in visceral adiposity is a major contributor to metabolic diseases with advancing age. In this regard, spexin and leptin are established as anorexigenic adipokines that can modulate adipogenesis and glucose metabolism by suppressing food intake or increasing energy expenditure, respectively. Emerging evidence points out that spexin levels are lower in the serum and adipose tissue of patients with obesity and/or insulin resistance, whereas circulating levels of leptin are higher in obesity and comorbidities. In turn, spexin and leptin pharmacologically induce beneficial effects on the brain's modulation of food intake and energy expenditure. On the other hand, endocrine crosstalk via spexin and leptin has also been reported in patients suffering from obesity and diabetes. Spexin plays a crucial role in the regulation of leptin secretion and leptin resistance. It should therefore be taken into account that studying the role of spexin in leptin regulation will help us combat the pathologies of obesity caused by leptin resistance.

Topics: Diabetes Mellitus, Type 2; Energy Metabolism; Feeding Behavior; Humans; Insulin Resistance; Leptin; Metabolic Diseases; Obesity

Recent biochemical and behavioural evidence indicates that metabolic hormones not only regulate energy intake and nutrient content, but also modulate plasticity and cognition in the central nervous system. Disruptions in metabolic hormone signalling may provide a link between metabolic syndromes like obesity and diabetes, and cognitive impairment. For example, altered metabolic homeostasis in obesity is a strong determinant of the severity of age-related cognitive decline and neurodegenerative disease. Here we review the evidence that eating behaviours and metabolic hormones-particularly ghrelin, leptin, and insulin-are key players in the delicate regulation of neural plasticity and cognition. Caloric restriction and antidiabetic therapies, both of which affect metabolic hormone levels can restore metabolic homeostasis and enhance cognitive function. Thus, metabolic hormone pathways provide a promising target for the treatment of cognitive decline.

Topics: Cognition; Energy Metabolism; Feeding Behavior; Ghrelin; Humans; Insulin; Leptin; Neurodegenerative Diseases; Obesity

Obesity hypoventilation syndrome (OHS) is defined as daytime hypercapnia in obese individuals in the absence of other underlying causes. In the United States, OHS is present in 10%-20% of obese patients with obstructive sleep apnea and is linked to hypoventilation during sleep. OHS leads to high cardiorespiratory morbidity and mortality, and there is no effective pharmacotherapy. The depressed hypercapnic ventilatory response plays a key role in OHS. The pathogenesis of OHS has been linked to resistance to an adipocyte-produced hormone, leptin, a major regulator of metabolism and control of breathing. Mechanisms by which leptin modulates the control of breathing are potential targets for novel therapeutic strategies in OHS. Recent advances shed light on the molecular pathways related to the central chemoreceptor function in health and disease. Leptin signaling in the nucleus of the solitary tract, retrotrapezoid nucleus, hypoglossal nucleus, and dorsomedial hypothalamus, and anatomical projections from these nuclei to the respiratory control centers, may contribute to OHS. In this review, we describe current views on leptin-mediated mechanisms that regulate breathing and CO2 homeostasis with a focus on potential therapeutics for the treatment of OHS.

Topics: Humans; Hypercapnia; Hypoventilation; Leptin; Obesity; Obesity Hypoventilation Syndrome

Obesity is a multifactorial and complex disease that often manifests in early childhood with a lifelong burden. Polygenic and monogenic obesity are driven by the interaction between genetic predisposition and environmental factors. Polygenic variants are frequent and confer small effect sizes. Rare monogenic obesity syndromes are caused by defined pathogenic variants in single genes with large effect sizes. Most of these genes are involved in the central nervous regulation of body weight; for example, genes of the leptin-melanocortin pathway. Clinically, patients with monogenic obesity present with impaired satiety, hyperphagia and pronounced food-seeking behaviour in early childhood, which leads to severe early-onset obesity. With the advent of novel pharmacological treatment options emerging for monogenic obesity syndromes that target the central melanocortin pathway, genetic testing is recommended for patients with rapid weight gain in infancy and additional clinical suggestive features. Likewise, patients with obesity associated with hypothalamic damage or other forms of syndromic obesity involving energy regulatory circuits could benefit from these novel pharmacological treatment options. Early identification of patients affected by syndromic obesity will lead to appropriate treatment, thereby preventing the development of obesity sequelae, avoiding failure of conservative treatment approaches and alleviating stigmatization of patients and their families.

Topics: Child, Preschool; Genetic Predisposition to Disease; Humans; Hyperphagia; Leptin; Melanocortins; Obesity; Phenotype; Receptors, Leptin

This narrative review aims to pinpoint mental and behavioral effects of starvation, which may be triggered by hypoleptinemia and as such may be amenable to treatment with leptin receptor agonists. The reduced leptin secretion results from the continuous loss of fat mass, thus initiating a graded triggering of diverse starvation related adaptive functions. In light of leptin receptors located in several peripheral tissues and many brain regions adaptations may extend beyond those of the hypothalamus-pituitary-end organ-axes. We focus on gastrointestinal tract and reward system as relevant examples of peripheral and central effects of leptin. Despite its association with extreme obesity, congenital leptin deficiency with its many parallels to a state of starvation allows the elucidation of mental symptoms amenable to treatment with exogenous leptin in both ob/ob mice and humans with this autosomal recessive disorder. For starvation induced behavioral changes with an intact leptin signaling we particularly focus on rodent models for which proof of concept has been provided for the causative role of hypoleptinemia. For humans, we highlight the major cognitive, emotional and behavioral findings of the Minnesota Starvation Experiment to contrast them with results obtained upon a lesser degree of caloric restriction. Evidence for hypoleptinemia induced mental changes also stems from findings obtained in lipodystrophies. In light of the recently reported beneficial cognitive, emotional and behavioral effects of metreleptin-administration in anorexia nervosa we discuss potential implications for the treatment of this eating disorder. We postulate that leptin has profound psychopharmacological effects in the state of starvation.

Topics: Animals; Anorexia Nervosa; Humans; Leptin; Mice; Obesity; Receptors, Leptin; Starvation

The early onset of colorectal cancer (CRC) in individuals younger than 50 years is an emerging phenomenon, and obesity is a strong risk factor. Inflammatory mechanisms are mediated by immune cells, with macrophages and their phenotypical changes playing a significant role in CRC. Obesity-related hormones, such as leptin and adiponectin, affect macrophage polarization and cytokine expression. Macrophage metabolism, and therefore polarization, directly affects tumor progression and survival in patients with CRC. Altered obesity-related hormone levels induce phosphoinositide kinase-3 (PI3K)/serine-threonine-protein kinase (AKT) activation in colon cancer, causing increased cell survival, hyperplasia, and proliferation. Investigating the effects of obesity-related mechanisms on PI3K/Akt signaling can provide new insights for targeting mechanisms in CRC and obesity among the young. Central molecules for the control of cell proliferation, differentiation, and tumorigenesis within the gastrointestinal tract include downstream targets of the PI3K/AKT pathway, such as Neurogenic locus notch homolog 4 (Notch4) and GATA binding proteins (GATA). Leptin and adiponectin both alter gene expression within this pathway, thereby affecting TAM-mediated CRC progression. Our goal is to introduce the NOTCH4-GATA4-IRG1 axis as a link between inflammation and sporadic CRC and to discuss this pathway as a new potential immunotherapeutic target in individuals affected with obesity and early-onset CRC.

Topics: Adiponectin; Age of Onset; Carboxy-Lyases; Cell Line, Tumor; Cell Proliferation; Colorectal Neoplasms; GATA4 Transcription Factor; Gene Expression Regulation, Neoplastic; Humans; Leptin; Obesity; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Receptor, Notch4

Whether diabetes and adipokine-driven inflammation explain the association of obesity to cognitive impairment is unknown.. Structural equation models estimated the total effects of waist circumference on cognitive outcomes among African American participants cross-sectionally (index exam) and longitudinally. Total effects were deconstructed into direct pathways of waist circumference to cognitive impairment and indirect mediation pathways through leptin, soluble tumor necrosis factor receptor 2 (sTNFR2), and diabetes. Waist circumference, leptin, and sTNFR2 were standardized. Cognitive impairment was defined as MMSE <21 or a z-score < -1.5 standard deviation (SD). Incident cognitive impairment was defined among those without cognitive impairment at the index exam as follow-up MMSE<21, z- score < -1.5, MMSE decline >1 point/year, or z-score decline of >0.1 SD/year.. Among 1008 participants (70% women, mean age 62.9 years, 14.5% with obesity, 26% with diabetes), 132 (13%) had baseline cognitive impairment. Each SD higher waist circumference was associated with higher odds of cognitive impairment, odds ratio (OR) = 1.63; (95% confidence interval: 1.17, 2.24), with mediating pathways explaining 65% of the total effect (58% from diabetes; 7% from inflammation). At follow-up (mean 6.8 years), 106 of 535 (19.8%) had developed cognitive impairment. Each SD higher waist circumference was associated with higher odds of developing cognitive impairment (OR = 1.87; 95%CI: 1.18, 2.74); the direct effect of waist circumference explained 37% of the total effect and mediating pathways explained 63% (61% from diabetes; 2% from inflammation), although individual pathways were not statistically supported in the smaller sample.. Diabetes, and to a lesser degree, adiposity-driven inflammation, appear to explain a substantial proportion of abdominal adiposity relationships with cognitive impairment. The impact of preventing and treating obesity on cognitive outcomes merits study.

Topics: Adipokines; Adiposity; Black or African American; Body Mass Index; Cognitive Dysfunction; Diabetes Mellitus; Female; Humans; Inflammation; Leptin; Male; Middle Aged; Obesity; Receptors, Tumor Necrosis Factor, Type II; Risk Factors; Waist Circumference

Pneumococcal pneumonia is the leading cause of community-acquired pneumonia. Obesity is a risk factor for pneumonia. Host factors play a critical role in susceptibility to pulmonary pathogens and outcome from pulmonary infections. Obesity impairs innate and adaptive immune responses, important in the host defence against pneumococcal disease. One area of emerging interest in understanding the complex relationship between obesity and pulmonary infections is the role of the hormone leptin. There is a substantive evidence base supporting the associations between obesity, leptin, pulmonary infections and host defence mechanisms. Despite this, there is a paucity of research that specifically focuses on

Topics: Animals; Community-Acquired Infections; Humans; Leptin; Lung; Mice; Obesity; Pneumonia, Pneumococcal; Streptococcus pneumoniae

Differences in adolescents and adults by sex in blood levels of leptin and adiposity have been described; however, it is not yet clear if these differences arise from the prepubertal stage in subjects with a normal-weight. Therefore, we examine whether there are differences by sex in levels of blood leptin and adiposity in children with a normal-weight between 0 and 10 years old.. Search strategy: eligible studies were obtained from three electronic databases (Ovid, Embase and LILACS) and contact with experts.. healthy children up to 10 years of age with normal-weight according to age.. data were extracted by four independent reviewers using a predesigned data collection form. For the analysis, we stratified according to age groups (newborns, 0.25-0.5 years, 3-5.9 years, 6-7.9 years, 8-10 years). The statistical analysis was performed in the R program.. Of the initially identified 13,712 records, 21 were selected in the systematic review and meta-analysis. The sex was associated with the overall effect on blood leptin (pooled MD = 1.72 ng/mL, 95% CI: 1.25-2.19) and body fat percentage (pooled MD = 3.43%, 95% CI: 2.53-4.33), being both higher in girls. This finding was consistent in the majority of age groups.. The results of our meta-analyses support the sexual dimorphism in circulating blood leptin and body fat percentage between girls and boys with normal-weight from prepuberty.

Topics: Adiposity; Adolescent; Adult; Child; Child, Preschool; Female; Humans; Infant; Infant, Newborn; Leptin; Male; Obesity; Sex Characteristics

Adipose tissue is a functional endocrine organ comprised of adipocytes and other cell types that are known to secrete a multiplicity of adipose-derived factors, including lipids and proteins. It is well established that adipose tissue and its secretome can impact systemic energy homeostasis. The endocrine and paracrine effects of adipose-derived factors have been widely studied over the last several decades. Owing to technological advances in genomics and proteomics, several additional adipose-derived protein factors have recently been identified. By learning from previous efforts, the next challenge will be to leverage these discoveries for the prevention or treatment of metabolic disorders. Here, we discuss recently discovered adipose-derived proteins secreted from white or brown adipose tissue and the opportunities and challenges of translating these biological findings into disease therapeutics.

Topics: Adipose Tissue; Adipose Tissue, Brown; Energy Metabolism; Humans; Leptin; Obesity; Secretome

Obesity is a complex multifactorial disorder with genetic and environmental factors. There is an increase in the worldwide prevalence of obesity in both developed and developing countries. The development of genome-wide association studies (GWAS) and next-generation sequencing (NGS) has increased the discovery of genetic associations and awareness of monogenic and polygenic causes of obesity. The genetics of obesity could be classified into syndromic and non-syndromic obesity. Prader-Willi, fragile X, Bardet-Biedl, Cohen, and Albright Hereditary Osteodystrophy (AHO) syndromes are examples of syndromic obesity, which are associated with developmental delay and early onset obesity. Non-syndromic obesity could be monogenic, polygenic, or chromosomal in origin. Monogenic obesity is caused by variants of single genes while polygenic obesity includes several genes with the involvement of members of gene families. New advances in genetic testing have led to the identification of obesity-related genes. Leptin (

Topics: Brain-Derived Neurotrophic Factor; Genome-Wide Association Study; Humans; Leptin; Obesity; Pro-Opiomelanocortin; Proprotein Convertase 1; Receptor, Melanocortin, Type 4; Receptor, trkB; Receptors, Leptin

Leptin is a peptide hormone, mainly known for its role as a mediator of adipose tissue endocrine functions, such as appetite control and energy homeostasis. In addition, leptin signaling is involved in several physiological processes as modulation of innate and adaptive immune responses and regulation of sex hormone levels. When adipose tissue expands, an imbalance of adipokines secretion may occur and increasing leptin levels contribute to promoting a chronic inflammatory state, which is largely acknowledged as a hallmark of cancer. Indeed, upon binding its receptor (LEPR), leptin activates several oncogenic pathways, such as JAK/STAT, MAPK, and PI3K/AKT, and seems to affect cancer immune response by inducing a proinflammatory immune polarization and eventually enhancing T-cell exhaustion. In particular, obesity-associated hyperleptinemia has been related to breast cancer risk development, although the underlying mechanism is yet to be completely clarified and needs to be deemed in light of multiple variables, such as menopausal state and immune response. The aim of this review is to provide an overview of the potential role of leptin as a bridge between obesity and breast cancer and to establish the physio-pathological basis of the linkage between these major health concerns in order to identify appropriate and novel therapeutic strategies to adopt in daily clinical practice.

Topics: Adipokines; Breast Neoplasms; Female; Humans; Leptin; Obesity; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt

The World Health Organization (WHO) refers to obesity as abnormal or excessive fat accumulation that presents a health risk. Obesity was first designated as a disease in 2012 and since then the cost and the burden of the disease have witnessed a worrisome increase. Obesity and hypertension are closely interrelated as abdominal obesity interferes with the endocrine and immune systems and carries a greater risk for insulin resistance, diabetes, hypertension, and cardiovascular disease. Many factors are at the interplay between obesity and hypertension. They include hemodynamic alterations, oxidative stress, renal injury, hyperinsulinemia, and insulin resistance, sleep apnea syndrome and the leptin-melanocortin pathway. Genetics, epigenetics, and mitochondrial factors also play a major role. The measurement of blood pressure in obese patients requires an adapted cuff and the search for other secondary causes is necessary at higher thresholds than the general population. Lifestyle modifications such as diet and exercise are often not enough to control obesity, and so far, bariatric surgery constitutes the most reliable method to achieve weight loss. Nonetheless, the emergence of new agents such as Semaglutide and Tirzepatide offers promising alternatives. Finally, several molecular pathways are actively being explored, and they should significantly extend the treatment options available.

Topics: Humans; Hypertension; Insulin Resistance; Leptin; Melanocortins; Obesity

The link between obesity and multiple disease comorbidities is well established. In 2003, Calle and colleagues presented the relationship between obesity and several cancer types, including breast, ovarian, and endometrial malignancies. Nearly, 20% of cancer-related deaths in females can be accounted for by obesity. Identifying obesity as a risk factor for cancer led to a focus on the role of fat-secreted cytokines, known as adipokines, on carcinogenesis and tumor progression. Early studies indicated that the adipokine leptin increases cell proliferation, invasion, and inhibition of apoptosis in multiple cancer types. As a greater appreciation of the obesity-cancer link has amassed, we now know that additional adipokines can impact tumorigenesis. A deeper understanding of the adipokine-activated signaling in cancer may identify new treatment strategies irrespective of obesity. Moreover, adipokines may serve as disease biomarkers, harnessing the potential of obesity-associated factors to serve as indicators of treatment response and disease prognosis. As studies investigating obesity and women's cancers continue to expand, it has become evident that breast, ovarian, and uterine cancers are distinctly impacted by adipokines. While complex, these distinct interactions may provide insight into cancer progression in these organs and new opportunities for targeted therapies. This review aims to organize and present the literature from the last 5 years investigating the mechanisms and implications of adipokine signaling in breast, endometrial, and ovarian cancers with a special focus on leptin and adiponectin.

Topics: Adipokines; Adiponectin; Female; Genital Neoplasms, Female; Humans; Leptin; Obesity

Obesity and hypertension are intimately linked due to the various ways that the important cell types such as vascular smooth muscle cells (VSMC), endothelial cells (EC), immune cells, and adipocytes, communicate with one another to contribute to these two pathologies. Adipose tissue is a very dynamic organ comprised primarily of adipocytes, which are well known for their role in energy storage. More recently adipose tissue has been recognized as the largest endocrine organ because of its ability to produce a vast number of signaling molecules called adipokines. These signaling molecules stimulate specific types of cells or tissues with many adipokines acting as indicators of adipocyte healthy function, such as adiponectin, omentin, and FGF21, which show anti-inflammatory or cardioprotective effects, acting as regulators of healthy physiological function. Others, like visfatin, chemerin, resistin, and leptin are often altered during pathophysiological circumstances like obesity and lipodystrophy, demonstrating negative cardiovascular outcomes when produced in excess. This review aims to explore the role of adipocytes and their derived products as well as the impacts of these adipokines on blood pressure regulation and cardiovascular homeostasis.

Topics: Adipocytes; Adipokines; Adipose Tissue; Endothelial Cells; Humans; Leptin; Obesity

Abdominal aortic aneurysm(AAA) is a chronic dilated artery disease induced by atherosclerosis,infection,trauma and other related causes.The available studies about AAA mainly focus on the inflammatory response,senility,and microenvironmental changes,while the research on the metabolic changes such as glucose metabolism and lipid metabolism remains to be conducted.As a critical regulatory factor in endocrine,glucose,and lipid metabolisms,leptin is associated with a variety of signaling pathways such as adenosine monophosphate-activated protein kinase,Janus kinase/signal transducer and activator of transcription,and cytokine-cytokine receptor,as demonstrated by the KEGG pathway enrichment analysis.Moreover,these signaling pathways are generally involved in regulating the occurrence of AAA.In addition,leptin affects the occurrence of a variety of diseases such as obesity,diabetes,and hyperlipidemia,which contribute to the formation of AAA.Diabetes might be a protective factor for the formation of AAA,while the relationship of hyperlipidemia and obesity with the formation of AAA remains unclear.Therefore,leptin might play an essential role in the formation of AAA.Further studies about the effect of leptin on AAA may provide the potential research direction and facilitate the discovery of therapeutic targets.

Topics: Aorta, Abdominal; Aortic Aneurysm, Abdominal; Diabetes Mellitus; Humans; Leptin; Obesity; Signal Transduction

Reproductive function is tightly regulated by both environmental and physiological factors. The adipose-derived hormone leptin has been identified as one such critical factor that relays information about peripheral energy availability to the centrally-governed HPG axis to ensure there is sufficient energy availability to support the high energy demands of mammalian reproduction. In the absence of adequate central leptin signaling, reproductive function is suppressed. While leptin levels are predominantly regulated by adiposity, circulating leptin levels are also under the modulatory influence of other factors, such as stress system activation, circadian rhythmicity, and immune activation and the inflammatory response. Furthermore, changes in leptin sensitivity can affect the degree to which leptin exerts its influence on the neuroendocrine reproductive axis. This review will discuss the different mechanisms by which leptin serves to integrate and relay information about metabolic, psychological, environmental and immune conditions to the central neuronal network that governs reproductive function.

Topics: Animals; Humans; Leptin; Mammals; Obesity; Reproduction; Signal Transduction

Perhaps the most unexpected development in pediatric endocrinology in the past 50 years has been the recognition of obesity as an endocrine/metabolic disorder rather than a life choice or moral failing. The history of obesity research is disjointed, having followed two separate paths in the 20th century, based on two independent yet overlapping paradigms. Proponents of the "Energy Storage" hypothesis point to data implicating monogenetic disorders, the ventromedial hypothalamus, insulin, cortisol, and the adipocyte itself in the pathogenesis of obesity. Alternatively, proponents of the "Energy Balance" hypothesis point to data implicating increased caloric intake, decreased caloric expenditure, gastrointestinal hormones, and microbiome changes as being critical for obesity. These two separate lines of research merged somewhat with the discovery of leptin in 1994, as leptin established a major hormonal role in weight control. Leptin has explained some of the dichotomy and has proved essential in understanding the importance of developmental programming and epigenetics. However, the mystery of leptin resistance remains unsolved. Despite all our collective knowledge, we appear no closer in solving the obesity puzzle today than we were 50 years ago.

Topics: Adipocytes; Biomedical Research; Child; Endocrinology; Humans; Insulin; Leptin; Obesity

Leptin is an adipokine directly correlated with the proinflammatory obese-associated phenotype. Leptin has been demonstrated to inhibit adipogenesis, promote fat demarcation, promote a chronic inflammatory state, increase insulin sensitivity, and promote angiogenesis. Leptin, a regulator of the immune response, is implicated in the pathology of asthma. Studies involved in the key cell reaction and animal models of asthma have provided vital insights into the proinflammatory role of leptin in asthma. Many studies described the immune cell and related cellular pathways activated by leptin, which are beneficial in asthma development and increasing exacerbations. Subsequent studies relating to animal models support the role of leptin in increasing inflammatory cell infiltration, airway hyperresponsiveness, and inflammatory responses. However, the conclusive effects of leptin in asthma are not well elaborated. In the present study, we explored the general functions and the clinical cohort study supporting the association between leptin and asthma. The main objective of our review is to address the knowns and unknowns of leptin on asthma. In this perspective, the arguments about the different faces of leptin in asthma are provided to picture the potential directions, thus yielding a better understanding of asthma development.

Topics: Adipokines; Animals; Asthma; Cohort Studies; Leptin; Obesity

Obesity, which is considered a pandemic due to its high prevalence, is a risk factor for many types of cancers, including lymphoma, through a variety of mechanisms by promoting an inflammatory state. Specifically, over the last few decades, obesity has been suggested not only to increase the risk of lymphoma but also to be associated with poor clinical outcomes and worse responses to different treatments for those diseases. Within the extensive range of proinflammatory mediators that adipose tissue releases, leptin has been demonstrated to be a key adipokine due to its pleotropic effects in many physiological systems and diseases. In this sense, different studies have analyzed leptin levels and leptin/leptin receptor expressions as a probable bridge between obesity and lymphomas. Since both obesity and lymphomas are prevalent pathophysiological conditions worldwide and their incidences have increased over the last few years, here we review the possible role of leptin as a promising proinflammatory mediator promoting lymphomas.

Topics: Adipokines; Adipose Tissue; Humans; Leptin; Lymphoma; Obesity; Receptors, Leptin

Research shows that reduced sleep duration is related to an increased risk of obesity. The relationship between sleep deprivation and obesity, type 2 diabetes, and other chronic diseases may be related to the imbalance of appetite regulation. To comprehensively illustrate the specific relationship between sleep deprivation and appetite regulation, this review introduces the pathophysiology of sleep deprivation, the research cutting edge of animal models, and the central regulatory mechanism of appetite under sleep deprivation. This paper summarizes the changes in appetite-related hormones orexin, ghrelin, leptin, and insulin secretion caused by long-term sleep deprivation based on the epidemiology data and animal studies that have established sleep deprivation models. Moreover, this review analyzes the potential mechanism of associations between appetite regulation and sleep deprivation, providing more clues on further studies and new strategies to access obesity and metabolic disease.

Topics: Animals; Appetite; Appetite Regulation; Diabetes Mellitus, Type 2; Ghrelin; Leptin; Obesity; Sleep; Sleep Deprivation

Asthma and obesity are considered as highly prevalent diseases with a great impact on public health. Obesity has been demonstrated to be an aggravating factor in the pathogenesis of asthma. Adipose tissue secretes proinflammatory cytokines and mediators, including leptin, which may promote the development and severity of asthma in obese patients. This study is a systematic review and a meta-analysis based on the relationship between leptin and asthma during obesity. MEDLINE, Cochrane, EMBASE and CINAHL databases were used. Data heterogeneity was analyzed using Cochran’s Q and treatment effect with the DerSimonian and Laird method. Random effect analyses were carried out to test data sensitivity. Asymmetry was estimated using Begg’s and Egger’s tests. All studies showed significant differences in leptin levels. The effect of the measures (p < 0.001), data sensitivity (p < 0.05) and data asymmetry were statistically significant, as well as tBegg’s test (p = 0.010) and Egge’s test (p < 0.001). Despite the existing limiting factors, the results of this study support the relevant role of leptin in the pathophysiology of asthma in obese subjects. Nevertheless, further studies are needed to obtain better insight in the relationship between leptin and asthma in obesity.

Topics: Adipose Tissue; Asthma; Cytokines; Humans; Leptin; Obesity

Obesity is a pandemic condition of complex etiology, resulting from the increasing exposition to obesogenic environmental factors combined with genetic susceptibility. In the past two decades, advances in genetic research identified variants of the leptin-melanocortin pathway coding for genes, which are related to the potentiation of satiety and hunger, immune system, and fertility. Here, we review cases of congenital leptin deficiency and the possible beneficial effects of leptin replacement therapy. In summary, the cases presented here show clinical phenotypes of disrupted bodily energy homeostasis, biochemical and hormonal disorders, and abnormal immune response. Some phenotypes can be partially reversed by exogenous administration of leptin. With this review, we aim to contribute to the understanding of leptin gene mutations as targets for obesity diagnostics and treatment strategies.

Topics: Energy Metabolism; Hormone Replacement Therapy; Humans; Leptin; Mutation; Obesity; Phenotype

Leptin for over 25 years has been a central theme in the study of appetite, obesity, and starvation. As the major site of leptin production is peripheral, and the site of action of greatest interest is the hypothalamus, how leptin accesses the central nervous system (CNS) and crosses the blood-brain barrier (BBB) has been of great interest. We review here the ongoing research that addresses fundamental questions such as the sites of leptin resistances in obesity and other conditions, the causes of resistances and their relations to one another, the three barrier sites of entry into the CNS, why recent studies using suprapharmacological doses cannot address these questions but give insight into nonsaturable entry of leptin into the CNS, and how that might be useful in using leptin therapeutically. The current status of the controversy of whether the short form of the leptin receptor acts as the BBB leptin transporter and how obesity may transform leptin transport is reviewed. Review of these and other topics summarizes in a new appreciation of what leptin may have actually evolved to do and what physiological role leptin resistance may play. © 2021 American Physiological Society. Compr Physiol 11:1-19, 2021.

Topics: Biological Transport; Blood-Brain Barrier; Exploratory Behavior; Humans; Leptin; Obesity

Obstructive sleep apnea syndrome (OSAS) is associated with various adipokines. Leptin, a common adipokine, has attracted considerable attention of many researchers in recent years. So far, there has been little agreement on whether blood leptin levels differ in patients with OSAS. Thus, this meta-analysis examined the relationship between serum/plasma leptin levels and the occurrence of OSAS.. WanFang, Embase, CNKI, Medline, SinoMed, Web of Science, and PubMed were searched for articles before March 30, 2021, with no language limitations. STATA version 11.0 and R software version 3.6.1 were used to analyze the obtained data. The weighted mean difference and correlation coefficients were used as the main effect sizes with a random-effects model and a fixed-effects model, respectively. Trial sequential analysis was conducted using dedicated software.. Screening of 34 publications identified 45 studies that met the inclusion criteria of this meta-analysis and meta-regression. Our results suggested that plasma/serum leptin levels were remarkably higher in individuals with OSAS than in healthy individuals. Subgroup analyses were performed based on OSAS severity, ethnicity, age, body mass index, assay type, and sample source. The serum and plasma leptin levels were increased in nearly all OSAS subgroups compared to those in the corresponding control groups. Meta-regression analysis indicated that age, BMI, severity, assay approaches, study design, PSG type and ethnicity did not have independent effect on leptin levels. Furthermore, a positive relationship between the serum/plasma leptin level and apnea-hypopnea index (AHI) was found in the meta-analysis. The results of the trial sequential analysis suggested that the enrolled studies surpassed the required information size, confirming that our study findings were reliable.. Our study results demonstrate that OSAS patients have higher leptin levels in serum/plasma compared to controls, and the serum/plasma leptin level is positively correlated with AHI, especially in adults.

Topics: Adult; Body Mass Index; Case-Control Studies; Humans; Leptin; Obesity; Regression Analysis; Risk Factors; Sleep Apnea, Obstructive

Sleep is often misunderstood in its impact on many chronic diseases including obesity. Obesity and restorative sleep are intertwined processes. Poor sleep negatively affects the key hormones of weight and appetite regulation, thereby potentially increasing weight via mechanisms that increase hunger and lower metabolism, thereby making the successful treatment of obesity more difficult. Clinicians should consider a comprehensive sleep history and proper treatment or referral to a sleep specialist in conjunction with obesity treatment. Adequate restorative sleep is integral to a comprehensive obesity treatment program.

Topics: Appetite; Ghrelin; Humans; Leptin; Melatonin; Obesity; Sleep; Sleep Deprivation; Stress, Psychological

Leptin promotes satiety and modulates energy balance and weight. Diet-induced obesity leads to leptin resistance, exacerbating overeating. We reviewed the literature on the relationship between diet and leptin, which suggests that addressing leptin resistance through dietary interventions can contribute counteracting obesity. Albeit some limitations (e.g., limited rigor, small samples sizes), studies in animals and humans show that diets high in fat, carbohydrates, fructose, and sucrose, and low in protein are drivers of leptin resistance. Despite methodological heterogeneity pertaining to this body of literature, experimental studies show that energy-restricted diets can reduce leptinemia both in the short and long term and potentially reverse leptin resistance in humans. We also discuss limitations of this evidence, future lines of research, and implications for clinical and public health translations. Main limitations include the lack of a single universally-accepted definition of leptin resistance, and of adequate ways to accurately measure it in humans. The use of leptin sensitizers (drugs) and genetically individualized diets are alternatives against leptin resistance that should be further researched in humans. The tested very-low-energy intervention diets are challenging to translate into wide clinical or population recommendations. In conclusion, the link between nutritional components and leptin resistance, as well as research indicating that this condition is reversible, emphasizes the potential of diet to recover sensitivity to this hormone. A harmonized definition of leptin resistance, reliable methods to measure it, and large-scale, translational, clinical, and precision nutrition research involving rigorous methods are needed to benefit populations through these approaches.

Topics: Adipose Tissue; Animals; Diet; Energy Intake; Energy Metabolism; Humans; Leptin; Obesity

Feeding behavior is integrated within a wide variety of eating behaviors, which depend on psychosocial, biological and environmental factors. These types of behavior can cause nutrition-related diseases such as obesity, which affects more than 650 million people worldwide. Ghrelin and leptin are key hormones that regulate appetite, food intake and energy metabolism. Research in genetics suggests that genetic variants of both hormones are associated with complex forms of eating behavior, such as a preference for palatable food, making individuals susceptible to the modern obesogenic environment. This review analyses the scientific evidence around polymorphisms in the ghrelin and leptin genes and their association with eating behavior. The understanding of these mechanisms is relevant since it could impact on the objectives of pharmacological or behavioral interventions for their treatment.

Topics: Appetite; Feeding Behavior; Ghrelin; Humans; Leptin; Obesity

Over the past decades, obesity and infertility in men increased in parallel, and the association between both phenomena have been examined by several researchers. despite the fact that there is no agreement, obesity appears to affect the reproductive potential of men through various mechanisms, such as changes in the hypothalamic-pituitary-testicular (HPT) axis, spermatogenesis, sperm quality and/or alteration of sexual health. Leptin is a hormone produced by the adipose tissue, and its production elevates with increasing body fat. Many studies have supported the relationship between raised leptin production and reproductive function regulation. In fact, Leptin acts on the HPT axis in men at all levels. However, most obese men are insensitive to increased production of endogenous leptin and functional leptin resistance development. Recently, it has been recommended that Kisspeptin neurons mediate the leptin's effects on the reproductive system. Kisspeptin binding to its receptor on gonadotropin-releasing hormone (GnRH) neurons, activates the mammal's reproductive axis and stimulates GnRH release. Increasing infertility associated with obesity is probably mediated by the Kisspeptin-GnRH pathway. In this review, the link between obesity, kisspeptin, leptin, and male fertility will be discussed.

Topics: Fertility; Gonadotropin-Releasing Hormone; Humans; Infertility, Male; Kisspeptins; Leptin; Male; Obesity; Semen

Dietary fibers may induce satiety through affecting gastro-intestinal and peripheral appetite regulating hormones. Thus, we aimed to investigate the effect of dietary fiber consumption on serum leptin level compared to control diet, in short- and long- term trials, through a systematic review and meta-analysis.. We searched PubMed, web of science, Scopus, ProQuest, EMBASE, and Cochrane Library to find randomized controlled clinical trials that evaluated effect of any type of dietary fiber on serum leptin level compared to control diet, until April 2019. Both short-term (1-4 days) and long-term (longer than 2 weeks) studies were selected. Mean differences (MD) of changes in serum leptin level and 95% confidence intervals were extracted from eligible studies, and random effects model was used to analyze data.. Thirteen studies included the systematic review and 11 entered in the meta-analysis. No significant change was seen in serum leptin level in short-term (MD=0.02, 95% CI; -0.15, 0.20, Tau. This meta-analysis found that taking dietary fiber for long term could lower serum leptin level, just in obese persons. However, further clinical trials are needed in this field to clarify this issue.

Topics: Dietary Fiber; Humans; Leptin; Obesity; Randomized Controlled Trials as Topic

Obesity, a global challenge, is a complex disorder linked to various diseases. Different kinds of treatments are currently used to treat or control this pandemic. Despite their positive effects on controlling obesity, they still have limitations and side effects including digestive problems, difficulties of daily infusion of some drugs, surgical complications, and weight regain. All these issues cause these conventional methods not to have desirable efficacy. In this regard, brown adipose tissue (BAT) transplantation as a new investigational treatment is proposed, which has beneficial effects with no documented side effect in studies up to now.. This systematic review protocol was registered in the International Prospective Register of Systematic Reviews (Registration Number: CRD42018110045). The systematical search was conducted on Web of Science, Scopus, PubMed, Embase, and ProQuest databases. The quality assessments in the included studies and data gathering were conducted independently by two authors. The main variables were anthropometric indices including body weight, levels of leptin, IGF-1, glucagon, adiponectin, fasting blood glucose, and UCP-1.. Following the search in mentioned databases, ten articles were entered into this systematic review. In most studies, weight gain and white adipocyte size were reduced in the BAT transplant group. It seems that the transplantation leads to the regeneration of healthy adipose tissue by activating the endogenous BAT.. Since BAT transplantation is one of the possible future treatments of obesity, many studies are conducted to evaluate the outcomes and related procedures precisely, so it can finally step into clinical application.

Topics: Adiponectin; Adipose Tissue, Brown; Animals; Blood Glucose; Disease Models, Animal; Female; Leptin; Male; Mice; Mice, Obese; Obesity

Obesity resulted by imbalance between the intake of energy and energy consumption can lead to growth and metabolic disease development in people. Both in obese men and animal models, several studies indicate that obesity leads to male infertility.. This review has discussed some mechanisms involved in obesity-induced male infertility.. Online documents were searched through Science Direct, Pubmed, Scopus, and Google Scholar websites dating from 1959 to recognize studies on obesity, kisspeptin, leptin, and infertility.. Obesity induced elevated inflammatory cytokines and oxidative stress can affect male reproductive functions, including spermatogenesis disorders, reduced male fertility power and hormones involved in the hypothalamus-pituitary-gonadal axis.. There is significant evidence that obesity resulted in male infertility. Obesity has a negative effect on male reproductive function via several mechanisms such as inflammation and oxidative stress.

Topics: Animals; Humans; Infertility, Male; Leptin; Male; Metabolic Diseases; Obesity; Oxidative Stress

Most known types of nonsyndromic monogenic obesity are caused by rare mutations in genes of the leptin-melanocortin pathway controlling appetite and adiposity. In contrast, congenital generalized lipodystrophy represents the most extreme form of leanness in humans caused by recessive mutations in four genes involved in phospholipid/triglyceride synthesis and lipid droplet/caveolae structure. In this disease, the inability to store triglyceride in adipocytes results in hypoleptinemia and ectopic hepatic and muscle fat accumulation leading to fatty liver, hypertriglyceridemia and severe insulin resistance. As a result of hypoleptinemia, patients with lipodystrophy show alterations in eating behaviour characterized by constant increased energy intake. As it occurs in obesity caused by genetic leptin deficiency, exogenous leptin rapidly reduces hunger scores in patients with congenital generalized lipodystrophy, with additional beneficial effects on glucose homeostasis and metabolic profile normalization. The melanocortin-4 receptor agonist setmelanotide has been used in the treatment of monogenic obesities. There is only one report on the effect of setmelanotide in a patient with partial lipodystrophy resulting in mild reductions in hunger scores, with no improvements in metabolic status. The assessment of contrasting phenotypes of obesity/leanness represents an adequate strategy to understand the pathophysiology and altered eating behaviour associated with adipose tissue excessive accumulation/paucity.

Topics: Adiposity; Feeding Behavior; Humans; Leptin; Lipodystrophy, Congenital Generalized; Obesity; Phenotype

Obesity, which has long since reached epidemic proportions worldwide, is associated with long-term stress to a variety of organs and results in diseases including type 2 diabetes. In the brain, overnutrition induces hypothalamic stress associated with the activation of several signalling pathways, together with central insulin and leptin resistance. This central action of nutrient overload appears very rapidly, suggesting that nutrition-induced hypothalamic stress is a major upstream initiator of obesity and associated diseases. The cellular response to nutrient overload includes the activation of the stress-activated c-Jun N-terminal kinases (JNKs) JNK1, JNK2 and JNK3, which are widely expressed in the brain. Here, we review recent findings on the regulation and effects of these kinases, with particular focus on the hypothalamus, a key brain region in the control of energy and glucose homeostasis. JNK1 blocks the hypothalamic-pituitary-thyroid axis, reducing energy expenditure and promoting obesity. Recently, opposing roles have been identified for JNK1 and JNK3 in hypothalamic agouti gene-related protein (AgRP) neurons: while JNK1 activation in AgRP neurons induces feeding and weight gain and impairs insulin and leptin signalling, JNK3 (also known as MAPK10) deletion in the same neuronal population produces very similar effects. The opposing roles of these kinases, and the unknown role of hypothalamic JNK2, reflect the complexity of JNK biology. Future studies should address the specific function of each kinase, not only in different neuronal subsets, but also in non-neuronal cells in the central nervous system. Decoding the puzzle of brain stress kinases will help to define the central stimuli and mechanisms implicated in the control of energy balance. Graphical abstract.

Topics: Agouti-Related Protein; Animals; Brain; Endoplasmic Reticulum Stress; Energy Metabolism; Feeding Behavior; Glucose; Humans; Hypothalamo-Hypophyseal System; Hypothalamus; Insulin; JNK Mitogen-Activated Protein Kinases; Leptin; Metabolic Diseases; Mitogen-Activated Protein Kinase 10; Mitogen-Activated Protein Kinase 8; Mitogen-Activated Protein Kinase 9; Neurons; Obesity; Thyroid Gland; Weight Gain

In obesity, an elevated accumulation and dysregulation of adipose tissue, due to an imbalance between energy intake and energy expenditure, usually coexists with the loss of responsiveness to leptin in central nervous system, and subsequently with hyperleptinemia. Leptin, a peptide hormone mainly produced by white adipose tissue, regulates energy homeostasis by stimulating energy expenditure and inhibiting food intake. Human obesity is characterized by increased plasma leptin levels, which have been related with different obesity-associated complications, such as chronic inflammatory state (risk factor for diabetes, cardiovascular and autoimmune diseases), as well as infertility and different types of cancer. Besides, leptin is also produced by placenta, and high leptin levels during pregnancy may be related with some pathological conditions such as gestational diabetes. This review focuses on the current insights and emerging concepts on potentially valuable nutrients and food components that may modulate leptin metabolism. Notably, several dietary food components, such as phenols, peptides, and vitamins, are able to decrease inflammation and improve leptin sensitivity by up- or down-regulation of leptin signaling molecules. On the other hand, some food components, such as saturated fatty acids may worsen chronic inflammation increasing the risk for pathological complications. Future research into nutritional mechanisms that restore leptin metabolism and signals of energy homeostasis may inspire new treatment options for obesity-related disorders.

Topics: Adipose Tissue; Adipose Tissue, White; Animals; Autoimmune Diseases; Diabetes Mellitus; Energy Intake; Energy Metabolism; Fatty Acids; Female; Humans; Infertility; Inflammation; Leptin; Male; Neoplasms; Nutritional Physiological Phenomena; Obesity

Far beyond the compelling proofs supporting that the metabolic syndrome represents a risk factor for diabetes and cardiovascular diseases, a growing body of evidence suggests that it is also a risk factor for different types of cancer. However, the involved molecular mechanisms underlying this association are not fully understood, and they have been mainly focused on the individual contributions of each component of the metabolic syndrome such as obesity, hyperglycemia, and high blood pressure to the development of cancer. The Receptor for Advanced Glycation End-products (RAGE) axis activation has emerged as an important contributor to the pathophysiology of many clinical entities, by fueling a chronic inflammatory milieu, and thus supporting an optimal microenvironment to promote tumor growth and progression. In the present review, we intend to highlight that RAGE axis activation is a crosswise element on the potential mechanistic contributions of some relevant components of metabolic syndrome into the association with cancer.

Topics: Adiponectin; Adipose Tissue; Animals; Disease Progression; Gene Expression Regulation; Humans; Hyperglycemia; Hypertension; Inflammation; Insulin-Like Growth Factor I; Leptin; Ligands; Metabolic Syndrome; Mice; Neoplasms; Obesity; Peroxisome Proliferator-Activated Receptors; Rats; Receptor for Advanced Glycation End Products; Signal Transduction; Vascular Endothelial Growth Factor A; Wnt Proteins

The landmark discoveries of leptin and adiponectin firmly established adipose tissue as a sophisticated and highly active endocrine organ, opening a new era of investigating adipose-mediated tissue crosstalk. Both obesity-associated hyperleptinemia and hypoadiponectinemia are important biomarkers to predict cardiovascular outcomes, suggesting a crucial role for adiponectin and leptin in obesity-associated cardiovascular disorders. Normal physiological levels of adiponectin and leptin are indeed essential to maintain proper cardiovascular function. Insufficient adiponectin and leptin signaling results in cardiovascular dysfunction. However, a paradox of high levels of both leptin and adiponectin is emerging in the pathogenesis of cardiovascular disorders. Here, we (1) summarize the recent progress in the field of adiponectin and leptin and its association with cardiovascular disorders, (2) further discuss the underlying mechanisms for this new paradox of leptin and adiponectin action, and (3) explore the possible application of partial leptin reduction, in addition to increasing the adiponectin/leptin ratio as a means to prevent or reverse cardiovascular disorders.

Topics: Adiponectin; Adipose Tissue; Animals; Anti-Obesity Agents; Bariatric Surgery; Cardiovascular Agents; Cardiovascular Diseases; Cardiovascular System; Humans; Leptin; Metabolism, Inborn Errors; Obesity; Signal Transduction

Adiposity is associated with an increased risk of various types of carcinoma. One of the plausible mechanisms underlying the tumor-promoting role of obesity is an aberrant secretion of adipokines, a group of hormones secreted from adipose tissue, which have exhibited both oncogenic and tumor-suppressing properties in an adipokine type- and context-dependent manner. Increasing evidence has indicated that these adipose tissue-derived hormones differentially modulate cancer cell-specific metabolism. Some adipokines, such as leptin, resistin, and visfatin, which are overproduced in obesity and widely implicated in different stages of cancer, promote cellular glucose and lipid metabolism. Conversely, adiponectin, an adipokine possessing potent anti-tumor activities, is linked to a more favorable metabolic phenotype. Adipokines may also play a pivotal role under the reciprocal regulation of metabolic rewiring of cancer cells in tumor microenvironment. Given the fact that metabolic reprogramming is one of the major hallmarks of cancer, understanding the modulatory effects of adipokines on alterations in cancer cell metabolism would provide insight into the crosstalk between obesity, adipokines, and tumorigenesis. In this review, we summarize recent insights into putative roles of adipokines as mediators of cellular metabolic rewiring in obesity-associated tumors, which plays a crucial role in determining the fate of tumor cells.

Topics: Adipokines; Adipose Tissue; Adiposity; Animals; Disease Progression; Glucose; Glycolysis; Humans; Inflammation; Leptin; Lipid Metabolism; Mice; Mitochondria; Neoplasms; Nicotinamide Phosphoribosyltransferase; Obesity; Oxidation-Reduction; Phenotype; Reactive Oxygen Species; Resistin; Tumor Microenvironment

Leptin has emerged over the past 2 decades as a key hormone secreted by adipose tissue that conveys information on energy stores. Leptin is considered an important regulator of both neuroendocrine function and energy homeostasis. Numerous studies (mainly preclinical and much less in humans) have investigated the mechanisms of leptin's actions both in the healthy state as well as in a wide range of metabolic diseases. In this review, the authors present leptin physiology and review the main findings from animal studies, observational and interventional studies, and clinical trials in humans that have investigated the role of leptin in metabolism and cardiometabolic diseases (energy deficiency, obesity, diabetes, cardiovascular diseases, nonalcoholic fatty liver disease). The authors discuss the similarities and discrepancies between animal and human biology and present clinical applications of leptin, directions for future research, and current approaches for the development of the next-generation leptin analogs.

Topics: Animals; Clinical Trials as Topic; Humans; Leptin; Obesity; Thinness

Obesity represents the single greatest ongoing roadblock to improving cardiovascular health. Prolonged obesity is associated with fundamental changes in the integrative control of energy balance, including the development of selective leptin resistance, which is thought to contribute to obesity-associated hypertension, and adaptation of resting metabolic rate (RMR) when excess weight is reduced. Leptin and the melanocortin system within the hypothalamus contribute to the control of both energy balance and blood pressure. While the development of drugs to stimulate RMR and thereby reverse obesity through activation of the melanocortin system has been pursued, most of the resulting compounds simultaneously cause hypertension. Evidence supports the concept that although feeding behaviors, RMR, and blood pressure are controlled through mechanisms that utilize similar molecular mediators, these mechanisms exist in anatomically dissociable networks. New evidence supports a major change in molecular signaling within AgRP (Agouti-related peptide) neurons of the arcuate nucleus of the hypothalamus during prolonged obesity and the existence of multiple distinct subtypes of AgRP neurons that individually contribute to control of feeding, RMR, or blood pressure. Finally, ongoing work by our laboratory and others support a unique role for AT

Topics: Angiotensins; Cardiometabolic Risk Factors; Central Nervous System; Drug Discovery; Humans; Hypertension; Leptin; Metabolism; Obesity

Obesity is a risk factor for developing several cancers. The dysfunctional metabolism and chronic activation of inflammatory pathways in obesity create a milieu that supports tumor initiation, progression, and metastasis. Obesity-associated metabolic, endocrine, and inflammatory mediators, besides interacting with cells leading to a malignant transformation, also modify the intrinsic metabolic and functional characteristics of immune myeloid cells. Here, the evidence supporting the hypothesis that obesity metabolically primes and promotes the expansion of myeloid cells with immunosuppressive and pro-oncogenic properties is discussed. In consequence, the accumulation of these cells, such as myeloid-derived suppressor cells and some subtypes of adipose-tissue macrophages, creates a microenvironment conducive to tumor development. In this review, the role of lipids, insulin, and leptin, which are dysregulated in obesity, is emphasized, as well as dietary nutrients in metabolic reprogramming of these myeloid cells. Moreover, emerging evidence indicating that obesity enhances immunotherapy response and hypothesized mechanisms are summarized. Priorities in deeper exploration involving the mechanisms of cross talk between metabolic disorders and myeloid cells related to cancer risk in patients with obesity are highlighted.

Topics: Adipose Tissue; Animals; Carcinogenesis; Humans; Immunotherapy; Inflammation Mediators; Leptin; Macrophages; Myeloid-Derived Suppressor Cells; Neoplasm Metastasis; Neoplasms; Obesity; Risk Factors; Tumor Microenvironment

Obesity is rapidly dispersing all around the world and is closely associated with a high risk of metabolic diseases such as insulin resistance, dyslipidemia, and nonalcoholic fatty liver disease (NAFLD), leading to carcinogenesis, especially hepatocellular carcinoma (HCC). It results from an imbalance between food intake and energy expenditure, leading to an excessive accumulation of adipose tissue (AT). Adipocytes play a substantial role in the tumor microenvironment through the secretion of several adipokines, affecting cancer progression, metastasis, and chemoresistance via diverse signaling pathways. AT is considered an endocrine organ owing to its ability to secrete adipokines, such as leptin, adiponectin, resistin, and a plethora of inflammatory cytokines, which modulate insulin sensitivity and trigger chronic low-grade inflammation in different organs. Even though the precise mechanisms are still unfolding, it is now established that the dysregulated secretion of adipokines by AT contributes to the development of obesity-related metabolic disorders. This review focuses on several obesity-associated adipokines and their impact on obesity-related metabolic diseases, subsequent metabolic complications, and progression to HCC, as well as their role as potential therapeutic targets. The field is rapidly developing, and further research is still required to fully understand the underlying mechanisms for the metabolic actions of adipokines and their role in obesity-associated HCC.

Topics: Adipokines; Adiponectin; Adipose Tissue; Amino Acids, Branched-Chain; Animals; Carcinoma, Hepatocellular; Hepatocytes; Humans; Insulin Resistance; Leptin; Lipid Metabolism; Liver; Liver Neoplasms; Obesity

Narcolepsy, a sleep disorder characterized by loss of hypocretin neurons, has been associated with metabolic disturbances. Although the metabolic alterations in narcolepsy patients are widely investigated in the literature, the results are controversial. We performed a systematic search of literature to identify metabolic profiling studies in narcolepsy patients. A total of 48 studies were included in the meta-analysis. Narcolepsy patients exhibited higher prevalence of obesity (log OR = 0.93 [0.73-1.13], P < 0.001), diabetes mellitus (log OR = 0.64 [0.34, 0.94], P < 0.001), hypertension (log OR = 0.33 [0.11, 0.55], P < 0.001), and dyslipidemia (log OR = 1.19 [0.60, 1.77], P < 0.001) compared with non-narcoleptic controls. Narcolepsy was associated with higher BMI (SMD = 0.50 [0.32-0.68], P < 0.001), waist circumference (MD = 8.61 [2.03-15.19], P = 0.01), and plasma insulin (SMD = 0.61 [0.14-1.09], P = 0.01). Levels of fasting blood glucose (SMD = -0.25 [-0.61,0.10], P = 0.15), BMR-RMR (SMD = -0.17 [-0.52-0.18], P = 0.34), systolic blood pressure (SMD = 0.29 [-0.39-0.97], P = 0.40), diastolic blood pressure (SMD = 0.39 [-0.62, 1.40], P = 0.45), CSF melanin-concentrating hormone (MD = 5.56 [-30.79-41.91], P = 0.76), serum growth hormone (SMD = 7.84 [-7.90-23.57], P = 0.33), as well as plasma and CSF leptin (SMD = 0.10 [-1.32-1.51], P = 0.89 and MD = 0.01 [-0.02-0.04], P = 0.56, respectively) did not significantly differ between narcolepsy patients and controls. These findings necessitate early screening of metabolic alterations and cardiovascular risk factors in narcolepsy patients to reduce the morbidity and mortality rates.

Topics: Humans; Leptin; Metabolome; Narcolepsy; Obesity; Orexins; Sleep Wake Disorders

Emerging evidence has identified sleep as a significant, but modifiable, risk factor for metabolic syndrome, diabetes, and obesity. Leptin, an adipocyte-derived peptide and a regulator of food intake and energy expenditure, has been shown to be associated with a short sleep duration in the pathophysiology of obesity and consequently type 2 diabetes. This review focuses on the current evidence indicating the effects of a short sleep duration on the regulation of leptin concentration in association with obesity and diabetes mellitus. In summary, the evidence suggests that sleep deprivation, by affecting leptin regulation, may lead to obesity and consequently development of type 2 diabetes through increased appetite and food intake. However, findings on the role of leptin in diabetes due to sleep deprivation are contradictory, and further studies with larger sample sizes are needed to confirm previous findings.

Topics: Diabetes Mellitus, Type 2; Humans; Leptin; Obesity; Sleep; Sleep Deprivation

Ramadan intermittent fasting may affect whole-body metabolism by affecting appetite-related hormones. This systematic review and meta-analysis aimed to clarify the possible effects of Ramadan intermittent fasting on the main hormones regulating appetite and satiety, including leptin and adiponectin.. All English language papers in the PubMed, Scopus, and Embase databases were searched using the keywords "Ramadan fasting", "adiponectin", and "leptin", up to 2020. Data extraction was conducted based on the main data of the studies; the primary outcomes of the analysis were mean changes of adiponectin and leptin levels during the holy month of Ramadan in fasted subjects.. Data of 16 eligible studies, conducted between 2003 and 2020, were included in the systematic review. Of these, 10 studies with complete data on leptin and adiponectin were included in the meta-analysis. A significant decrease in leptin levels was observed after Ramadan fasting (WMD = -2.28 ng/ml, 95% CI = -3.72, -0.84). Ramadan fasting had no significant effect on adiponectin levels (WMD = 2.19 ng/ml, 95% CI = -0.29, 4.67). Sub-group analysis demonstrated a greater decrease in leptin levels among normal-weight subjects compared to those of overweight/obese subjects (WMD = -4.67 ng/ml, 95% CI = -6.03, -3.31 vs. WMD = -3.43 ng/ml, 95% CI = -5.69, -1.17).. Ramadan fasting may decrease leptin levels, especially in normal-weight subjects. There was high heterogeneity, which may be explained by the differences between the wide ranges of study conditions.

Topics: Adiponectin; Fasting; Holidays; Humans; Leptin; Obesity

Leptin is an obesity-associated adipokine that is known to regulate energy metabolism and reproduction and to control appetite via the leptin receptor. Recent work has identified specific cell types other than adipocytes that harbor leptin and leptin receptor expression, particularly in cancers and tumor microenvironments, and characterized the role of this signaling axis in cancer progression. Furthermore, the prognostic significance of leptin in various types of cancer and the ability to noninvasively detect leptin levels in serum samples have attracted attention for potential clinical applications. Emerging findings have demonstrated the direct and indirect biological effects of leptin in regulating cancer proliferation, metastasis, angiogenesis and chemoresistance, warranting the exploration of the underlying molecular mechanisms to develop a novel therapeutic strategy. In this review article, we summarize and integrate transcriptome and clinical data from cancer patients together with the recent findings related to the leptin signaling axis in the aforementioned malignant phenotypes. In addition, a comprehensive analysis of leptin and leptin receptor distribution in a pancancer panel and in individual cell types of specific organs at the single-cell level is presented, identifying those sites that are prone to leptin-mediated tumorigenesis. Our results shed light on the role of leptin in cancer and provide guidance and potential directions for further research for scientists in this field.

Topics: Adipocytes; Animals; Carcinogenesis; Humans; Leptin; Neoplasms; Obesity; Receptors, Leptin; Signal Transduction; Tumor Microenvironment

The recent pandemic Sars-CoV2 infection and studies on previous influenza epidemic have drawn attention to the association between the obesity and infectious diseases susceptibility and worse outcome. Metabolic complications, nutritional aspects, physical inactivity, and a chronic unbalance in the hormonal and adipocytokine microenvironment are major determinants in the severity of viral infections in obesity. By these pleiotropic mechanisms obesity impairs immune surveillance and the higher leptin concentrations produced by adipose tissue and that characterize obesity substantially contribute to such immune response dysregulation. Indeed, leptin not only controls energy balance and body weight, but also plays a regulatory role in the interplay between energy metabolism and immune system. Since leptin receptor is expressed throughout the immune system, leptin may exert effects on cells of both innate and adaptive immune system. Chronic inflammatory states due to metabolic (i.e., obesity) as well as infectious diseases increase leptin concentrations and consequently lead to leptin resistance further fueling inflammation. Multiple factors, including inflammation and ER stress, contribute to leptin resistance. Thus, if leptin is recognized as one of the adipokines responsible for the low grade inflammation found in obesity, on the other hand, impairments of leptin signaling due to leptin resistance appear to blunt the immunologic effects of leptin and possibly contribute to impaired vaccine-induced immune responses. However, many aspects concerning leptin interactions with inflammation and immune system as well as the therapeutical approaches to overcome leptin resistance and reduced vaccine effectiveness in obesity remain a challenge for future research.

Topics: Animals; Antiviral Agents; COVID-19; COVID-19 Drug Treatment; Energy Metabolism; Humans; Immune System; Leptin; Obesity; Viral Vaccines; Virus Diseases

Obesity is a globally increasing health problem, entailing diverse comorbidities such as infectious diseases. An obese weight status has marked effects on lung function that can be attributed to mechanical dysfunctions. Moreover, the alterations of adipocyte-derived signal mediators strongly influence the regulation of inflammation, resulting in chronic low-grade inflammation. Our review summarizes the known effects regarding pulmonary bacterial and viral infections. For this, we discuss model systems that allow mechanistic investigation of the interplay between obesity and lung infections. Overall, obesity gives rise to a higher susceptibility to infectious pathogens, but the pathogenetic process is not clearly defined. Whereas, viral infections often show a more severe course in obese patients, the same patients seem to have a survival benefit during bacterial infections. In particular, we summarize the main mechanical impairments in the pulmonary tract caused by obesity. Moreover, we outline the main secretory changes within the expanded adipose tissue mass, resulting in chronic low-grade inflammation. Finally, we connect these altered host factors to the influence of obesity on the development of lung infection by summarizing observations from clinical and experimental data.

Topics: Adipocytes; Adipokines; Adiponectin; Adipose Tissue; Animals; Anti-Inflammatory Agents; Bacterial Infections; Cells, Cultured; Comorbidity; Female; Humans; Inflammation; Leptin; Lung; Macrophages; Male; Mice; Obesity; Risk Factors; Virus Diseases

The discovery of the archetypal adipocytokine leptin and how it regulates energy homeostasis have represented breakthroughs in our understanding of the endocrine function of the adipose tissue and the biological determinants of human obesity. Investigations on leptin have also been instrumental in identifying physio-pathological connections between metabolic regulation and multiple immunological functions. For example, the description of the promoting activities of leptin on inflammation and cell proliferation have recognized the detrimental effects of leptin in connecting dysmetabolic conditions with cancer and with onset and/or progression of autoimmune disease. Here we review the multiple biological functions and complex framework of operations of leptin, discussing why and how the pleiotropic activities of this adipocytokine still pose major hurdles in the development of effective leptin-based therapeutic opportunities for different clinical conditions.

Topics: Animals; Energy Metabolism; Gene Expression Regulation; Homeostasis; Humans; Inflammation; Leptin; Mutation; Neoplasms; Obesity

The association of adiponectin with metabolism and cancer is well established. Since its discovery in 1990, adiponectin, as one of the adipose tissue-secreted adipokines, has been very widely studied in biomedical research. Low levels of circulatory adiponectin have been reported in obesity, inflammatory diseases and various types of cancers including colorectal cancer (CRC), which is highly linked with obesity and gut inflammation. However, the function and underlying mechanisms of adiponectin in CRC is not well understood. In addition, there are contradictory reports on the role of adiponectin in cancer. Therefore, further investigation is needed. In this review, we explore the information available on the relationship between adiponectin and CRC with respect to proliferation, cell survival, angiogenesis and inflammation. We also highlighted the knowledge gaps, filling in which could help us better understand the function and mechanisms of adiponectin in CRC.

Topics: Adipokines; Adiponectin; Adipose Tissue; Animals; Biomarkers, Tumor; Cell Proliferation; Cell Survival; Colorectal Neoplasms; Gene Expression Regulation, Neoplastic; Humans; Inflammation; Leptin; Mice; Neoplasm Metastasis; Neovascularization, Pathologic; Obesity; Tumor Microenvironment

The complex nature of folliculogenesis regulation accounts for its susceptibility to maternal physiological fitness. In obese mothers, progressive expansion of adipose tissue culminates with severe hyperestrogenism and hyperleptinemia with detrimental effects for ovarian performance. Indeed, maternal obesity is associated with the establishment of ovarian leptin resistance. This review summarizes current knowledge on potential effects of impaired leptin signaling throughout folliculogenesis and oocyte developmental competence in mice and women.

Topics: Adipokines; Animals; Biomarkers; Cell Differentiation; Female; Gene Expression Regulation, Developmental; Humans; Leptin; Mice; Models, Biological; Mothers; Obesity; Oocytes; Oogenesis; Ovarian Follicle; Ovulation; Pregnancy; Signal Transduction

During aging, body adiposity increases with changes in the metabolism of lipids and their metabolite levels. Considering lipid metabolism, excess adiposity with increased lipotoxicity leads to various age-related diseases, including cardiovascular disease, cancer, arthritis, type 2 diabetes, and Alzheimer's disease. However, the multifaceted nature and complexities of lipid metabolism make it difficult to delineate its exact mechanism and role during aging. With advances in genetic engineering techniques, recent studies have demonstrated that changes in lipid metabolism are associated with aging and age-related diseases. Lipid accumulation and impaired fatty acid utilization in organs are associated with pathophysiological phenotypes of aging. Changes in adipokine levels contribute to aging by modulating changes in systemic metabolism and inflammation. Advances in lipidomic techniques have identified changes in lipid profiles that are associated with aging. Although it remains unclear how lipid metabolism is regulated during aging, or how lipid metabolites impact aging, evidence suggests a dynamic role for lipid metabolism and its metabolites as active participants of signaling pathways and regulators of gene expression. This review describes recent advances in our understanding of lipid metabolism in aging, including established findings and recent approaches.

Topics: Adiponectin; Adipose Tissue; Adiposity; Aging; Alzheimer Disease; Arthritis; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Fatty Acids; Gene Expression Regulation; Humans; Leptin; Lipid Metabolism; Lipidomics; Neoplasms; Obesity; Signal Transduction

Obesity and endometriosis are two very common entities, yet there is uncertainty on their exact relationship. Observational studies have repeatedly shown an inverse correlation between endometriosis and a low body mass index (BMI). However, obesity does not protect against endometriosis and on the contrary an increased BMI may lead to more severe forms of the disease. Besides, BMI is not accurate in all cases of obesity. Consequently, other anthropometric and phenomic traits have been studied, including body adiposity content, as well as the effect of BMI early in life on the manifestation of endometriosis in adulthood. Some studies have shown that the phenotypic inverse correlation between the two entities has a genetic background; however, others have indicated that certain polymorphisms are linked with endometriosis in females with increased BMI. The advent of metabolic bariatric surgery and pertinent research have led to the emergence of biomolecules that may be pivotal in understanding the pathophysiological interaction of the two entities, especially in the context of angiogenesis and inflammation. Future research should focus on three objectives: detection and interpretation of obesity-related biomarkers in experimental models with endometriosis; integration of endometriosis-related queries into bariatric registries; and multidisciplinary approach and collaboration among specialists.

Topics: Adiponectin; Adiposity; Anthropometry; Bariatric Surgery; Biomarkers; Body Mass Index; Case-Control Studies; Chemokines; Endometriosis; Female; Gene Expression Regulation; Gene-Environment Interaction; Ghrelin; Humans; Leptin; Obesity; Phenomics; Phenotype

Obesity and dementia are two growing problems worldwide. Obesity act as a crucial risk factor for various diseases including Alzheimer's disease (AD). Several preclinical studies showed that middle-age obesity can be act as a possible feature of mild cognitive impairment in later years. Some studies have also demonstrated that a high-fat diet causes AD pathology, including extracellular amyloid-beta accumulation, hyperphosphorylation of tau, and cognition impairment. The correlation and molecular mechanism related to obesity-associated AD needs to be better evaluated. Presently, obesity results in an altered expression of several hormones, growth factors, and adipokines. Multiple signaling pathways such as leptin, insulin, adiponectin, and glutamate are involved to regulate vital functions in the brain and act as neuroprotective mediators for AD in a normal state. In obesity, altered adiponectin (APN) level and its associated downstream pathway could result in multiple signaling pathway disruption. Presently, Adiponectin and its inducers or agonist are considered as potential therapeutics for obesity-associated AD. This review mainly focuses on the pleiotropic effects of adiponectin and its potential to treat obesity-associated AD.

Topics: Adiponectin; Alzheimer Disease; Animals; Humans; Insulin; Leptin; Obesity; Signal Transduction

The triad of obesity, metabolic syndrome (MetS), Type 2 diabetes mellitus (T2DM) and advancing age are currently global societal problems that are expected to grow over the coming decades. This triad is associated with multiple end-organ complications of diabetic vasculopathy (maco-microvessel disease), neuropathy, retinopathy, nephropathy, cardiomyopathy, cognopathy encephalopathy and/or late-onset Alzheimer's disease. Further, obesity, MetS, T2DM and their complications are associated with economical and individual family burdens. This review with original data focuses on the white adipose tissue-derived adipokine/hormone leptin and how its deficient signaling is associated with brain remodeling in hyperphagic, obese, or hyperglycemic female mice. Specifically, the ultrastructural remodeling of the capillary neurovascular unit, brain endothelial cells (BECs) and their endothelial glycocalyx (ecGCx), the blood-brain barrier (BBB), the ventricular ependymal cells, choroid plexus, blood-cerebrospinal fluid barrier (BCSFB), and tanycytes are examined in female mice with impaired leptin signaling from either dysfunction of the leptin receptor (DIO and

Topics: Animals; Blood-Brain Barrier; Brain; Diabetes Mellitus, Type 2; Disease Models, Animal; Humans; Leptin; Mice, Obese; Obesity; Signal Transduction

Increasing adipose tissue mass in obesity directly correlates with elevated circulating leptin levels. Leptin is an adipokine known to play a role in numerous biological processes including regulation of energy homeostasis, inflammation, vascular function and angiogenesis. While physiological concentrations of leptin may exhibit multiple beneficial effects, chronically elevated pathophysiological levels or hyperleptinemia, characteristic of obesity and diabetes, is a major risk factor for development of atherosclerosis. Hyperleptinemia results in a state of selective leptin resistance such that while beneficial metabolic effects of leptin are dampened, deleterious vascular effects of leptin are conserved attributing to vascular dysfunction. Leptin exerts potent proatherogenic effects on multiple vascular cell types including macrophages, endothelial cells and smooth muscle cells; these effects are mediated via an interaction of leptin with the long form of leptin receptor, abundantly expressed in atherosclerotic plaques. This review provides a summary of recent in vivo and in vitro studies that highlight a role of leptin in the pathogenesis of atherosclerotic complications associated with obesity and diabetes.

Topics: Animals; Atherosclerosis; Diabetes Mellitus; Endothelial Cells; Humans; Leptin; Macrophages; Myocytes, Smooth Muscle; Obesity

The role of the autonomic nervous system in obesity and insulin-resistant conditions has been largely explored. However, the exact mechanisms involved in this relation have not been completely elucidated yet, since most of these mechanisms display a bi-directional effect. Insulin-resistance, for instance, can be caused by sympathetic activation, but, in turn, the associated hyperinsulinemia can activate the sympathetic branch of the autonomic nervous system. The picture is made even more complex by the implicated neural, hormonal and nutritional mechanisms. Among them, leptin plays a pivotal role, being involved not only in appetite regulation and glucose homeostasis but also in energy expenditure. The purpose of this review is to offer a comprehensive view of the complex interplay between leptin and the central nervous system, providing further insights on the impact of autonomic nervous system balance on adipose tissue and insulin-resistance. Furthermore, the link between the circadian clock and leptin and its effect on metabolism and energy balance will be evaluated.

Topics: Animals; Autonomic Nervous System; Central Nervous System; Humans; Insulin Resistance; Leptin; Obesity

Obesity is a global health issue for which no major effective treatments have been well established. High-fat diet consumption is closely related to the development of obesity because it negatively modulates the hypothalamic control of food intake due to metaflammation and lipotoxicity. The use of animal models, such as rodents, in conjunction with in vitro models of hypothalamic cells, can enhance the understanding of hypothalamic functions related to the control of energy balance, thereby providing knowledge about the impact of diet on the hypothalamus, in addition to targets for the development of new drugs that can be used in humans to decrease body weight. Recently, sphingolipids were described as having a lipotoxic effect in peripheral tissues and the central nervous system. Specifically, lipid overload, mainly from long-chain saturated fatty acids, such as palmitate, leads to excessive ceramide levels that can be sensed by the hypothalamus, triggering the dysregulation of energy balance control. However, no systematic review has been undertaken regarding studies of sphingolipids, particularly ceramide and sphingosine-1-phosphate (S1P), the hypothalamus, and obesity. This review confirms that ceramides are associated with hypothalamic dysfunction in response to metaflammation, endoplasmic reticulum (ER) stress, and lipotoxicity, leading to insulin/leptin resistance. However, in contrast to ceramide, S1P appears to be a central satiety factor in the hypothalamus. Thus, our work describes current evidence related to sphingolipids and their role in hypothalamic energy balance control. Hypothetically, the manipulation of sphingolipid levels could be useful in enabling clinicians to treat obesity, particularly by decreasing ceramide levels and the inflammation/endoplasmic reticulum stress induced in response to overfeeding with saturated fatty acids.

Topics: Animals; Ceramides; Diet, High-Fat; Endoplasmic Reticulum Stress; Energy Metabolism; Fatty Acids; Humans; Hypothalamus; Insulin Resistance; Leptin; Lysophospholipids; Obesity; Signal Transduction; Sphingolipids; Sphingosine

The peptide hormone leptin regulates food intake, body mass, and reproductive function and plays a role in fetal growth, proinflammatory immune responses, angiogenesis and lipolysis. Leptin is a product of the obese (

Topics: Animals; Energy Metabolism; Humans; Hypothalamus; Leptin; Obesity; Risk Factors; Satiety Response; Signal Transduction

Obesity is strongly related to leptin resistance that refers to the state in which leptin fails to inhibit appetite, enhance energy expenditure and regulate glycolipid metabolism, whereas decreasing leptin resistance is important for obesity treatment. Leptin resistance that develops in brain and also directly in peripheral tissues is considered as central and peripheral leptin resistance, respectively. The mechanism of central leptin resistance is the focus of intensive studies but still not totally clarified. A challenged notion about the effect of impaired leptin BBB transport emerges and a concept of "selective leptin resistance" is discussed. Peripheral leptin resistance, especially leptin resistance in muscle, has drawn more attention recently, while its mechanism remains unclear. Exercise is an effective way to reduce obesity, which is at least in part due to the alleviation of leptin resistance. Here, we summarized newly discovered data about the associated factors of central leptin resistance and peripheral leptin resistance, and the actions of exercise on leptin resistance, which is important to understand the mechanisms of leptin resistance and exercise-induced alleviation of leptin resistance, and to facilitate clinical application of leptin in obesity treatment.

Topics: Brain; Energy Metabolism; Exercise; Humans; Leptin; Obesity

Metabolic syndrome (MetS) is a complex of diseases that lead to mortality due to the development of cardiovascular problems. Quercetin, as an important flavonoid, has various properties such as decreasing blood pressure, anti-hyperlipidemia, anti-hyperglycemia, anti-oxidant, antiviral, anticancer, anti-inflammatory, anti-microbial, neuroprotective, and cardio-protective effects. In this review article, we collected original articles from different sources such as Google Scholar, Medline, Scopus, and Pubmed, which is related to the effect of quercetin on the improvement of the signs of MetS, including elevated glucose level, hyperlipidemia, obesity, and blood pressure. According to these data, quercetin may also have a role in the management of metabolic disorders via different mechanisms such as increasing adiponectin, decreasing leptin, anti-oxidant activity, reduction of insulin resistance, the elevation of insulin level, and blocking of calcium channel. We have attempted to make some recommendations on the quercetin application in patients. However, it needs to do further clinical trials and more investigations to show the real clinical value of quercetin on metabolic syndrome.

Topics: Adiponectin; Humans; Leptin; Metabolic Syndrome; Obesity; Quercetin

Leptin is an important regulator of basal metabolism and food intake, with a pivotal role in obesity. Leptin exerts many different actions on various tissues and systems, including cancer, and is considered as a linkage between metabolism and the immune system. During the last decades, obesity and leptin have been associated with the initiation, proliferation and progression of many types of cancer. Obesity is also linked with complications and mortality, irrespective of the therapy used, affecting clinical outcomes. However, some evidence has suggested its beneficial role, called the "obesity paradox", and the possible antitumoral role of leptin. Recent data regarding the immunotherapy of cancer have revealed that overweight leads to a more effective response and leptin may probably be involved in this beneficial process. Since leptin is a positive modulator of both the innate and the adaptive immune system, it may contribute to the increased immune response stimulated by immunotherapy in cancer patients and may be proposed as a good actor in cancer. Our purpose is to review this dual role of leptin in cancer, as well as trying to clarify the future perspectives of this adipokine, which further highlights its importance as a cornerstone of the immunometabolism in oncology.

Topics: Adaptive Immunity; Animals; Humans; Immunotherapy; Leptin; Neoplasm Proteins; Neoplasms; Obesity

Leptin is a principal adipose-derived hormone mostly implicated in the regulation of energy balance through the activation of anorexigenic neuronal pathways. Comprehensive studies have established that the maintenance of certain concentrations of circulating leptin is essential to avoid an imbalance in nutrient intake. Indeed, genetic modifications of the leptin/leptin receptor axis and the obesogenic environment may induce changes in leptin levels or action in a manner that accelerates metabolic dysfunctions, resulting in a hyperphagic status and adipose tissue expansion. As a result, a vicious cycle begins wherein hyperleptinaemia and leptin resistance occur, in turn leading to increased food intake and fat enlargement, which is followed by leptin overproduction. In addition, in the context of obesity, a defective thermoregulatory response is associated with impaired leptin signalling overall within the ventromedial nucleus of the hypothalamus. These recent findings highlight the role of leptin in the regulation of adaptive thermogenesis, thus suggesting leptin to be potentially considered as a new thermolipokine. This review provides new insight into the link between obesity, hyperleptinaemia, leptin resistance and leptin deficiency, focusing on the ability to restore leptin sensitiveness by way of enhanced thermogenic responses and highlighting novel anti-obesity therapeutic strategies.

Topics: Animals; Biomarkers; Body Temperature Regulation; Disease Management; Disease Susceptibility; Energy Metabolism; Humans; Hypothalamus; Leptin; Obesity; Signal Transduction; Thermogenesis; Treatment Outcome

Obesity is a global health problem that is associated with adverse consequences such as the development of metabolic disorders, including cardiovascular disease, neurodegenerative disorders, and type 2 diabetes. A major cause of obesity is metabolic imbalance, which results from insufficient physical activity and excess energy intake. Understanding the pathogenesis of obesity, as well as other metabolic disorders, is important in the development of methods for prevention and therapy. The coordination of energy balance takes place in the hypothalamus, a major brain region that maintains body homeostasis. The primary cilium is an organelle that has recently received attention because of its role in controlling energy balance in the hypothalamus. Defects in proteins required for ciliary function and formation, both in humans and in mice, have been shown to cause various metabolic disorders. In this review, we provide an overview of the critical functions of primary cilia, particularly in hypothalamic areas, and briefly summarize the studies on the primary roles of cilia in specific neurons relating to metabolic homeostasis.

Topics: Animals; Bardet-Biedl Syndrome; Cilia; Energy Metabolism; Homeostasis; Humans; Hypothalamus; Leptin; Metabolic Diseases; Mice; Neurons; Obesity; Proteins

Natural killer cells (NK cells) are a crucial constituent of the innate immune system as they mediate immunity against viruses, bacteria, parasites, and most importantly, tumor cells. The exact mechanism of how the innate immune system and specifically NK cells interact with cancer cells is complex and is yet to be understood. Several factors that constitute the tumor microenvironment (TME) such as hypoxia and TGF-

Topics: Adipokines; Adipose Tissue; Animals; Breast Neoplasms; Cytokines; Disease Models, Animal; Female; Humans; Immunity, Innate; Immunotherapy; Killer Cells, Natural; Leptin; Lymphocyte Activation; Obesity; Resistin; Tumor Microenvironment

Obesity is one of the foremost risk factors in coronavirus infection resulting in severe illness and mortality as the pandemic progresses. Obesity is a well-known predisposed chronic inflammatory condition. The dynamics of obesity and its impacts on immunity may change the disease severity of pneumonia, especially in acute respiratory distress syndrome, a primary cause of death from SARS-CoV-2 infection. The adipocytes of adipose tissue secret leptin in proportion to individuals' body fat mass. An increase in circulating plasma leptin is a typical characteristic of obesity and correlates with a leptin-resistant state. Leptin is considered a pleiotropic molecule regulating appetite and immunity. In immunity, leptin functions as a cytokine and coordinates the host's innate and adaptive responses by promoting the Th1 type of immune response. Leptin induced the proliferation and functions of antigen-presenting cells, monocytes, and T helper cells, subsequently influencing the pro-inflammatory cytokine secretion by these cells, such as TNF-α, IL-2, or IL-6. Leptin scarcity or resistance is linked with dysregulation of cytokine secretion leading to autoimmune disorders, inflammatory responses, and increased susceptibility towards infectious diseases. Therefore, leptin activity by leptin long-lasting super active antagonist's dysregulation in patients with obesity might contribute to high mortality rates in these patients during SARS-CoV-2 infection. This review systematically discusses the interplay mechanism between leptin and inflammatory cytokines and their contribution to the fatal outcomes in COVID-19 patients with obesity.

Topics: Adipocytes; Antigen-Presenting Cells; COVID-19; Cytokines; Disease Susceptibility; Humans; Leptin; Monocytes; Obesity; Risk Factors; SARS-CoV-2; Severity of Illness Index; Th1 Cells

Neural circuits in the hypothalamus play a key role in the regulation of human energy homeostasis. A critical circuit involves leptin-responsive neurons in the hypothalamic arcuate nucleus (the infundibular nucleus in humans) expressing the appetite-suppressing neuropeptide proopiomelanocortin (POMC) and the appetite-stimulating Agouti-related peptide. In the fed state, the POMC-derived melanocortin peptide α-melanocyte-stimulating hormone stimulates melanocortin-4 receptors (MC4Rs) expressed on second-order neurons in the paraventricular nucleus of the hypothalamus (PVN). Agonism of MC4R leads to reduced food intake and increased energy expenditure. Disruption of this hypothalamic circuit by inherited mutations in the genes encoding leptin, the leptin receptor, POMC, and MC4R can lead to severe obesity in humans. The characterization of these and closely related genetic obesity syndromes has informed our understanding of the neural pathways by which leptin regulates energy balance, neuroendocrine function, and the autonomic nervous system. A broader understanding of these neural and molecular mechanisms has paved the way for effective mechanism-based therapies for patients whose severe obesity is driven by disruption of these pathways.

Topics: Energy Metabolism; Humans; Hypothalamus; Leptin; Obesity; Pro-Opiomelanocortin; Receptor, Melanocortin, Type 4; Receptors, Leptin; Syndrome

Many approaches have been used in the effective management of type 2 diabetes mellitus. A recent paradigm shift has focused on the role of adipose tissues in the development and treatment of the disease. Brown adipose tissues (BAT) and white adipose tissues (WAT) are the two main types of adipose tissues with beige subsets more recently identified. They play key roles in communication and insulin sensitivity. However, WAT has been shown to contribute significantly to endocrine function. WAT produces hormones and cytokines, collectively called adipocytokines, such as leptin and adiponectin. These adipocytokines have been proven to vary in conditions, such as metabolic dysfunction, type 2 diabetes, or inflammation. The regulation of fat storage, energy metabolism, satiety, and insulin release are all features of adipose tissues. As such, they are indicators that may provide insights on the development of metabolic dysfunction or type 2 diabetes and can be considered routes for therapeutic considerations. The essential roles of adipocytokines vis-a-vis satiety, appetite, regulation of fat storage and energy, glucose tolerance, and insulin release, solidifies adipose tissue role in the development and pathogenesis of diabetes mellitus and the complications associated with the disease.

Topics: Adipokines; Adiponectin; Adipose Tissue; Adipose Tissue, Beige; Adipose Tissue, Brown; Adipose Tissue, White; Animals; Diabetes Complications; Diabetes Mellitus; Energy Metabolism; Humans; Insulin; Insulin Resistance; Leptin; Obesity

Adiponectin is an adipokine associated with the healthy obese phenotype. Adiponectin increases insulin sensitivity and has cardio and vascular protection actions. Studies related to adiponectin, a modulator of the innate and acquired immunity response, have suggested a role of this molecule in asthma. Studies based on various asthma animal models and on the key cells involved in the allergic response have provided important insights about this relation. Some of them indicated protection and others reversed the balance towards negative effects. Many of them described the cellular pathways activated by adiponectin, which are potentially beneficial for asthma prevention or for reduction in the risk of exacerbations. However, conclusive proofs about their efficiency still need to be provided. In this article, we will, briefly, present the general actions of adiponectin and the epidemiological studies supporting the relation with asthma. The main focus of the current review is on the mechanisms of adiponectin and the impact on the pathobiology of asthma. From this perspective, we will provide arguments for and against the positive influence of this molecule in asthma, also indicating the controversies and sketching out the potential directions of research to complete the picture.

Topics: Adipokines; Adiponectin; Asthma; Humans; Insulin Resistance; Leptin; Obesity

The escalating epidemic of overweight and obesity is currently recognized as one of the most significant health and economic concern worldwide. At the present time, over 1.9 billion adults and more than 600 million people can be, respectively, classified as overweight or obese, and numbers will continue to increase in the coming decades. This alarming scenario implies important clinical implications since excessive adiposity can progressively cause and/or exacerbate a wide spectrum of co-morbidities, including type 2 diabetes mellitus, hypertension, cardiovascular disease, and even certain types of cancer, including breast cancer. Indeed, pathological remodelling of white adipose tissue and increased levels of fat-specific cytokines (mainly leptin), as a consequence of the obesity condition, have been associated with several hallmarks of breast cancer, such as sustained proliferative signaling, cellular energetics, inflammation, angiogenesis, activating invasion and metastasis. Different preclinical and clinical data have provided evidence indicating that obesity may worsen the incidence, the severity, and the mortality of breast cancer. In the present review, we will discuss the epidemiological connection between obesity and breast cancer progression and metastasis and we will highlight the candidate players involved in this dangerous relationship. Since the major cause of death from cancer is due to widespread metastases, understanding these complex mechanisms will provide insights for establishing new therapeutic interventions to prevent/blunt the effects of obesity and thwart breast tumor progression and metastatic growth.

Topics: Biomarkers; Breast Neoplasms; Disease Progression; Epithelial-Mesenchymal Transition; Female; Humans; Leptin; Neoplasm Metastasis; Neoplasm Staging; Neovascularization, Pathologic; Obesity

Biochemical markers correlate positively with the development and severity of obesity, depression, and anxiety, and can be modulated by changes in intestinal microbiota composition.. A systematic review and meta-analysis was conducted to determine the effects of prebiotics or synbiotics on blood biomarkers of obesity, depression, and anxiety (including: ACTH [adrenocorticotropic hormone], cortisol, leptin, ghrelin, TSH [thyroid-stimulating hormone], PTH [parathyroid hormone], vitamin D, BDNF [brain-derived neurotrophic factor], and PCR [polymerase chain reaction]) in individuals with overweight or obesity.. MEDLINE, Web of Science, Scopus, and CENTRAL databases were searched, along with the reference lists of included articles. Authors were contacted for unpublished data.. RCT in individuals with overweight or obesity, supplemented with prebiotics or synbiotics, assessing any of the outcomes of interest.. Data were extracted independently by three researchers.. Thirteen studies were identified up to March 7, 2018. Regarding outcomes, 1 study assessed leptin, 4 studies assessed ghrelin, and 10 studies assessed CRP (C-reactive protein). Meta-analysis showed reduction in serum concentrations of ghrelin (-37.17 pg/mL; 95%CI = -69.62, -4.73; P = 0.025) and CRP (SMD [standardized mean difference] = -0.31; 95%CI = -0.58, -0.04; P = 0.027) after supplementation of inulin-type fructans.. Prebiotics may help regulate blood concentrations of ghrelin and CRP in overweight or obese individuals.

Topics: Adolescent; Adrenocorticotropic Hormone; Adult; Aged; Biomarkers; C-Reactive Protein; Gastrointestinal Microbiome; Ghrelin; Humans; Hydrocortisone; Leptin; Middle Aged; Obesity; Overweight; Prebiotics; Synbiotics; Vitamin D; Young Adult

Diet-induced hypothalamic inflammation, which leads to hypothalamic dysfunction and a loss of regulation of energy balance, is emerging as a potential driver of obesity. Excessive intake of long-chain saturated fatty acids is held to be the causative dietary component in hypothalamic inflammation. This review summarizes current evidence on the role of long-chain saturated fatty acids in promoting hypothalamic inflammation and the related induction of central insulin and leptin insensitivity. Particularly, the present review focuses on the molecular mechanisms linking long-chain saturated fatty acids and hypothalamic inflammation, emphasizing the metabolic fate of fatty acids and the resulting lipotoxicity, which is a key driver of hypothalamic dysfunction. In conclusion, long-chain saturated fatty acids are key nutrients that promote hypothalamic inflammation and dysfunction by fostering the build-up of lipotoxic lipid species, such as ceramide. Furthermore, when long-chain saturated fatty acids are consumed in combination with high levels of refined carbohydrates, the proinflammatory effects are exacerbated via a mechanism that relies on the formation of advanced glycation end products.

Topics: Animals; Diet, High-Fat; Dietary Fats; Energy Metabolism; Fatty Acids; Humans; Hypothalamus; Insulin; Insulin Resistance; Leptin; Obesity

Weight loss is traditionally viewed as straightforward counting of calories in and calories out, with little regard to the role of the adipocytes tasked with storing said calories. However, the body executes a complex compensatory response to any intervention that depletes its energy stores. Here, the authors discuss the methods used to attain weight loss, the body's response to this weight loss, and the difficulties in maintaining weight loss. Furthermore, the authors provide an overview of the literature on the physiological effects of liposuction.. To describe the role of adipose tissue in energy homeostasis, methods of weight loss, weight regain, and the effect of liposuction on endocrine signaling.. The authors conducted a narrative review of representative studies.. A variety of strategies for weight loss exist, and optimizing one's weight status may in turn optimize the aesthetic outcomes of liposuction. This is most apparent in the preferential reaccumulation of fat in certain areas after liposuction and the ability to avoid this with a negative energy balance.

Topics: Combined Modality Therapy; Diet, Healthy; Exercise Therapy; Humans; Leptin; Lipectomy; Lipid Metabolism; Obesity; Recurrence; Subcutaneous Fat; Treatment Outcome; Weight Gain; Weight Loss

Topics: Antidepressive Agents; Depressive Disorder, Major; Humans; Ketamine; Leptin; Obesity

Infertility is somewhat more prevalent in men who are obese. They are also reported to have low sperm concentration, higher fraction of spermatozoa that look morphologically abnormal, higher DNA fragmentation index and evidence of oxidative stress. The precise cause for this remains uncertain. Leptin levels in serum and percentage body fat correlate positively, and obese men therefore usually have elevated serum leptin levels. Although leptin is important for normal reproductive function, but when present in excess, leptin could seriously affect reproductive function in men. Reports on the findings of sperm parameters in obese men, particularly those who are subfertile or infertile, seem to be similar to those reported from studies on normal-weight rats treated with leptin. Collectively, the observations reported in human and experimental animal studies point to leptin as a possible link between infertility and obesity. Herein, we review some findings on sperm function in obese subfertile or infertile men and those from animal studies following leptin treatment, and discuss the possible link between leptin and reproductive dysfunction in obese men. The large amounts of leptin secreted by the adipose tissue and its higher circulating levels could indeed be responsible for the higher prevalence of infertility in obese men.

Topics: Animals; Disease Models, Animal; Humans; Infertility, Male; Leptin; Male; Obesity; Prevalence; Rats; Sperm Count; Sperm Motility

Animals that lack the hormone leptin become grossly obese, purportedly for 2 reasons: increased food intake and decreased energy expenditure (thermogenesis). This review examines the experimental evidence for the thermogenesis component. Analysis of the data available led us to conclude that the reports indicating hypometabolism in the leptin-deficient ob/ob mice (as well as in the leptin-receptor-deficient db/db mice and fa/fa rats) derive from a misleading calculation artefact resulting from expression of energy expenditure per gram of body weight and not per intact organism. Correspondingly, the body weight-reducing effects of leptin are not augmented by enhanced thermogenesis. Congruent with this, there is no evidence that the ob/ob mouse demonstrates atrophied brown adipose tissue or diminished levels of total UCP1 mRNA or protein when the ob mutation is studied on the inbred C57BL/6 mouse background, but a reduced sympathetic nerve activity is observed. On the outbred "Aston" mouse background, brown adipose tissue atrophy is seen, but whether this is of quantitative significance for the development of obesity has not been demonstrated. We conclude that leptin is not a thermogenic hormone. Rather, leptin has effects on body temperature regulation, by opposing torpor bouts and by shifting thermoregulatory thresholds. The central pathways behind these effects are largely unexplored.

Topics: Animals; Energy Metabolism; Humans; Leptin; Mice; Obesity; Rats; Thermogenesis

Numerous rodent studies have evaluated the effects of maternal stress (MS) on later in life susceptibility to Metabolic Syndrome (MetS) intermediate phenotypes with varying results. The aim of this study was to quantitatively synthesize the available data on the effects of MS on offspring obesity, estimated indirectly by body mass (BM), body fat (BF) and plasma leptin; systolic blood pressure (SBP); plasma glucose (and insulin) and blood lipid concentrations.. Literature was screened and summary estimates of the effect of MS outcomes were calculated by using random-effects models. Data on the effects of exogenous corticosteroid administration (or inhibition of 11β-HSD2) during pregnancy in rodents was analysed separately to characterize the direct phenotypic effects of prenatal corticosteroid excess (PCE).. We conducted 14 separate meta-analyses and synthesized relevant data on outcomes scarcely reported in literature. Both MS and PCE were associated with low birth weight without rapid catch-up growth resulting in decreased body mass later in life. Our analysis also revealed significant and contradictory effects on offspring adiposity. Little evidence was found for effects on glucose metabolism and blood lipids. We identified increased SBP in offspring exposed to PCE; however, there is not enough data to draw any conclusion about effects of MS on SBP.. Neonatal weight proved to be decreased in offspring prenatally exposed to stress or corticosteroids, but laboratory rodents in the absence of a challenging environment did not show catch-up growth. The available evidence is inconclusive regarding the effect on adiposity revealing clear methodological and knowledge gaps. This meta-analysis also confirmed a significant positive association between PCE and SBP. Nevertheless, additional studies should address the association with MS.

Topics: Adipose Tissue; Adiposity; Animals; Birth Weight; Blood Glucose; Blood Pressure; Body Mass Index; Body Weight; Female; Insulin; Leptin; Lipids; Metabolic Syndrome; Mice; Obesity; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Risk Factors; Rodentia; Stress, Psychological; Triglycerides

Obstructive sleep apnea (OSA), obesity, and disturbed glucose homeostasis are usually considered distinct clinical condition, although they are tightly related to each other. The aim of our manuscript is to provide an overview of the current evidence on OSA, obesity, and disturbed glucose homeostasis providing epidemiologic evidence, biological insights, and therapeutic strategies.. The mechanisms hypothesized to be involved in this complex interplay are the following: (1) "direct weight-dependent" mechanisms, according to which fat excess compromises respiratory mechanics, and (2) "indirect weight-dependent" mechanisms such as hyperglycemia, insulin resistance and secondary hyperinsulinemia, leptin resistance and other hormonal dysregulations frequently found in subjects with obesity, type 2 diabetes, and/or sleep disorders. Moreover, the treatment of each of these clinical conditions, through weight loss induced by diet or bariatric surgery, the use of anti-obesity or antidiabetic drugs, and continuous positive airway pressure (CPAP), seems to positively influence the others. These recent data suggest not only that there are multiple connections among these diseases but also that treating one of them may result in an improvement of the others.

Topics: Bariatric Surgery; Body Weight; Continuous Positive Airway Pressure; Diabetes Mellitus, Type 2; Diet; Glucose; Homeostasis; Humans; Hyperinsulinism; Insulin Resistance; Leptin; Obesity; Risk Factors; Sleep Apnea, Obstructive; Weight Loss

Low sperm concentration, increased fraction of morphologically abnormal sperm, and raised levels of markers of oxidative stress are often reported in the seminal plasma of infertile obese males. The precise reason for changes remains unknown. This short review summarises evidence from human and animal studies linking leptin to the reproductive dysfunction reported in obese males and presents a possible mechanism for this based on the available data in the literature. Serum leptin concentrations correlate positively with body fat mass but its precise link to semen abnormalities reported in obese males has yet to be conclusively established. Decreased sperm concentration, increased fraction of morphologically abnormal sperm and increased markers of oxidative stress have been reported following six weeks of daily leptin treatment to normal weight rats. In addition, decreased expression of endogenous antioxidant enzymes and increased expression of respiratory chain enzymes noted in the testes of leptin treated rats increases the propensity to oxidative stress. Besides that, leptin's interference with histone to protamine transition in the DNA of sperm increases the susceptibility of sperm to free radical attack and may explain the often reported higher DNA fragmentation index in sperm of obese males. Concurrent supplementation of melatonin, a natural anti-oxidant, to these rats prevents the effects of leptin. The role of leptin in obesity-related reproductive dysfunction has to be considered seriously and these effects of leptin might involve increased oxidative stress.

Topics: Animals; Humans; Infertility, Male; Leptin; Male; Obesity; Reproduction

Vitamin D deficiency has become an increasing focus of clinical interest, especially in understanding its associations with obesity in adults. The pathological associations linking the two appear to demonstrate complex cellular inflammatory, hormonal and genetic pathways. Enhanced understanding at both microcellular and clinical levels will help clarify the role of obesity in the development of vitamin D deficiency.

Topics: Adiponectin; Adipose Tissue; Cytokines; Humans; Leptin; Obesity; Vitamin D Deficiency

Throughout the animal kingdom sucrose is one of the most palatable and preferred tastants. From an evolutionary perspective, this is not surprising as it is a primary source of energy. However, its overconsumption can result in obesity and an associated cornucopia of maladies, including type 2 diabetes and cardiovascular disease. Here we describe three physiological levels of processing sucrose that are involved in the decision to ingest it: the tongue, gut, and brain. The first section describes the peripheral cellular and molecular mechanisms of sweet taste identification that project to higher brain centers. We argue that stimulation of the tongue with sucrose triggers the formation of three distinct pathways that convey sensory attributes about its quality, palatability, and intensity that results in a perception of sweet taste. We also discuss the coding of sucrose throughout the gustatory pathway. The second section reviews how sucrose, and other palatable foods, interact with the gut-brain axis either through the hepatoportal system and/or vagal pathways in a manner that encodes both the rewarding and of nutritional value of foods. The third section reviews the homeostatic, hedonic, and aversive brain circuits involved in the control of food intake. Finally, we discuss evidence that overconsumption of sugars (or high fat diets) blunts taste perception, the post-ingestive nutritional reward value, and the circuits that control feeding in a manner that can lead to the development of obesity.

Topics: Animals; Brain; Humans; Leptin; Neurons; Nutritive Value; Obesity; Receptors, G-Protein-Coupled; Sugars; Taste

Leptin is a hormone released by adipose tissue that plays a key role in the control of energy homeostasis through its binding to leptin receptors (LepR), mainly expressed in the hypothalamus. Most scientific evidence points to leptin's satiating effect being due to its dual capacity to promote the expression of anorexigenic neuropeptides and to reduce orexigenic expression in the hypothalamus. However, it has also been demonstrated that leptin can stimulate (i) thermogenesis in brown adipose tissue (BAT) and (ii) the browning of white adipose tissue (WAT). Since the demonstration of the importance of BAT in humans 10 years ago, its study has aroused great interest, mainly in the improvement of obesity-associated metabolic disorders through the induction of thermogenesis. Consequently, several strategies targeting BAT activation (mainly in rodent models) have demonstrated great potential to improve hyperlipidemias, hepatic steatosis, insulin resistance and weight gain, leading to an overall healthier metabolic profile. Here, we review the potential therapeutic ability of leptin to correct obesity and other metabolic disorders, not only through its satiating effect, but by also utilizing its thermogenic properties.

Topics: Adipose Tissue, Brown; Adipose Tissue, White; Animals; Energy Metabolism; Humans; Hypothalamus; Leptin; Obesity; Receptors, Leptin; Satiation; Thermogenesis

Metabolic syndrome (MetS) has been associated with osteoarthritis (OA). Leptin, which is one of the markers of MetS, has been associated with OA pathophysiology. This study aimed to provide an update on the association between MetS and OA and on the potential role of leptin in OA. In this review, we summarized the current knowledge of the association between MetS and OA and updated the evidence on the potential role of leptin in OA. Clinical studies have investigated the epidemiologic association between MetS or its components and OA. Results suggested strong epidemiologic associations between MetS and OA, especially in the Asian population. Animal studies also indicated that metabolic dysregulation may lead to OA pathogenesis. The systemic role of MetS in OA pathophysiology is associated with obesity-related inflammation, the beneficial role of n-3 polyunsaturated fatty acids and deleterious role of cholesterol, physical inactivity, hypertension-induced subchondral ischemia, dyslipidemia-induced ectopic lipid deposition in chondrocytes, hyperglycemia-induced local effects of oxidative stress and advanced glycation end-products, low-grade systemic inflammation, and obesity-related adipokines by inducing the expression of proinflammtory factors. Leptin levels in serum/plasma and synovial fluid were associated with joint pain, radiographic progression, bone formation biomarkers, cartilage volume, knee OA incidence, and total joint arthroplasty in OA patients. Elevated leptin expression and increased effect of leptin on infrapatellar fat pad, synovium, articular cartilage, and bone were also involved in the pathogenesis of OA. Current knowledge indicates a convincing epidemiologic association between MetS and OA, especially in the Asian population. Animal studies have also shown that metabolic dysregulation may lead to OA pathogenesis. Accumulating evidence suggests that leptin may play a potential role in OA pathogenesis. Therefore, leptin and its receptor may be an emerging target for intervention in metabolic-associated OA.

Topics: Adipokines; Animals; Chondrocytes; Humans; Inflammation; Leptin; Metabolic Syndrome; Obesity; Osteoarthritis

Obesity increases sympathetic nerve activity (SNA) in men, but not women. Here, we review current evidence suggesting that sexually dimorphic sympathoexcitatory responses to leptin and insulin may contribute. More specifically, while insulin increases SNA similarly in lean males and females, this response is markedly amplified in obese males, but is abolished in obese females. In lean female rats, leptin increases a subset of sympathetic nerves only during the high estrogen proestrus reproductive phase; thus, in obese females, because reproductive cycling can become impaired, the sporadic nature of leptin-induced sympathoexcitaton could minimize its action, despite elevated leptin levels. In contrast, in males, obesity preserves or enhances the central sympathoexcitatory response to leptin, and current evidence favors leptin's contribution to the well-established increases in SNA induced by obesity in men. Leptin and insulin increase SNA via receptor binding in the hypothalamic arcuate nucleus and a neuropathway that includes arcuate neuropeptide Y (NPY) and proopiomelanocortin (POMC) projections to the paraventricular nucleus. These metabolic hormones normally suppress sympathoinhibitory NPY neurons and activate sympathoexcitatory POMC neurons. However, obesity appears to alter the ongoing activity and responsiveness of arcuate NPY and POMC neurons in a sexually dimorphic way, such that SNA increases in males but not females. We propose hypotheses to explain these sex differences and suggest areas of future research.

Topics: Animals; Female; Humans; Hypothalamus; Insulin; Leptin; Male; Neurons; Neuropeptide Y; Obesity; Pro-Opiomelanocortin; Sex Characteristics; Sympathetic Nervous System

Several studies suggest a strong association between leptin, obesity, and infertility with respect to the hypothalamic-pituitary-gonadal (HPG) axis, androgen regulation, and sperm production, but the direct mechanistic association between these is still largely unexplored. This review focuses on understanding the association between leptin, obesity, and male infertility.. Obesity is linked to fertility dysfunction in both genders. Obesity in men may affect their fertility by impaired spermatogenesis, reduced testosterone levels, erectile dysfunction, and poor libido by putatively targeting the HPG and hypothalamic-pituitary-adrenal axes. Leptin plays key roles in many metabolic functions, including reproduction. High concentrations of leptin have been found in infertile men with disorders affecting the testicular parenchyma, including nonobstructive azoospermia, oligozoospermia, and oligo-astheno-teratozoospermia. Additionally, serum leptin levels have negative associations with serum testosterone levels and sperm parameters and positive associations with serum follicle-stimulating hormone and luteinizing hormone levels and abnormal sperm morphology.. Excessive leptin production may be a significant contributor to the development of androgen insufficiency and reduced reproductive function in obese men. Understanding the relation between leptin, obesity, and reproduction may shed light on future targeted treatments for male infertility.

Topics: Body Mass Index; Female; Humans; Hypothalamo-Hypophyseal System; Infertility, Male; Leptin; Male; Obesity

Epidemiological evidence indicates the presence of dysregulated homeostatic biological pathways in depressed patients, such as increased inflammation and disrupted energy-regulating neuroendocrine signaling (e.g., leptin, insulin). Alterations in these biological pathways may explain the considerable comorbidity between depression and cardiometabolic conditions (e.g., obesity, metabolic syndrome, diabetes) and represent a promising target for intervention. This review describes how immunometabolic dysregulations vary as a function of depression heterogeneity by illustrating that such biological dysregulations map more consistently to atypical behavioral symptoms reflecting altered energy intake/expenditure balance (hyperphagia, weight gain, hypersomnia, fatigue, and leaden paralysis) and may moderate the antidepressant effects of standard or novel (e.g., anti-inflammatory) therapeutic approaches. These lines of evidence are integrated in a conceptual model of immunometabolic depression emerging from the clustering of immunometabolic biological dysregulations and specific behavioral symptoms. The review finally elicits questions to be answered by future research and describes how the immunometabolic depression dimension could be used to dissect the heterogeneity of depression and potentially to match subgroups of patients to specific treatments with higher likelihood of clinical success.

Topics: Depression; Humans; Leptin; Metabolic Syndrome; Obesity; Weight Gain

Different adipokines secreted from adipose tissue, exert a range of physiological effects. The aim of present systematic review and meta-analysis was to critically investigate the consequence of bariatric surgery on circulating adipokines, that is, adiponectin, leptin, visfatin, resistin, plasminogen activator inhibitor, and chemerin. After systematically checking the following electronic databases: ISI web of Science, Scopus and PubMed without limitation in time and language up to February 2019, a pool based on a random effect model was established. Eighty-five eligible studies were entered for quantitative analysis. Our meta-analysis revealed that circulating adiponectin increased significantly after bariatric surgery [Standardized mean difference (SMD)=1.401, 95% CI: 1.101, 1.701, p<0.001]; whilst leptin (SMD=-2.178, 95% CI: -2.433, -1.923, p<0.001), PAI-1 (-14.928 ng/ml 95% CI: -21.794, -8.063, p<0.001), and chemerin (-50.238 ng/ml 95% CI: -85.708, -14.768, p<0.001) decreased. However, serum visfatin (2.05 ng/ml, 95% CI: -5.07, 9.17, p=0.573) and resistin (-2.080 ng/ml, 95% CI: -5.352, 1.192, p=0.21) were unchanged. In conclusion, bariatric surgery is associated with a reduction in specific adipokines including leptin, chemerin, and PAI-1, whereas adiponectin is raised, adaptations that could be indicative of improved fat mass and function.

Topics: Adiponectin; Adipose Tissue; Bariatric Surgery; Chemokines; Cytokines; Diabetes Mellitus, Type 2; Humans; Leptin; Nicotinamide Phosphoribosyltransferase; Obesity; Organ Size; Plasminogen Activator Inhibitor 1; Postoperative Period; Resistin; Weight Loss

The epidemic of obesity has become pandemic, putting a significant burden on the world's healthcare system. While the heritability of the disease is high, all the identified genetic variants associated to obesity account for a very small percentage of phenotypic variation. The origins of the obesity pandemic cannot be explained exclusively due to genetic factors. In recent years, epigenetic studies have offered valuable information for a deeper understanding of the steep increase in global obesity rates. Existing evidence indicate that environmental exposures induce alterations to the epigenome, leading to the transmission of obesity risk across generations. In this review, we provide insight into the epigenetic disturbances associated with obesity and discuss the impact of harmful diets, particularly calorie-dense foods, in the epigenetic regulation of obesity. The epigenetics of obesity is an expanding area of research, and current reports suggest potential in the use of epigenetic mechanisms as clinical biomarkers and therapeutic candidates.

Topics: Diabetes Mellitus, Type 2; Diet; DNA Methylation; Epigenesis, Genetic; Genetic Predisposition to Disease; Humans; Leptin; Obesity; Pro-Opiomelanocortin; Receptor, Melanocortin, Type 4

Obstructive sleep apnea (OSA), characterized by recurrent episodes of apnea during sleep and daytime sleepiness, seriously affects human health and may lead to systemic organ dysfunction. The pathogenesis of OSA is complex and still uncertain, but multiple surveys have shown that obesity is an important factor, and the incidence of OSA in people with obesity is as high as 30%. Adipokines are a group of proteins secreted from adipocytes, which are dysregulated in obesity and may contribute to OSA. Here, we review the most important and representative research results regarding the correlation between obesity-related adipokines including leptin, adiponectin, omentin-1, chemerin, and resistin and OSA in the past 5 years, provide an overview of these key adipokines, and analyze possible intrinsic mechanisms and influencing factors. The existing research shows that OSA is associated with an increase in the serum levels of leptin, chemerin, and resistin and a decrease in the levels of adiponectin and omentin-1; the findings presented here can be used to monitor the development of OSA and obesity, prevent future comorbidities, and identify risk factors for cardiovascular and other diseases, while different adipokines can be linked to OSA through different pathways such as insulin resistance, intermittent hypoxia, and inflammation, among others. We hope our review leads to a deeper and more comprehensive understanding of OSA based on the relevant literature, which will also provide directions for future clinical research.

Topics: Adipokines; Adiponectin; Chemokines; Cytokines; GPI-Linked Proteins; Humans; Lectins; Leptin; Obesity; Resistin; Risk Factors; Sleep Apnea, Obstructive

Hyperinsulinemia and insulin resistance were proposed more than 30 years ago to be important contributors to elevated blood pressure (BP) associated with obesity and the metabolic syndrome, also called syndrome X. Support for this concept initially came from clinical and population studies showing correlations among hyperinsulinemia, insulin resistance, and elevated BP in individuals with metabolic syndrome. Short-term studies in experimental animals and in humans provided additional evidence that hyperinsulinemia may evoke increases in sympathetic nervous system (SNS) activity and renal sodium retention that, if sustained, could increase BP. Although insulin infusions may increase SNS activity and modestly raise BP in rodents, chronic insulin administration does not significantly increase BP in lean or obese insulin-resistant rabbits, dogs, horses, or humans. Multiple studies in humans and experimental animals have also shown that severe insulin resistance and hyperinsulinemia may occur in the absence of elevated BP. These observations question whether insulin resistance and hyperinsulinemia are major factors linking obesity/metabolic syndrome with hypertension. Other mechanisms, such as physical compression of the kidneys, activation of the renin-angiotensin-aldosterone system, hyperleptinemia, stimulation of the brain melanocortin system, and SNS activation, appear to play a more critical role in initiating hypertension in obese subjects with metabolic syndrome. However, the metabolic effects of insulin resistance, including hyperglycemia and dyslipidemia, appear to interact synergistically with increased BP to cause vascular and kidney injury that can exacerbate the hypertension and associated injury to the kidneys and cardiovascular system.

Topics: Animals; Humans; Hyperinsulinism; Hypertension; Insulin Resistance; Kidney; Leptin; Metabolic Syndrome; Obesity; Renin-Angiotensin System; Sodium; Sympathetic Nervous System

Leptin-based obesity pharmacotherapies were originally developed according to the lipostatic view that elevated circulating leptin levels promote a negative energy balance. A series of independent preclinical findings suggest, however, that a partial reduction in circulating leptin levels (either by immunoneutralization, a peripherally restricted CB1 receptor inverse agonist, or bariatric surgery) can paradoxically lead to weight loss.

Topics: Animals; Antibodies, Neutralizing; Bariatric Surgery; Cannabinoid Receptor Agonists; Leptin; Obesity; Receptor, Cannabinoid, CB1

Leptin and adiponectin are two adipokines. Their circulating concentrations, high for leptin and low for adiponectin, are predictive of insulin resistance and of an unfavorable cardiometabolic evolution in patients with obesity, metabolic syndrome or type 2 diabetes. In addition, recently, the adiponectin/leptin ratio has been proposed as an index of adipose tissue dysfunction together with threshold values for cardiometabolic risk for this index. The relevance and potential applications of the adiponectin/leptin and leptin/adiponectin ratios are discussed in the light of recent literature in this brief update.

Topics: Adiponectin; Biomarkers; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Diagnostic Techniques, Endocrine; Humans; Insulin Resistance; Leptin; Metabolic Syndrome; Obesity; Prognosis; Risk Factors

Recently, some studies claim that adipokines may modulate plasma lipids. More interestingly, the ADRB3 Trp64Arg polymorphism may regulate adipokines and play an essential role in lipids metabolism. This study aims to clarify the associations of ADRB3 Trp64Arg polymorphism with plasma adipokines and lipid levels.. Twenty-two studies (5527 subjects) and 121 studies (54,059 subjects) were respectively identified for the association analyses of adipokines and lipids. Standardized mean difference (SMD) and 95% confidence interval (CI) were used to estimate the strength of the Trp64Arg variant in adipokines and plasma lipids. All results were recalculated after eliminating the studies with heterogeneity.. The carriers of the C allele (Arg at 64th position was encoded by the C allele) had higher levels of leptin and lower levels of adiponectin than the non-carriers. The carriers of the C allele had higher levels of triglycerides (TG), total cholesterol (TC), and lower levels of high-density lipoprotein cholesterol (HDL-C) than the non-carriers. Subgroup analysis certified an ethnicity (Asians), disease status (obesity), and gender (females) specific association. Sensitivity analysis indicated that the analysis results were robust and stable. Meta-regression indicated that obesity was related to adiponectin.. The C allele carriers of Trp64Arg polymorphism had a slight but significant influence on lipid levels, and the remarkable effects specific existed in obese Asian women. The associations of Trp64Arg polymorphism with dyslipidemia may partly be mediated by the effect of this polymorphism on adipokines. The association of Trp64Arg polymorphism with obesity may partly be mediated by the effect of this polymorphism on adipokines. The C allele carriers had abnormal levels of adipokines and lipids, and it indicated that the Trp64Arg polymorphism might represent a genetic risk factor for coronary artery disease (CAD).

Topics: Adiponectin; Cholesterol; Cholesterol, HDL; Dyslipidemias; Female; Gene Expression Regulation; Genetic Predisposition to Disease; Humans; Leptin; Lipids; Male; Obesity; Polymorphism, Single Nucleotide; Receptors, Adrenergic, beta-3; Sex Factors; Triglycerides

The body composition and fat distribution is different between men and women, with different levels of circulating adipokines. These differences become more evident when suffering from an inflammatory disease, such as spondyloarthritris. In this review, we will explore the influence of obesity, body composition and adipokines on the differences in disease activity, progression and response to treatment, between men and women with spondyloarthritis.. Obesity, mainly determined by the body fat content, which is higher in women, is related to worse disease activity scores. Men with higher disease activity lose more muscle mass than women. Leptin, which is usually found at higher levels in overweight women, seems to be associated with greater spinal radiographic progression when it rises during the course of the disease. Being a woman and obesity, mainly because of the body fat content, are related to a worse response to TNF-α blockers.. Overlooking biological sex variation in body composition, circulating adipokines and hormonal levels, and the subsequent differences in clinical presentation, may ultimately hamper clinical treatment.

Topics: Adipokines; Adipose Tissue; Body Composition; Body Fat Distribution; Body Mass Index; Disease Progression; Female; Humans; Leptin; Male; Obesity; Severity of Illness Index; Sex Factors; Spondylarthritis

Epidemiological data from the last decades point to an exponential growth in the number of obese people. Different behavioral factors, mainly associated with food consumption, appear to contribute significantly to its development. Concomitant with increased obesity rates, an increase in the consumption of fructose has been observed; therefore, fructose consumption has been implicated as an important obesogenic factor. However, changes in brain activity due to fructose consumption are possible, especially in relation to hypothalamic satiety mechanisms. In addition, the obese state may provide an environment of chronic inflammation and further contribute to the discontinuation of satiety mechanisms in the hypothalamus. We briefly review the intrinsic alterations to the increased adipose tissue, its connections with the hypothalamus in the control of energy signaling mechanisms and, consequently, the participation of fructose as a co-adjuvant or trigger. Presenting the current context with clinical trials involving human and animal studies, we seek to contribute to a better understanding of the role of fructose in the progression of obesity.

Topics: Animals; Energy Metabolism; Fructose; Humans; Hypothalamus; Leptin; Obesity

The identification of leptin allowed the discovery of a new endocrine system. This major adipokine controlling energy homeostasis is also involved in the regulation of neuroendocrine function and fertility. Unfortunately, leptin is not able to treat common obesity, which associates hyperleptinemia and resistance to the hormone. Conversely, treatment with recombinant leptin is effective in situations of leptin deficiency. Several pathophysiological situations associated with adipose tissue dysfunctions and abnormal regulation of leptin secretion are discussed in this review. The advantage of the potential use of the leptin assay in some pathophysiological conditions is proposed.

Topics: Adipokines; Adipose Tissue; Animals; Homeostasis; Humans; Leptin; Obesity; Secretory Pathway

Leptin is a hormone that plays a major role as mediator of long-term regulation of energy balance, suppressing food intake, and stimulating weight loss. More recently, important physiological roles other than controlling appetite and energy expenditure have been suggested for leptin, including neuroendocrine, reparative, reproductive, and immune functions. These emerging peripheral roles let hypothesize that leptin can modulate also cancer progression. Indeed, many studies have demonstrated that elevated chronic serum concentrations of leptin, frequently seen in obese subjects, represent a stimulatory signal for tumor growth. Current knowledge indicates that also different non-tumoral cells resident in tumor microenvironment may respond to leptin creating a favorable soil for cancer cells. In addition, leptin is produced also within the tumor microenvironment creating the possibility for paracrine and autocrine action. In this review, we describe the main mechanisms that regulate peripheral leptin availability and how leptin can shape tumor microenvironment.

Topics: Animals; Energy Metabolism; Humans; Leptin; Neoplasms; Obesity; Tumor Microenvironment

Leptin is highly expressed in the placenta, mainly by trophoblastic cells, where it has an important autocrine trophic effect. Moreover, increased leptin levels are found in the most frequent pathology of pregnancy: gestational diabetes, where leptin may mediate the increased size of the placenta and the fetus, which becomes macrosomic. In fact, leptin mediates the increased protein synthesis, as observed in trophoblasts from gestational diabetic subjects. In addition, leptin seems to facilitate nutrients transport to the fetus in gestational diabetes by increasing the expression of the glycerol transporter aquaporin-9. The high plasma leptin levels found in gestational diabetes may be potentiated by leptin resistance at a central level, and obesity-associated inflammation plays a role in this leptin resistance. Therefore, the importance of anti-inflammatory nutrients to modify the pathology of pregnancy is clear. In fact, nutritional intervention is the first-line approach for the treatment of gestational diabetes mellitus. However, more nutritional intervention studies with nutraceuticals, such as polyphenols or polyunsaturated fatty acids, or nutritional supplementation with micronutrients or probiotics in pregnant women, are needed in order to achieve a high level of evidence. In this context, the Mediterranean diet has been recently found to reduce the risk of gestational diabetes in a multicenter randomized trial. This review will focus on the impact of maternal obesity on placental inflammation and nutrients transport, considering the mechanisms by which leptin may influence maternal and fetal health in this setting, as well as its role in pregnancy pathologies.

Topics: Anti-Inflammatory Agents; Diabetes, Gestational; Diet, Mediterranean; Female; Fetal Macrosomia; Humans; Leptin; Nutrition Therapy; Nutritional Status; Obesity; Placenta; Pregnancy; Pregnancy Complications; Trophoblasts

Overweight and obesity are major risk factors for diabetes, cardiovascular disease, and lung disease. These diseases are the most commonly reported health conditions that predispose individuals with SARS-CoV-2 infection to require hospitalization including intensive care unit admissions. The innate immune response is the host's first line of defense against a human coronavirus infection. However, most coronaviruses are armed with one strategy or another to overcome host antiviral defense, and the pathogenicity of the virus is related to its capacity to suppress host immunity. The multifaceted nature of obesity including its effects on immunity can fundamentally alter the pathogenesis of acute respiratory distress syndrome and pneumonia, which are the major causes of death due to SARS-CoV-2 infection. Elevated circulating leptin concentrations are a hallmark of obesity, which is associated with a leptin-resistant state. Leptin is secreted by adipocytes in proportion to body fat and regulates appetite and metabolism through signaling in the hypothalamus. However, leptin also signals through the Jak/STAT and Akt pathways, among others, to modulate T cell number and function. Thus, leptin connects metabolism with the immune response. Therefore, it seems appropriate that its dysregulation would have serious consequences during an infection. We propose that leptin may be the link between obesity and its high prevalence as a comorbidity of the SARS-CoV-2 infection. In this article, we present a synthesis of the mechanisms underpinning susceptibility to respiratory viral infections and the contribution of the immunomodulatory effects of obesity to the outcome.

Topics: Betacoronavirus; Comorbidity; Coronavirus Infections; COVID-19; Host-Pathogen Interactions; Humans; Leptin; Obesity; Pandemics; Pneumonia, Viral; SARS-CoV-2; Signal Transduction

The adipocyte-derived adipokine leptin exerts pleiotropic effects, which are essential for the regulation of energy balance and cell metabolism, for controlling inflammatory and immune responses, and for the maintenance of homeostasis of the cardiovascular system. Leptin resistance in obese or type 2 diabetes mellitus (T2DM) patients is defined as a decrease in tissue response to leptin. In the cardiovascular system, leptin resistance exhibits the adverse effect on the heart's response to stress conditions and promoting cardiac remodeling due to impaired cardiac metabolism, increased fibrosis, vascular dysfunction, and enhanced inflammation. Leptin resistance or leptin signaling deficiency results in the risk increase of cardiac dysfunction and heart failure, which is a leading cause of obesity- and T2DM-related morbidity and mortality. Animal studies using leptin- and leptin receptor- (Lepr) deficient rodents have provided many useful insights into the underlying molecular and pathophysiological mechanisms of obese- and T2DM-associated metabolic and cardiovascular diseases. However, none of the animal models used so far can fully recapitulate the phenotypes of patients with obese or T2DM. Therefore, the role of leptin in the human cardiovascular system, and whether leptin affects cardiac function directly or acts through a leptin-regulated neurohumoral pathway, remain elusive. As the prevalence of obesity and diabetes is continuously increasing, strategies are needed to develop and apply human cell-based models to better understand the precise role of leptin directly in different cardiac cell types and to overcome the existing translational barriers. The purpose of this review is to discuss the mechanisms associated with leptin signaling deficiency or leptin resistance in the development of metabolic and cardiovascular diseases. We analyzed and comprehensively addressed substantial findings in pathophysiological mechanisms in commonly used leptin- or Lepr-deficient rodent models and highlighted the differences between rodents and humans. This may open up new strategies to develop directly and reliably applicable models, which resemble the human pathophysiology in order to advance health care management of obesity- and T2DM-related cardiovascular complications.

Topics: Animals; Cardiovascular Diseases; Humans; Leptin; Obesity

Inflammation is an essential immune response for the maintenance of tissue homeostasis. In a general sense, acute and chronic inflammation are different types of adaptive response that are called into action when other homeostatic mechanisms are insufficient. Although considerable progress has been made in understanding the cellular and molecular events that are involved in the acute inflammatory response to infection and tissue injury, the causes and mechanisms of systemic chronic inflammation are much less known. The pathogenic capacity of this type of inflammation is puzzling and represents a common link of the multifactorial diseases, such as cardiovascular diseases and type 2 diabetes. In recent years, interest has been raised by the discovery of novel mediators of inflammation, such as microRNAs and adipokines, with different effects on target tissues. In the present review, we discuss the data emerged from research of leptin in obesity as an inflammatory mediator sustaining multifactorial diseases and how this knowledge could be instrumental in the design of leptin-based manipulation strategies to help restoration of abnormal immune responses. On the other direction, chronic inflammation, either from autoimmune or infectious diseases, or impaired microbiota (dysbiosis) may impair the leptin response inducing resistance to the weight control, and therefore it may be a cause of obesity. Thus, we are reviewing the published data regarding the role of leptin in inflammation, and the other way around, the role of inflammation on the development of leptin resistance and obesity.

Topics: Adaptive Immunity; Animals; Autoimmune Diseases; Communicable Diseases; Humans; Immunity, Innate; Leptin; Obesity

Leptin is a hormone discovered almost 30 years ago with important implications in metabolism. It is primarily produced by white adipose tissue (WAT) in proportion to the amount of fat. The discovery of leptin was a turning point for two principle reasons: on one hand, it generated promising expectations for the treatment of the obesity, and on the other, it changed the classical concept that white adipose tissue was simply an inert storage organ. Thus, adipocytes in WAT produce the majority of leptin and, although its primary role is the regulation of fat stores by controlling lipolysis and lipogenesis, this hormone also has implications in other physiological processes within WAT, such as apoptosis, browning and inflammation. Although a massive number of questions related to leptin actions have been answered, the necessity for further clarification facilitates constantly renewing interest in this hormone and its pathways. In this review, leptin actions in white adipose tissue will be summarized in the context of obesity.

Topics: Adipocytes; Adipose Tissue, Brown; Adipose Tissue, White; Animals; Apoptosis; Cytokines; Gene Expression Regulation; Glucose; Humans; Insulin; Leptin; Lipogenesis; Lipolysis; Obesity; Receptors, Leptin; Signal Transduction; Thyroid Hormones

The adipokine leptin is expressed at higher concentrations in obese subjects, who also incidentally have a higher prevalence of hypertension. The pathogenesis of this obesity-related hypertension is controversial and is believed to be related to many factors including increased sympathetic activity, abnormalities of the renin-angiotensin system, sodium retention, and an endotheliopathy acting independently or in concert with increased circulating leptin. This review discusses the potential mechanisms through which changes in leptin signal transduction pathways in tissues with the leptin receptor, especially the hypothalamus, mediate the pathogenetic relationships between obesity and hypertension. The hypothesis is explored that leptin effects on blood pressure (BP) are meditated by the downstream effects of hypothalamic leptin signaling and ultimately result in activation of specific melanocortin receptors located on sympathetic neurons in the spinal cord. The physiological consequences of this sympathetic activation of the heart and kidney are activation of the renin-angiotensin system, sodium retention and circulatory expansion and finally, elevated BP. This sequence of events has been elegantly demonstrated with leptin infusion and gene knockout studies in animal models but has not been convincingly reproducibly confirmed in humans. Further studies in human subjects on the specific roles of hypothalamic leptin in essential hypertension are indicated as elucidation of the signaling pathways should provide better understanding of the role of weight loss in BP control and afford an additional mechanism for pharmacologic control of BP in adults and children at risk of cardiovascular disease.

Topics: Animals; Gene Deletion; Genotype; Humans; Hypertension; Hypothalamus; Kidney; Leptin; Mice; Obesity; Pro-Opiomelanocortin; Promoter Regions, Genetic; Signal Transduction; Spinal Cord; Sympathetic Nervous System

Obesity is a global epidemic in developed countries accounting for many of the metabolic and cardiorespiratory morbidities that occur in adults. These morbidities include type 2 diabetes, sleep-disordered breathing (SDB), obstructive sleep apnea, chronic intermittent hypoxia, and hypertension. Leptin, produced by adipocytes, is a master regulator of metabolism and of many other biological functions including central and peripheral circuits that control breathing. By binding to receptors on cells and neurons in the brainstem, hypothalamus, and carotid body, leptin links energy and metabolism to breathing. In this comprehensive article, we review the central and peripheral locations of leptin's actions that affect cardiorespiratory responses during health and disease, with a particular focus on obesity, SDB, and its effects during early development. Obesity-induced hyperleptinemia is associated with centrally mediated hypoventilation with decrease CO

Topics: Adiponectin; Animals; Humans; Leptin; Metabolism, Inborn Errors; Obesity; Sleep Apnea Syndromes; Sleep Apnea, Obstructive

Obesity is a complex, multifactorial disorder. About 5% of obese patients actually present with a monogenic form of obesity where only one mutation is sufficient to cause the disease. So far, the genes that have been found to be mutated in these monogenic forms play a key role in the leptin/melanocortin pathway which is mainly active in the hypothalamus and which regulates food intake and energy expenditure. Our laboratory has recently reported a novel monogenic form of obesity due to MRAP2 deficiency where, contrary to previously described monogenic forms of obesity, the carriers presented with hyperglycemia and hypertension in addition to obesity, suggesting that MRAP2 might play a pleiotropic role in metabolic tissues, in addition to its role in brain control of food intake and energy expenditure.. Du nouveau dans la génétique des formes monogéniques d’obésité et son impact pour mieux en comprendre la physiopathologie.. L’obésité est une maladie complexe multifactorielle. Chez environ 5 % des individus obèses, il existe des formes monogéniques d’obésité pour laquelle une seule mutation est suffisante pour entraîner la maladie. Jusqu’à présent, les gènes mutés identifiés dans ces formes monogéniques sont impliqués dans la voie leptine/mélanocortine, principalement active au niveau de l’hypothalamus et régissant la satiété. Récemment, notre laboratoire a décrit une nouvelle forme monogénique d’obésité. Elle est due à une déficience du gène MRAP2 (melanocortin-2 receptor accessory protein 2) pour laquelle, contrairement aux formes précédemment décrites, on retrouve chez les porteurs une hyperglycémie et une hypertension, suggérant que MRAP2 joue un rôle biologique général dans les tissus métaboliques en plus de son rôle dans l’hypothalamus.

Topics: Animals; Appetite Regulation; Genetic Predisposition to Disease; Humans; Leptin; Mutation; Obesity; Precision Medicine; Pro-Opiomelanocortin; Receptor, Melanocortin, Type 4; Receptors, Leptin

Adipose tissue is a highly dynamic endocrine tissue and constitutes a central node in the interorgan crosstalk network through adipokines, which cause pleiotropic effects, including the modulation of angiogenesis, metabolism, and inflammation. Specifically, digestive cancers grow anatomically near adipose tissue. During their interaction with cancer cells, adipocytes are reprogrammed into cancer-associated adipocytes and secrete adipokines to affect tumor cells. Moreover, the liver is the central metabolic hub. Adipose tissue and the liver cooperatively regulate whole-body energy homeostasis via adipokines. Obesity, the excessive accumulation of adipose tissue due to hyperplasia and hypertrophy, is currently considered a global epidemic and is related to low-grade systemic inflammation characterized by altered adipokine regulation. Obesity-related digestive diseases, including gastroesophageal reflux disease, Barrett's esophagus, esophageal cancer, colon polyps and cancer, non-alcoholic fatty liver disease, viral hepatitis-related diseases, cholelithiasis, gallbladder cancer, cholangiocarcinoma, pancreatic cancer, and diabetes, might cause specific alterations in adipokine profiles. These patterns and associated bases potentially contribute to the identification of prognostic biomarkers and therapeutic approaches for the associated digestive diseases. This review highlights important findings about altered adipokine profiles relevant to digestive diseases, including hepatic, pancreatic, gastrointestinal, and biliary tract diseases, with a perspective on clinical implications and mechanistic explorations.

Topics: Adipocytes; Adipokines; Adiponectin; Adipose Tissue; Biomarkers; Digestive System; Digestive System Diseases; Homeostasis; Humans; Inflammation; Leptin; Liver; Non-alcoholic Fatty Liver Disease; Obesity

It is now established that adipose tissue, skeletal muscle, and heart are endocrine organs and secrete in normal and in pathological conditions several molecules, called, respectively, adipokines, myokines, and cardiokines. These secretory proteins constitute a closed network that plays a crucial role in obesity and above all in cardiac diseases associated with obesity. In particular, the interaction between adipokines, myokines, and cardiokines is mainly involved in inflammatory and oxidative damage characterized obesity condition. Identifying new therapeutic agents or treatment having a positive action on the expression of these molecules could have a key positive effect on the management of obesity and its cardiac complications. Results from recent studies indicate that several nutritional interventions, including nutraceutical supplements, could represent new therapeutic agents on the adipo-myo-cardiokines network. This review focuses the biological action on the main adipokines, myokines and cardiokines involved in obesity and cardiovascular diseases and describe the principal nutraceutical approaches able to regulate leptin, adiponectin, apelin, irisin, natriuretic peptides, and follistatin-like 1 expression.

Topics: Adipokines; Adipose Tissue; Animals; Caloric Restriction; Cardiovascular Diseases; Dietary Supplements; Humans; Leptin; Mice; Models, Biological; Muscle, Skeletal; Myocardium; Obesity; Peptide Hormones; Prebiotics; Probiotics

Obesity as an independent risk factor for cardiovascular diseases (CVDs) leads to an increase in morbidity, mortality, and a shortening of life span. The changes in heart structure and function as well as metabolic profile are caused by obese people, including those free of metabolic disorders. Obesity alters heart function structure and affects lipid and glucose metabolism, blood pressure, and increase inflammatory cytokines. Adipokines, specific cytokines of adipocytes, are involved in the progression of obesity and the associated co-morbidities. In the current study, we review the scientific evidence on the effects of obesity on CVDs, focusing on the changes in adipokines. Several adipokines have anti-inflammatory and cardioprotective effects comprising omentin, apelin, adiponectin, and secreted frizzled-related protein (Sfrp-5). Other adipokines have pro-inflammatory impacts on the cardiovascular system and obesity including leptin, tumor necrosis factor (TNF), retinol-binding protein4 (RBP-4), visfatin, resistin, and osteopontin. We found that obesity is associated with multiple CVDs, but can only occur in unhealthy metabolic patients. However, more studies should be designed to clarify the association between obesity, adipokine changes, and the occurrence of CVDs.

Topics: Adipokines; Adiponectin; Animals; Biomarkers; Cardiovascular Diseases; Genome; Humans; Inflammation; Leptin; Metabolic Syndrome; Obesity; Resistin; Risk Factors

Obesity is one of the most prevalent health conditions in humans and companion animals globally. It is associated with premature mortality, metabolic dysfunction, and multiple health conditions across species. Obesity is, therefore, of importance in the fields of medicine and veterinary medicine. The regulation of adiposity is a homeostatic process vulnerable to disruption by a multitude of genetic and environmental factors. It is well established that the heritability of obesity is high in humans and laboratory animals, with ample evidence that the same is true in companion animals. In this review, we provide an overview of how genes link to obesity in humans, drawing on a wealth of information from laboratory animal models, and summarise the mechanisms by which obesity causes related disease. Throughout, we focus on how large-scale human studies and niche investigations of rare mutations in severely affected patients have improved our understanding of obesity biology and can inform our ability to interpret results of animal studies. For dogs, cats, and horses, we compare the similarities in obesity pathophysiology to humans and review the genetic studies that have been previously reported in those species. Finally, we discuss how veterinary genetics may learn from humans about studying precise, nuanced phenotypes and implementing large-scale studies, but also how veterinary studies may be able to look past clinical findings to mechanistic ones and demonstrate translational benefits to human research.

Topics: Animals; Cat Diseases; Cats; Comorbidity; Dog Diseases; Dogs; Genetic Predisposition to Disease; Genome-Wide Association Study; Horse Diseases; Horses; Humans; Leptin; Melanocortins; Metabolic Diseases; Obesity; Pets

Nutritional environment in the perinatal period has a great influence on health and diseases in adulthood. In rodents, litter size reduction reproduces the effects of postnatal overnutrition in infants and reveals that postnatal overfeeding (PNOF) not only permanently increases body weight but also affects the cardiovascular function in the short- and long-term. In addition to increased adiposity, the metabolic status of PNOF rodents is altered, with increased plasma insulin and leptin levels, associated with resistance to these hormones, changed profiles and levels of circulating lipids. PNOF animals present elevated arterial blood pressure with altered vascular responsiveness to vasoactive substances. The hearts of overfed rodents exhibit hypertrophy and elevated collagen content. PNOF also induces a disturbance of cardiac mitochondrial respiration and produces an imbalance between oxidants and antioxidants. A modification of the expression of crucial genes and epigenetic alterations is reported in hearts of PNOF animals. In vivo, a decreased ventricular contractile function is observed during adulthood in PNOF hearts. All these alterations ultimately lead to an increased sensitivity to cardiac pathologic challenges such as ischemia-reperfusion injury. Nevertheless, caloric restriction and physical exercise were shown to improve PNOF-induced cardiac dysfunction and metabolic abnormalities, drawing a path to the potential therapeutic correction of early nutritional programming.

Topics: Adiposity; Animals; Body Weight; Female; Heart; Insulin; Leptin; Litter Size; Male; Obesity; Overnutrition; Pregnancy; Rats, Sprague-Dawley; Rats, Wistar

An imbalance between calorie intake and energy expenditure produces obesity. It has been a major problem in societies of the developing and developed world. In obesity an excessive amount of fat accumulates in adipose tissue cells as well as in other vital organs like liver, muscles, and pancreas. The adipocytes contain ob genes and express leptin, a 16 kDa protein. In the present communication, we reviewed the molecular basis of the etiopathophysiology of leptin in obesity. Special emphasis has been given to the use of leptin as a drug target for obesity treatment, the role of diet in the modulation of leptin secretion, and reduction of obesity at diminished level of blood leptin induced by physical exercise.

Topics: Adipocytes; Animals; Anti-Obesity Agents; Caloric Restriction; Energy Intake; Energy Metabolism; Exercise Therapy; Humans; Leptin; Obesity; Signal Transduction

Leptin is a critical mediator of the immune response to changes in overall nutrition. Leptin is produced by adipocytes in proportion to adipose tissue mass and is therefore increased in obesity. Despite having a well-described role in regulating systemic metabolism and appetite, leptin displays pleiotropic actions, and it is now clear that leptin has a key role in influencing immune cell function. Indeed, many immune cells have been shown to respond to leptin directly

Topics: Adipose Tissue; Autoimmune Diseases; Diabetes Mellitus, Type 2; Humans; Infections; Leptin; Obesity; Receptors, Leptin

It is an indisputable fact that obesity is associated with a series of health problems. One important hallmark of obesity is excessive accumulation of lipids in the adipocyte, especially triglyceride (TG). Currently, the adipocyte has been considered not only as a huge repository of excess energy in the form of fat but also as an important source of multiple hormones and cytokines called adipokines. In obesity, the adipocyte is dysfunctional with excessive production and secretion of pro-inflammatory adipokines, such as tumor necrosis factor α (TNF-α), interleukin 6 (IL-6), and leptin. On the other hand, accumulating evidence has shown that leptin plays a vital role in stimulating angiogenesis, controlling lipid metabolism, and modulating the production of pro-inflammatory cytokines. Furthermore, the various activities of leptin are related to the wide distribution of leptin receptors. Notably, it has been reported that enhanced leptin levels and dysfunction of the leptin signaling pathway can influence diverse skin diseases. Recently, several studies revealed the roles of leptin in wound healing, the hair cycle, and the pathogenic development of skin diseases, such as psoriasis, lupus erythematosus, and dermatological cancers. However, the exact mechanisms of leptin in modulating the dermatological diseases are still under investigation. Therefore, in the present review, we summarized the regulatory roles of leptin in the pathological progression of diverse diseases of skin and skin appendages. Furthermore, we also provided evidence to elucidate the complicated relationship between leptin and different dermatological diseases, such as systemic lupus erythematosus (SLE), psoriasis, hidradenitis suppurativa, and some skin tumors.

Topics: Animals; Biomarkers; Disease Susceptibility; Energy Metabolism; Gene Expression Regulation; Hair; Hair Diseases; Humans; Leptin; Obesity; Organ Specificity; Reactive Oxygen Species; Skin Diseases

This systematic review and meta-analysis of randomized controlled trials (RCTs) was conducted to summarize the effect of resveratrol intake on weight loss. We searched the following databases until July 2018: MEDLINE, EMBASE, Web of Science and Cochrane Central Register of Controlled Trials. Data were pooled using the inverse variance method and expressed as standardized mean difference (SMD) with 95% confidence intervals (95% CI). Out of 831 reports, 36 RCTs were eligible for including to our meta-analysis. The pooled results, using random-effects model showed that resveratrol supplementation significantly decreased body weight (SMD = -0.17; 95% CI, -0.33, -0.01;

Topics: Adiponectin; Diabetes Mellitus, Type 2; Dietary Supplements; Humans; Leptin; Obesity; Randomized Controlled Trials as Topic; Resveratrol; Weight Loss

Obesity has become a world-wide pandemic and is considered a major risk factor for various diseases. Despite this, recent intriguing clinical observations have been made suggesting that being overweight has some advantages. Overweight and some obese patients were reported to have significantly lower all-cause mortality, described as the 'obesity paradox'. This phenomenon resulted in increased research aimed at investigating the influence of adipose tissue on outcomes of various clinical states including critical illness. In this review, we summarise research findings on the effect burn injury and trauma-related critical illness have on adipose tissue and discuss potential mechanisms by which adipose tissue influences outcomes in burn and other critically ill patients. Burn injury and critical illness influence adipose tissue functionally and morphologically, with circulating levels of fat derived hormones, adipokines, altered in patients following injury and/or critical illness. As adipokines regulate a variety of processes including inflammation and metabolism, this disruption in the adipokine axis may explain the obesity paradox phenomenon observed in critically ill patients. We conclude that further research on the influence of individual adipokines on prognosis in burn and critically ill patients and the mechanisms involved is required to increase understanding of their therapeutic potential.

Topics: Adipokines; Adiponectin; Adipose Tissue; Burns; Critical Illness; Fibrosis; Ghrelin; Humans; Inflammation; Leptin; Nicotinamide Phosphoribosyltransferase; Obesity; Overweight; Resistin; Skin; Wound Healing

The overwhelming rates of obesity worldwide are a major concern due to the elevated medical costs associated and the poor quality of life of obese patients. In the recent years, it has become evident that the intrauterine milieu can have a long-term impact on the foetus health. The placenta is a highly dynamic organ; whose primary function is to carry nutrients from the mother to the foetus and to remove waste products from the foetus. Any alteration in maternal circulating metabolites elicits a response in order to ensure the developing foetus an adequate growth environment. This response can be translated into epigenetic modifications in coding genes for metabolic-related receptors located in the placenta and foetal tissues. The most studied receptors involved in the metabolic sensing are the leptin and the insulin receptors. A maternal metabolic disease-like state can alter the expression of these receptors in different organs, including placenta. There is evidence that these alterations not only affect the expression level of these receptors, but there are also differences in epigenetic marks in regulatory elements of these genes that may become permanent despite the mother's treatment. This review provides evidence about possible mechanisms involved in the foetal programming of metabolic diseases originated from the pre-natal environment that could contributive to increasing levels of obesity in the world.

Topics: DNA Methylation; Epigenesis, Genetic; Female; Fetal Development; Homeostasis; Humans; Insulin; Leptin; Metabolic Diseases; Obesity; Placenta; Pregnancy; Receptor, Insulin; Receptors, Leptin; Signal Transduction

Obesity has been proposed as a risk factor for prostate cancer (PCa). In obesity, serum levels of the appetite-regulating hormones-leptin, adiponectin, and ghrelin-become deregulated.. To explore whether serum levels of appetite-regulating hormones associate with the incidence of PCa, the incidence of advanced disease, or PCa-specific mortality.. PRISMA guidelines were followed. A systematic search for relevant articles published until March 2019 was performed using the databases PubMed, EMBASE, and Web of Science. Observational studies with data on serum levels of leptin, adiponectin, or ghrelin and PCa outcome were included. Meta-analysis was used to combine risk estimates. Meta-relative risks (mRRs) were calculated using random effects models. When available, raw data was pooled. Publication bias was assessed by funnel plot and Begg's test.. Thirty-five studies were eligible for inclusion. The qualitative analysis indicated that leptin was not consistently associated with any PCa outcome, although several cohorts reported decreased adiponectin levels in men who later developed advanced PCa. Based on the meta-analysis, there was no significant effect of leptin on PCa incidence (mRR = 0.93 (95% CI 0.75-1.16), p = 0.52) or advanced PCa (mRR = 0.90 (95% CI 0.74-1.10), p = 0.30). There were insufficient studies to estimate the mRR of PCa incidence for men with the highest levels of adiponectin. The combined risk of advanced PCa for men with the highest levels of adiponectin was reduced but did not reach significance (mRR = 0.81 (95% CI 0.61-1.08), p = 0.15).. The current evidence does not suggest an association between leptin and PCa outcome. However, there may be an inverse association between adiponectin and the incidence of advanced PCa that should be investigated by further studies. Serum ghrelin has not been largely investigated.

Topics: Adiponectin; Appetite; Disease Susceptibility; Epithelial Cells; Gene Expression Regulation; Ghrelin; Humans; Leptin; Male; Obesity; Peptide Hormones; Prostatic Neoplasms; Publication Bias; Signal Transduction

Recently, obesity has become a common worldwide concern. Leptin, as an adipocytokine, plays a major role in the etiology of obesity. Prior studies have demonstrated that zinc potentially affects serum leptin levels. However, clinical trials carried out in this regard are not consistent. Therefore, current meta-analysis was conducted to ascertain the actual effect of zinc supplementation on serum leptin levels in adults. Databases of PubMed, SCOPUS, and Google Scholar were methodically searched to identify relevant articles up to April 2018. Clinical trials that examined the effect of zinc supplementation on serum leptin concentrations as outcome variables in human adults were included. The mean difference (SD) of leptin changes in the intervention and placebo groups were used to calculate the overall effect size. Totally, 663 articles were identified, of which 6 studies were eligible randomized controlled trials (RCTs) with 7 treatment arms. The analysis suggested that zinc supplementation exerts no significant effect on overall serum leptin (WMD: 0.74 ng/ml; 95% CI: -1.39 to 2.87, p=0.49). Nevertheless, sex and duration of intervention seemed to impact the extent of zinc's influence. In trials with female subjects, zinc consumption led to a significant decrease in serum leptin level (WMD: -1.93 ng/ml; 95% CI: -3.72 to -0.14, p=0.03) as well as trials that lasted for more than 6 weeks (WMD: -1.71 ng/ml; 95% CI: -3.07 to -0.35, p=0.01), in comparison to the control group. Zinc supplementation did not significantly improve leptin concentrations, but it may result in a decreased circulating leptin level in studies with a duration of more than 6 weeks especially among females.

Topics: Biomarkers; Dietary Supplements; Humans; Leptin; Obesity; Prognosis; Randomized Controlled Trials as Topic; Zinc

Nowadays, it is well-known that the deregulation of epigenetic machinery is a common biological event leading to the development and progression of metabolic disorders. Moreover, the expression level and actions of leptin, a vast adipocytokine regulating energy metabolism, appear to be strongly associated with epigenetics. Therefore, the aim of this review was to summarize the current knowledge of the epigenetic regulation of leptin as well as the leptin-induced epigenetic modifications in metabolic disorders and associated phenomena. The collected data indicated that the deregulation of leptin expression and secretion that occurs during the course of metabolic diseases is underlain by a variation in the level of promoter methylation, the occurrence of histone modifications, along with miRNA interference. Furthermore, leptin was proven to epigenetically regulate several miRNAs and affect the activity of the histone deacetylases. These epigenetic modifications were observed in obesity, gestational diabetes, metabolic syndrome and concerned various molecular processes like glucose metabolism, insulin sensitivity, liver fibrosis, obesity-related carcinogenesis, adipogenesis or fetal/early postnatal programming. Moreover, the circulating miRNA profiles were associated with the plasma leptin level in metabolic syndrome, and miRNAs were found to be involved in hypothalamic leptin sensitivity. In summary, the evidence suggests that leptin is both a target and a mediator of epigenetic changes that develop in numerous tissues during metabolic disorders.

Topics: Adipogenesis; Animals; Diabetes, Gestational; DNA Methylation; Epigenesis, Genetic; Female; Fetal Development; Histone Code; Humans; Hypothalamus; Leptin; Metabolic Diseases; Metabolic Syndrome; MicroRNAs; Obesity; Pregnancy

The social problems and medical burdens caused by obesity have become more serious in recent years. Obesity is mainly caused by the imbalance of energy intake and consumption in the body. The central nervous system and related neurons regulate the balance of energy metabolism. The hypothalamic arcuate nucleus (ARC) contains anorexigenic proopiomelanocortin (POMC) neurons and orexigenic neuropeptid Y(NPY)/agouti-related protein (AgRP) neurons that regulate the feeding behavior of body. High-fat diet induces phosphorylation of Rb protein in POMC neurons, and inactivation of Rb phosphorylation leads to re-entry of POMC neurons from the resting-state into the cell cycle, which rapidly shifts to apoptosis. High-fat diet also causes the inhibition of neuronal regeneration, induces inflammation and neuronal damage, loss of neuronal homeostasis, leptin resistance, and ultimately leads to obesity. This review discusses the relationship between loss of neuronal homeostasis and dietary obesity, as well as the underlying mechanisms, which might provide the evidence for prevention and treatment of these diseases.. 近年来，因肥胖症所造成的社会问题和医疗负担越发严重。肥胖主要是由于机体能量的摄入与消耗不平衡所致，而中枢神经系统以及相关神经元在机体能量代谢平衡的调控中发挥着重要作用。下丘脑弓状核含有抑食性阿黑皮素原 (Proopiomelanocortin，POMC) 神经元和促食性神经肽Y (Neuropeptid Y，NPY)/刺鼠相关蛋白(Agouti-related protein，AgRP) 神经元，是调控机体摄食行为的主要神经元。研究显示，高脂饮食会诱导POMC神经元中的Rb 蛋白发生磷酸化修饰并失活，导致POMC 神经元从静息状态重新进入细胞周期循环，进而迅速转向细胞凋亡。高脂饮食也会引起神经元再生抑制，并诱导炎症发生和神经元损伤，使神经元稳态失衡，引发瘦素抵抗，最终导致肥胖症的发生。文中就神经元稳态失衡以及肥胖症等疾病之间的关系进行了综述，希望能为饮食诱导肥胖症等疾病的治疗和预防提供新的方向和思路。.

Topics: Arcuate Nucleus of Hypothalamus; Homeostasis; Humans; Leptin; Obesity; Pro-Opiomelanocortin

To review the latest reports of the contributions of the endothelial mineralocorticoid receptor to endothelial dysfunction and hypertension to begin to determine the clinical potential for this pathway for hypertension treatment.. Endothelial mineralocorticoid receptor expression is sex-specifically increased in female mice and humans compared with males. Moreover, the expression of endothelial mineralocorticoid receptors is increased by endothelial progesterone receptor activation and naturally occurring fluctuations in progesterone levels (estrous, pregnancy) predict endothelial mineralocorticoid receptor expression levels in female mice. These data follow many previous reports that have indicated that endothelial mineralocorticoid receptor deletion is protective in the development of obesity- and diabetes-associated endothelial dysfunction in female mouse models. These studies have more recently been followed up by reports indicating that both intact endothelial mineralocorticoid receptor and progesterone receptor expression are required for obesity-associated, leptin-mediated endothelial dysfunction in female mice. In addition, the intra-endothelial signaling pathway for endothelial mineralocorticoid receptors to induce dysfunction requires the intact expression of α-epithelial sodium channels (αENaC) in endothelial cells in females. Endothelial mineralocorticoid receptors are sex-specifically upregulated in the vasculature of females, a sex difference which is driven by endothelial progesterone receptor activation, and increased activity of these endothelial mineralocorticoid receptors is a crucial mediator of endothelial dysfunction, and potentially hypertension, in obese female experimental models.

Topics: Aldosterone; Animals; Disease Models, Animal; Endothelial Cells; Endothelium, Vascular; Epithelial Sodium Channels; Female; Humans; Hypertension; Leptin; Male; Mice; Mineralocorticoid Receptor Antagonists; Obesity; Receptors, Mineralocorticoid; Receptors, Progesterone; Sex Factors; Vascular Diseases

Leptin, the product of the

Topics: Animals; Bone Remodeling; Cardiovascular System; Energy Metabolism; Glucose; Humans; Immune System; Leptin; Lipid Metabolism; Nitric Oxide; Obesity; Reproduction; Signal Transduction

Psoriasis is a chronic, systemic, hyper-proliferative immune-mediated inflammatory skin disease. The results of epidemiological investigations have shown that psoriasis affects around 2% of the general population worldwide, and the total number of psoriasis patients is more than 6 million in China. Apart from the skin manifestations, psoriasis has been verified to associate with several metabolic comorbidities, such as insulin resistance, diabetes and obesity. However, the underlying mechanism is still not elucidated. Adipocytes, considered as the active endocrine cells, are dysfunctional in obesity which displays increased synthesis and secretion of adipokines with other modified metabolic properties. Currently, growing evidence has pointed to the central role of adipokines in adipose tissue and the immune system, providing new insights into the effect of adipokines in linking the pathophysiology of obesity and psoriasis. In this review, we summarize the current understanding of the pathological role of adipokines and the potential mechanisms whereby different adipokines link obesity and psoriasis. Furthermore, we also provide evidence which identifies a potential therapeutic target aiming at adipokines for the management of these two diseases.

Topics: Adipocytes; Adiponectin; Adipose Tissue; Cytokines; Gene Expression Regulation; GPI-Linked Proteins; Humans; Immune System; Immunologic Factors; Interleukin-1beta; Interleukin-6; Lectins; Leptin; Molecular Targeted Therapy; Obesity; Psoriasis; Signal Transduction; Tumor Necrosis Factor-alpha

Obesity is highly heritable and arises from the interplay of many genes and environmental factors. It can be defined as the result of prolonged imbalance between calorie intake and energy utilization. About 5% of cases of non-syndromic obesity are monogenic (Mendelian obesity). The amount of adipose tissue in the body is mainly regulated by leptin, a hormone produced by adipocytes, and Mendelian obesity is mainly caused by mutations that disrupt the leptin/melanocortin pathway. In this article, we summarize the genes involved in genetic obesity and the test we use for genetic analysis.

Topics: Adipogenesis; Genetic Predisposition to Disease; Genetic Testing; High-Throughput Nucleotide Sequencing; Humans; Leptin; Melanocortins; Mutation; Obesity

Obesity is caused by an imbalance between energy intake and output, influenced by numerous environmental, biological, and genetic factors. Only a minority of people with obesity have a genetic defect that is the main cause of their obesity. A key symptom for most of these disorders is early-onset obesity and hyperphagia. For some genetic obesity disorders, the hyperphagia is the main characteristic, often caused by disruptions of the leptin-melanocortin pathway, the central pathway that regulates the body's satiety and energy balance. For other disorders, obesity is part of a distinct combination of other clinical features such as intellectual disability, dysmorphic facial features, or organ abnormalities. This chapter focuses on genetic obesity disorders and also summarizes the present knowledge on the genetics of the more common polygenic/multifactorial obesity.

Topics: Energy Intake; Energy Metabolism; Humans; Hyperphagia; Leptin; Melanocortins; Obesity; Satiation

The evolutionary origin of obesity is classically believed to be genetic or developmentally induced thrift, as an adaptation to ancestral feast and famine conditions. However, recently the thrift family of hypotheses have attracted serious criticism necessitating alternative thinking. Optimization of foraging behaviour is an important aspect of behavioural evolution. For a species evolved for optimizing nutritional benefits against predation or other foraging risks, reduction in foraging risk below a threshold dramatically increases the steady-state body weight. In modern life where feeding is detached from foraging, the behavioural regulation mechanisms are likely to fail resulting into escalation of adiposity. At a proximate level the signalling pathways for foraging optimization involve fear induced signal molecules in the brain including Cocaine and Amphetamine Regulated Transcript (CART) interacting with adiposity signals such as leptin. While leptin promotes the expression of the fear peptides, the fear peptides promote anorectic action of leptin. This interaction promotes foraging drive and risk tolerance when the stored energy is low and suppresses hunger and foraging drive when the perceived risk is high. The ecological model of foraging optimization and the molecular model of interaction of these peptides converge in the outcome that the steady state adiposity is an inverse square root function of foraging risk. The foraging optimization model is independent of thrift or insurance hypotheses, but not mutually exclusive. We review existing evidence and suggest testable predictions of the model. Understanding obesity simultaneously at proximate and ultimate levels is likely to suggest effective means to curb the obesity epidemic.

Topics: Anthropology, Physical; Anxiety; Appetitive Behavior; Biological Evolution; Body Weight; Fear; Humans; Leptin; Metabolism; Models, Biological; Obesity

Sepsis has become a global health problem with rising incidence and high mortality, creating a substantial social and economic burden. Early diagnosis and treatment can improve outcome, but reliable sepsis biomarkers are lacking. This review summarizes current evidence of the pathophysiological mechanisms linking adipose tissue to sepsis and presents experimental and clinical data on adipokines and sepsis along with important insights into the obesity paradox in sepsis survival.. Sepsis is characterized by significant alterations in circulating cytokines and adipokines, biologically active molecules produced by the adipose tissue, being implicated in metabolic and inflammatory processes. Although data are inconclusive regarding classic adipokines such as leptin and adiponectin, recent evidence have highlighted the striking elevation of resistin and visfatin in critical illness and sepsis as well as their association with sepsis severity and outcomes. Given that inflammatory and metabolic pathways are involved in sepsis, studying adipokines presents an attractive, innovative, and promising research field that may provide more powerful diagnostic and prognostic biomarkers as well as novel therapeutic targets, empowering the therapeutic armamentarium for sepsis management in order to improve survival.

Topics: Adipokines; Adiponectin; Adipose Tissue; Animals; Biomarkers; Cytokines; Humans; Hyperglycemia; Insulin Resistance; Leptin; Nicotinamide Phosphoribosyltransferase; Obesity; Resistin; Sepsis; Severity of Illness Index

The current review shows evidence for the role of adipokines in breast cancer (BC) pathogenesis summarizing the mechanisms underlying the association between adipokines and breast malignancy. Special emphasis is given also on intriguing insights into the relationship between obesity and BC as well as on the role of novel adipokines in BC development.. Recent evidence has underscored the role of the triad of obesity, insulin resistance, and adipokines in postmenopausal BC. Adipokines exert independent and joint effects on activation of major intracellular signal networks implicated in BC cell proliferation, growth, survival, invasion, and metastasis, particularly in the context of obesity, considered a systemic endocrine dysfunction characterized by chronic inflammation. To date, more than 10 adipokines have been linked to BC, and this catalog is continuously increasing. The majority of circulating adipokines, such as leptin, resistin, visfatin, apelin, lipocalin 2, osteopontin, and oncostatin M, is elevated in BC, while some adipokines such as adiponectin and irisin (adipo-myokine) are generally decreased in BC and considered protective against breast carcinogenesis. Further evidence from basic and translational research is necessary to delineate the ontological role of adipokines and their interplay in BC pathogenesis. More large-scale clinical and longitudinal studies are awaited to assess their clinical utility in BC prognosis and follow-up. Finally, novel more effective and safer adipokine-centered therapeutic strategies could pave the way for targeted oncotherapy.

Topics: Adipokines; Adiponectin; Adipose Tissue; Animals; Apelin; Breast Neoplasms; Cell Proliferation; Cytokines; Female; Fibronectins; Humans; Inflammation; Leptin; Lipocalin-2; Nicotinamide Phosphoribosyltransferase; Obesity; Oncostatin M; Osteopontin; Resistin

Obesity is a worldwide epidemic with rates nearly doubling over the last 30 years. Despite increasing prevalence, the multifactorial pathogenesis of obesity continues to be widely misunderstood. Investigating genetic drivers in the development of obesity is an important area of focus, as genetics move to the forefront of medicine and personalized treatment evolves. Thus, this narrative review focused on four genes which have genome-wide association study-documented links to obesity and obesity syndromes. We explored their involvement in the predisposition, progression, and prognosis of obesity. Leptin, leptin receptor, pro-opiomelanocortin, and melanocortin 4 receptor are our four genes of interest, and herein we elaborated on the current literature, pathogenesis, and available treatments for patients with these specific genetic mutations.

Topics: Disease Progression; Genetic Predisposition to Disease; Genome-Wide Association Study; Genotype; Humans; Leptin; Mutation; Obesity; Pro-Opiomelanocortin; Receptor, Melanocortin, Type 4; Receptors, Leptin

Obesity, which is a worldwide epidemic, confers increased risk for multiple serious conditions including type 2 diabetes, nonalcoholic fatty liver disease, and cardiovascular diseases. Adipose tissue is considered one of the largest endocrine organs in the body as well as an active tissue for cellular reactions and metabolic homeostasis rather than an inert tissue only for energy storage. The functional pleiotropism of adipose tissue relies on its ability to synthesize and release a large number of hormones, cytokines, extracellular matrix proteins, and growth and vasoactive factors, which are collectively called adipokines known to influence a variety of physiological and pathophysiological processes. In the obese state, excessive visceral fat accumulation causes adipose tissue dysfunctionality that strongly contributes to the onset of obesity-related comorbidities. The mechanisms underlying adipose tissue dysfunction include adipocyte hypertrophy and hyperplasia, increased inflammation, impaired extracellular matrix remodeling, and fibrosis together with an altered secretion of adipokines. This review describes the relevance of specific adipokines in the obesity-associated cardiovascular disease.

Topics: Adipokines; Adipose Tissue; Cardiovascular Diseases; Humans; Leptin; Obesity; Risk Factors

Leptin, a hormone that is capable of effectively reducing food intake and body weight, was initially considered for use in the treatment of obesity. However, obese subjects have since been found to have high levels of circulating leptin and to be insensitive to the exogenous administration of leptin. The inability of leptin to exert its anorexigenic effects in obese individuals, and therefore, the lack of clinical utility of leptin in obesity, is defined as leptin resistance. This phenomenon has not yet been adequately characterized. Elucidation of the molecular mechanisms underlying leptin resistance is of vital importance for the application of leptin as an effective treatment for obesity. Leptin must cross the blood-brain barrier (BBB) to reach the hypothalamus and exert its anorexigenic functions. The mechanisms involved in leptin transportation across the blood-brain barrier continue to be unclear, thereby preventing the clinical application of leptin in the treatment of obesity. In recent years, new strategies have been developed to recover the response to leptin in obesity. We have summarized these strategies in this review.

Topics: Adiposity; Anti-Obesity Agents; Blood-Brain Barrier; Brain; Capillary Permeability; Feeding Behavior; Humans; Leptin; Obesity; Signal Transduction; Weight Gain

The discovery of leptin changed the view of adipose tissue from that of a passive vessel that stores fat to that of a dynamic endocrine organ that actively regulates behaviour and metabolism. Secreted by adipose tissue, leptin functions as an afferent signal in a negative feedback loop, acting primarily on neurons in the hypothalamus and regulating feeding and many other functions. The leptin endocrine system serves a critical evolutionary function by maintaining the relative constancy of adipose tissue mass, thereby protecting individuals from the risks associated with being too thin (starvation and infertility) or too obese (predation). In this Review, the biology of leptin is summarized, and a conceptual framework is established for studying the pathogenesis of obesity, which, analogously to diabetes, can result from either leptin hyposecretion or leptin resistance. Herein, these two states are distinguished with the terms 'type 1 obesity' and 'type 2 obesity': type 1 obesity describes a subset of obese individuals with low endogenous plasma leptin levels who respond to leptin therapy, whereas type 2 obesity describes most obese individuals, who are leptin resistant but might respond to leptin therapy in combination with other drugs, such as leptin sensitizers.

Topics: Adipose Tissue; Animals; Energy Metabolism; Humans; Leptin; Models, Genetic; Obesity

Dietary fat has been implicated in the rise of obesity due to its energy density, palatability and weak effects on satiety. As fat is a major contributor to overall energy intake, incorporating fat with satiating properties could potentially reduce energy intake. This review outlines the potential mechanisms, as far as we know, by which Medium-Chain Triglycerides (MCT), Conjugated Linoleic Acid (CLA), Short-Chain Fatty Acids (SCFA), Diacylglycerol (DAG),

Topics: Appetite; Dietary Fats; Digestion; Diglycerides; Energy Intake; Fatty Acids, Omega-3; Fatty Acids, Volatile; Gastric Emptying; Hormones; Humans; Leptin; Linoleic Acids, Conjugated; Lipid Metabolism; Lipids; Obesity; Oxidation-Reduction; Satiation; Triglycerides

Depression and obesity are common conditions with major public health implications that tend to co-occur within individuals. The relationship between these conditions is bidirectional: the presence of one increases the risk for developing the other. It has thus become crucial to gain a better understanding of the mechanisms responsible for the intertwined downward physiological spirals associated with both conditions. The present review focuses specifically on shared biological pathways that may mechanistically explain the depression-obesity link, including genetics, alterations in systems involved in homeostatic adjustments (HPA axis, immuno-inflammatory activation, neuroendocrine regulators of energy metabolism including leptin and insulin, and microbiome) and brain circuitries integrating homeostatic and mood regulatory responses. Furthermore, the review addresses interventional opportunities and questions to be answered by future research that will enable a comprehensive characterization and targeting of the biological links between depression and obesity.

Topics: Brain; Depression; Depressive Disorder; Depressive Disorder, Major; Energy Metabolism; Female; Homeostasis; Humans; Hypothalamo-Hypophyseal System; Inflammation; Insulin; Leptin; Male; Melanocortins; Microbiota; Obesity; Pituitary-Adrenal System

Hypothalamic integration of gastrointestinal and adipose tissue-derived hormones serves as a key element of neuroendocrine control of food intake. Leptin, adiponectin, oleoylethanolamide, cholecystokinin, and ghrelin, to name a few, are in a constant "cross talk" with the feeding-related brain circuits that encompass hypothalamic populations synthesizing anorexigens (melanocortins, CART, oxytocin) and orexigens (Agouti-related protein, neuropeptide Y, orexins). While this integrated neuroendocrine circuit successfully ensures that enough energy is acquired, it does not seem to be equally efficient in preventing excessive energy intake, especially in the obesogenic environment in which highly caloric and palatable food is constantly available. The current review presents an overview of intricate mechanisms underlying hypothalamic integration of energy balance-related peripheral endocrine input. We discuss vulnerabilities and maladaptive neuroregulatory processes, including changes in hypothalamic neuronal plasticity that propel overeating despite negative consequences.

Topics: Eating; Energy Metabolism; Humans; Hyperphagia; Hypothalamus; Leptin; Obesity

As the global mean Body Mass Index (BMI) is on the rise, the importance of understanding exactly how female fertility is impacted by once outlier BMI values, becomes ever more important. Studies have implicated abnormal BMI on the female reproductive system by contributing to anovulation, irregular menses, adverse oocyte quality, endometrial alterations, and hormonal imbalances. These well ultimately result in female infertility, which could complicate natural conception efforts and request considering assisted reproductive technology (ART) in such couples. With an increase in the demand for ART, it is crucial to understand what factors can be altered by the female BMI in order to maximize the opportunity for successful pregnancy. The current manuscript aimed to review the information about the effect of BMI on the female fertility and ART outcomes. The complex nature of the female reproductive system leaves space for multiple factors to adversely affect its processes. Imbalances in the hypothalamus-pituitary-ovarian axis can impede efforts for couples to conceive. Leptin and estrogen are two hormones that have been implicated in regulating BMI as well as reproductive physiology. Lifestyle modifications prior to, and during ART have shown promise in enhancing fecundity. The intricacies in female reproductive system leaves much to the unknown, and often with conflicting results. Further research is required to fully elucidate what aspects of female fertility are influenced by BMI, and how the healthcare provider can facilitate successful outcomes. The current review will enable a better consultation and treatment.

Topics: Body Mass Index; Endometrium; Estrogens; Female; Fertility; Humans; Infertility, Female; Leptin; Obesity; Overweight; Ovulation; Pregnancy; Reproductive Techniques, Assisted

Obesity is related to many major diseases and cancers. Women have higher rates of obesity and obesity is linked to commonly occurring cancers in women. However, there is a lack of knowledge of the unique mechanism(s) involved in each type of cancer. The objective of this review is to highlight the need for novel experimental approaches and a better understanding of the common and unique pathways to resolve controversies regarding the role of obesity in cancer. In women, there is a link between hormones and obesity-associated genes in cancer development. Leptin is an obesity-associated gene that has been studied extensively in cancers; however, whether the defect is in the leptin gene or in its signaling pathways remains unclear. Both leptin and its receptor have been positively correlated with cancer progression in some endocrine-related cancers in women. This review offers an up-to-date and cohesive review of both upstream and downstream pathways of leptin signaling in cancer and a comprehensive picture of cancer pathogenesis in light of current evidence of leptin effects in several major types of cancer. This work is intended to aid in the design of better therapeutic strategies for obese/overweight women with cancer.

Topics: Endocrine Gland Neoplasms; Female; Humans; Leptin; Obesity; Receptors, Leptin; Sex Factors; Signal Transduction

Epidemiological studies suggested an association between obesity and sleep disturbances. Obstructive sleep apnea is the most prevalent type of obesity-related sleep disorder that lead to an increased risk for numerous chronic health conditions. In addition the increased visceral adipose tissue might be responsible for the secretion of inflammatory cytokines that could contribute to alter the sleep-wake rhythm. Unhealthy food characterized by high consumption of fat and carbohydrate seems to negatively influence the quality of sleep while diet rich of fiber is associated to more restorative and deeper sleep. Although obesity could cause through several pathogenetic mechanisms an alteration of sleep, it has been reported that subjects suffering from sleep disorders are more prone to develop obesity. Experimental laboratory studies have demonstrated that decreasing either the amount or quality of sleep increase the risk of developing obesity. Experimental sleep restriction also causes physiological, hormonal and food behavioral changes that promote a positive energy balance and a compensatory disproportionate increase in food intake, decrease in physical activity, and weight gain. Thus, the aim of this review is to provide observational evidence on the association of obesity with sleep disturbances and

Topics: Diet; Endocannabinoids; Energy Metabolism; Exercise; Ghrelin; Humans; Hydrocortisone; Leptin; Melatonin; Obesity; Sleep Apnea, Obstructive; Sleep Wake Disorders; Weight Gain

In just over a generation overweight and obesity has become a worldwide health concern. The ramifications for this on future health care costs and longevity are consequent, whilst increased adiposity is a harbinger for diabetes, kidney and bone failure, and cancer. An area of intense interest where the role of adiposity is avidly discussed is in inflammatory bowel disease (IBD), which presents mainly as Crohn's disease (CD) and ulcerative colitis (UC). Studies in patients associating IBD with a western diet are divergent. Nevertheless, elegant studies have found gene polymorphisms in humans that in murine models parallel the inflammatory and gut microbiome changes seen in IBD patients. However, an area not to be ignored are the alterations in adipocyte function with ensuing adiposity, in particular and a focus of this review, the dysregulation of the levels of adipocytokines such as leptin and adiponectin. Herein, we present and discuss the known influences of a western diet on IBD in patients and rodent models and how adipocytokines could influence the IBD disease process.

Topics: Adipocytes; Adipokines; Adiponectin; Adiposity; Animals; Colitis, Ulcerative; Crohn Disease; Diet, Western; Disease Progression; Gastrointestinal Microbiome; Genome-Wide Association Study; Humans; Inflammatory Bowel Diseases; Leptin; Mice; Obesity; Polymorphism, Genetic; Risk Factors

Insulin and leptin are critical metabolic hormones that play essential but distinct roles in regulating the physiologic switch between the fed and starved states. The discoveries of insulin and leptin, in 1922 and 1994, respectively, arose out of radically different scientific environments. Despite the dearth of scientific tools available in 1922, insulin's discovery rapidly launched a life-saving therapy for what we now know to be type I diabetes, and continually enhanced insulin therapeutics are now effectively applied to both major forms of this increasingly prevalent disease. In contrast, although the discovery of leptin provided deep insights into the regulation of central nervous system energy balance circuits, as well as an effective therapy for an extremely rare form of obesity, its therapeutic impact beyond that has been surprisingly limited. Despite an enormous accumulated body of information, many important questions remain unanswered about the mechanisms of action and role in disease of both hormones. Additionally, although many decades apart, both discoveries reveal the complexities inherent to scientific collaboration and the assignment of credit, even when the efforts are spectacularly successful.

Topics: Diabetes Mellitus; Endocrinology; History, 20th Century; Humans; Insulin; Leptin; Obesity

The discovery of leptin, an adipocyte-secreted hormone, set the stage for unraveling the mechanisms dictating energy homeostasis, revealing adipose tissue as an endocrine system that regulates appetite and body weight. Fluctuating leptin levels provide molecular signals to the brain regarding available energy reserves modulating energy homeostasis and neuroendocrine response in states of leptin deficiency and to a lesser extent in hyperleptinemic states. While leptin replacement therapy fails to provide substantial benefit in common obesity, it is an effective treatment for congenital leptin deficiency and states of acquired leptin deficiency such as lipodystrophy. Current evidence suggests that regulation of eating behavior in humans is not limited to homeostatic mechanisms and that the reward, attention, memory and emotion systems are involved, participating in a complex central nervous system network. It is critical to study these systems for the treatment of typical obesity. Although progress has been made, further studies are required to unravel the physiology, pathophysiology and neurobehavioral mechanisms underlying potential treatments for weight-related problems in humans.

Topics: Adipose Tissue; Body Weight; Brain; Energy Metabolism; Homeostasis; Humans; Leptin; Neurosecretory Systems; Obesity

Changes in added sugar intake have been associated with corresponding changes in body weight. Potential mechanisms, particularly the impact of added sugar intake on appetite, warrant exploration. A systematic literature review of randomised controlled trials investigated the association between added sugar consumption and appetite in overweight and obese adults. A systematic search of Medline, Cochrane CENTRAL, Web of Science and CINAHL included studies that examined the relationship between added sugar intake and appetite markers, in comparison with a group with lower added sugar intake. A total of twenty-one articles describing nineteen studies were included in the review. The effect of added sugar on appetite was explored separately by reported comparisons of added sugar type and their effect to three study outcomes: energy consumption (n 20 comparisons); satiety (n 18); and appetite hormones, leptin (n 4) or ghrelin (n 7). Increased added sugar consumption did not impact subsequent energy intake (n 9), nor did it influence satiety (n 12) or ghrelin levels (n 4). Differences in the total daily energy intake were comparable with the differences in energy values of tested products (n 3). Added sugar intake was reported to increase leptin levels (n 3). This review did not find a consistent relationship between added sugar intake and appetite measures, which may be partially explained by variations in study methodologies. There is a need for randomised controlled trials examining a range of added sugar sources and doses on appetite in overweight and obese adults to better understand implications for weight gain.

Topics: Adult; Appetite; Body Mass Index; Diet; Dietary Sugars; Energy Intake; Female; Ghrelin; Humans; Leptin; Male; MEDLINE; Middle Aged; Obesity; Overweight; Satiation; Weight Gain

Chronic sympathetic nervous system overactivity is a hallmark of aging and obesity and contributes to the development of cardiovascular diseases including hypertension and heart failure. The cause of this chronic sympathoexcitation in aging and obesity is multifactorial and centrally mediated. In this mini-review, we have provided an overview of the key and emerging central mechanisms contributing to the pathogenesis of sympathoexcitation in obesity and healthy aging, specifically focusing on hypertension. A clear understanding of these mechanisms will pave way for targeting the sympathetic nervous system for the treatment of cardiovascular diseases in obesity and aging.

Topics: Aging; Animals; Cardiovascular Diseases; Cellular Senescence; Humans; Hypertension; Inflammation; Leptin; Obesity; Oxidative Stress; Renin-Angiotensin System; Sympathetic Nervous System

The present review focuses on adipocytes-released peptides known to be involved in the control of gastrointestinal motility, acting both centrally and peripherally. Thus, four peptides have been taken into account: leptin, adiponectin, nesfatin-1, and apelin. The discussion of the related physiological or pathophysiological roles, based on the most recent findings, is intended to underlie the close interactions among adipose tissue, central nervous system, and gastrointestinal tract. The better understanding of this complex network, as gastrointestinal motor responses represent peripheral signals involved in the regulation of food intake through the gut-brain axis, may also furnish a cue for the development of either novel therapeutic approaches in the treatment of obesity and eating disorders or potential diagnostic tools.

Topics: Adipocytes; Adiponectin; Adipose Tissue; Animals; Apelin; Brain; Calcium-Binding Proteins; DNA-Binding Proteins; Eating; Feeding and Eating Disorders; Gastrointestinal Motility; Gastrointestinal Tract; Humans; Leptin; Muscle, Smooth; Nerve Tissue Proteins; Nucleobindins; Obesity

The prominence of obesity in the clinical population as well as the strong association of cardiovascular risk factors with obesity has prompted the investigation of the adipose tissue and its physiological contribution to cardiovascular health. A notable finding in these investigations was the discovery of the adipocyte-derived hormone leptin. Leptin is secreted from the adipose tissue, increases in linear fashion in the circulation with increased body mass and is implicated in the development of cardiovascular disease in obesity, notably via pro-hypertensive mechanisms. Leptin stimulates the activation of the sympathetic nervous system in male patients and mice, which has been implicated as the pro-hypertensive pathway for leptin in obesity. However, obese premenopausal females do not exhibit increased sympathetic activation in response to hyperleptinemia in obesity, indicating a sex-discrepancy in mechanisms of obesity-associated hypertension. Our lab recently demonstrated that leptin also induces the adrenal production of aldosterone in a direct fashion and that this pathway leads to the hyperaldosteronemia that is characteristic of obesity. We have also published data that indicate that the implications of leptin-induced aldosterone are of particular impact in obese females. Leptin-mediated hypertension and endothelial dysfunction, a significant predictor of hypertension clinically, require activation of the mineralocorticoid receptor in female mice. The clinical potential of this pathway remains under investigation; however, existing data indicate that a sex discrepancy exists in mechanisms of leptin-mediated hypertension between males and females and that leptin-stimulated aldosterone plays a significant role in females.

Topics: Aldosterone; Animals; Female; Gene Expression Regulation; Humans; Hypertension; Leptin; Male; Obesity; Sex Factors

Obesity has reached epidemic proportions and its prevalence is climbing. Obesity is characterized by hypertrophied adipocytes with a dysregulated adipokine secretion profile, increased recruitment of inflammatory cells, and impaired metabolic homeostasis that eventually results in the development of systemic insulin resistance, a phenotype of type 2 diabetes. Nitric oxide synthase (NOS) is an enzyme that converts L-arginine to nitric oxide (NO), which functions to maintain vascular and adipocyte homeostasis. Arginase is a ureohydrolase enzyme that competes with NOS for L-arginine. Arginase activity/expression is upregulated in obesity, which results in diminished bioavailability of NO, impairing both adipocyte and vascular endothelial cell function. Given the emerging role of NO in the regulation of adipocyte physiology and metabolic capacity, this review explores the interplay between arginase and NO, and their effect on the development of metabolic disorders, cardiovascular diseases, and mitochondrial dysfunction in obesity. A comprehensive understanding of the mechanisms involved in the development of obesity-induced metabolic and vascular dysfunction is necessary for the identification of more effective and tailored therapeutic avenues for their prevention and treatment.

Topics: Adipogenesis; Adipokines; Adiponectin; Adipose Tissue; Angiopoietin-Like Protein 2; Angiopoietin-like Proteins; Animals; Arginase; Cellular Senescence; Cytokines; Endoplasmic Reticulum Stress; Glucose; GPI-Linked Proteins; Humans; Inflammation; Insulin; Lectins; Leptin; Lipid Metabolism; Lipocalin-2; Metabolic Diseases; Mice; Mitochondria; Nicotinamide Phosphoribosyltransferase; Nitric Oxide; Obesity; Rats; Resistin; Retinol-Binding Proteins, Plasma; Tumor Necrosis Factor-alpha; Vascular Diseases

The prevalence of overweight and obesity has increased significantly in the United States and worldwide. Among the many complications of obesity, hypertension is the most common and major one accounting for about 70% in the obese subjects. However, the pathophysiologic factors of obesity-related hypertension and its therapeutic options are not well understood at present. To better understand the pathophysiology of obesity-related hypertension and its treatment options, a Medline search of the English language literature was contacted between 2010 and 2018 and 22 pertinent papers were selected. The information from these papers together with collateral literature will be discussed in this review.

Topics: Adult; Animals; Body Mass Index; Dogs; Female; Humans; Hypertension; Leptin; Male; Mice; Middle Aged; Natriuretic Peptides; Obesity; Overweight; Prevalence; Renin-Angiotensin System; Sympathetic Nervous System; United States

Leptin resistance refers to states in which leptin fails to promote its anticipated effects, frequently coexisting with hyperleptinaemia. Leptin resistance is closely associated with obesity and also observed in physiological situations such as pregnancy and in seasonal animals. Leptin resensitisation refers to the reversion of leptin-resistant states and is associated with improvement in endocrine and metabolic disturbances commonly observed in obesity and a sustained decrease of plasma leptin levels, possibly below a critical threshold level. In obesity, leptin resensitisation can be achieved with treatments that reduce body adiposity and leptinaemia, or with some pharmacological compounds, while physiological leptin resistance reverts spontaneously. The restoration of leptin sensitivity could be a useful strategy to treat obesity, maintain weight loss and/or reduce the recidivism rate for weight regain after dieting. This review provides an update and discussion about reversion of leptin-resistant states and modulation of the molecular mechanisms involved in each situation.

Topics: Adiposity; Animals; Blood Pressure; Body Weight; Diet; Eating; Energy Intake; Female; Fertility; Humans; Hyperglycemia; Leptin; Male; Mice; Obesity; Phosphorylation; Photoperiod; Pregnancy; Pregnancy, Animal; Signal Transduction; Thermogenesis; Weight Loss

Increasing prevalence of obesity requires the investigation of respective comorbidities, including tumor diseases like colorectal, renal, post-menopausal breast, prostate cancer, and leukemia. To date, molecular mechanisms of the malignant transformation of these peripheral tissues induced by obesity remain unclear. Adipose tissue secretes factors with hormone-like functions, the adipokines, and is therefore categorized as an endocrine organ. Current research demonstrates the ability of adipose tissue to alter DNA methylation and gene expression in peripheral tissues, probably affecting microRNA (miR) expression.. Literature was analyzed for adipokine-regulated miRs. Many of these adipokine upregulated or downregulated miRs exert either oncogenic or anti-tumoral potential.. The three selected and analyzed adipokines, adiponectin, leptin, and resistin, induce more strongly oncogenic miRs and simultaneously reduce anti-tumoral miRs than vice versa. This effect is not only true for the pure number of regulated miRs, it is also the case by consideration of the abundance of the respective miR expression based on actual data sets derived from next-generation sequencing.. The link of obesity and cancer is analyzed under the aspect of adipokine-regulated miRs. At the same time the impact of miR abundance is considered as a regulatory variable. This context offers new strategies for tumor therapy and diagnostics.

Topics: Adipokines; Adipose Tissue; Female; Gene Expression Regulation, Neoplastic; Genes, Tumor Suppressor; Humans; Leptin; Male; MicroRNAs; Neoplasms; Obesity; Oncogenes

Excessive adiposity raises blood pressure and accounts for 65-75% of primary hypertension, which is a major driver of cardiovascular and kidney diseases. In obesity, abnormal kidney function and associated increases in tubular sodium reabsorption initiate hypertension, which is often mild before the development of target organ injury. Factors that contribute to increased sodium reabsorption in obesity include kidney compression by visceral, perirenal and renal sinus fat; increased renal sympathetic nerve activity (RSNA); increased levels of anti-natriuretic hormones, such as angiotensin II and aldosterone; and adipokines, particularly leptin. The renal and neurohormonal pathways of obesity and hypertension are intertwined. For example, leptin increases RSNA by stimulating the central nervous system proopiomelanocortin-melanocortin 4 receptor pathway, and kidney compression and RSNA contribute to renin-angiotensin-aldosterone system activation. Glucocorticoids and/or oxidative stress may also contribute to mineralocorticoid receptor activation in obesity. Prolonged obesity and progressive renal injury often lead to the development of treatment-resistant hypertension. Patient management therefore often requires multiple antihypertensive drugs and concurrent treatment of dyslipidaemia, insulin resistance, diabetes and inflammation. If more effective strategies for the prevention and control of obesity are not developed, cardiorenal, metabolic and other obesity-associated diseases could overwhelm health-care systems in the future.

Topics: Adipokines; Aldosterone; Angiotensin II; Humans; Hypertension; Kidney; Kidney Tubules; Leptin; Obesity; Oxidative Stress; Pro-Opiomelanocortin; Receptor, Melanocortin, Type 4; Receptors, Mineralocorticoid; Renal Reabsorption; Renin; Sodium; Sympathetic Nervous System

Growing scientific evidence has unveiled increased incidences of obesity in domestic animals and its influence on a plethora of associated disorders. Leptin, an adipokine regulating body fat mass, represents a key molecule in obesity, able to modulate immune responses and foster chronic inflammatory response in peripheral tissues. High levels of cytokines and inflammatory markers suggest an association between inflammatory state and obesity in dogs, highlighting the parallelism with humans. Canine obesity is a relevant disease always accompanied with several health conditions such as inflammation, immune-dysregulation, insulin resistance, pancreatitis, orthopaedic disorders, cardiovascular disease, and neoplasia. However, leptin involvement in many disease processes in veterinary medicine is poorly understood. Moreover, hyperleptinemia as well as leptin resistance occur with cardiac dysfunction as a consequence of altered cardiac mitochondrial metabolism in obese dogs. Similarly, leptin dysregulation seems to be involved in the pancreatitis pathophysiology. This review aims to examine literature concerning leptin and immunological status in obese dogs, in particular for the aspects related to obesity-associated diseases.

Topics: Adaptive Immunity; Animals; Dog Diseases; Dogs; Immunity, Innate; Leptin; Obesity

The obesity epidemic is one of the biggest health challenges globally and rates have tripled since 1975. Overeating is the largest determinant of obesity, yet little is understood of the neural mechanisms underlying why individuals consume food regardless of satiety. The lateral hypothalamic (LH) input to the ventral tegmental area (VTA) has been critically implicated in regulating appetitive and reward-related behaviours. However, these projections are genetically heterogeneous and have different responses to leptin. Therefore each of these projections may play a different role in modulating the VTA. This review characterizes each of these known LH to VTA projections in their roles in regulating appetitive behaviour. This article is part of the Special Issue entitled 'Hypothalamic Control of Homeostasis'.

Topics: Animals; Humans; Hypothalamic Area, Lateral; Leptin; Nerve Net; Obesity; Ventral Tegmental Area

We aimed to perform a systematic review and meta-analysis of appetite regulating hormones in patients with first-episode psychosis (FEP). Meta-analyses were conducted using random-effects models with Hedges' g as the effect size estimate. We identified 31 eligible studies, investigating the levels of 7 appetite regulating hormones (adiponectin, insulin, leptin, ghrelin, orexin, resistin and visfatin) in 1792 FEP patients and 1364 controls. The insulin levels in FEP patients were higher than in controls (g = 0.34, 95%CI: 0.19 - 0.49, p < 0.001), even considering only antipsychotic-naïve patients (g = 0.39, 95%CI: 0.12 - 0.66, p = 0.005). The severity of negative symptoms was positively associated with the effect size estimates (β = 0.08, 95%CI: 0.01 - 0.16, p = 0.030). Moreover, we found lower levels of leptin in antipsychotic-naïve FEP patients (g = -0.62, 95%CI: -1.11 - 0.12, p = 0.015). Impaired appetite regulation, in terms of elevated insulin levels and decreased leptin levels, occurs in early psychosis, before antipsychotic treatment. Hyperinsulinemia might be related to negative symptoms.

Topics: Appetite Regulation; Humans; Insulin; Leptin; Obesity; Psychotic Disorders; Schizophrenia

Leptin, an adipocyte-derived hormone and its receptor (ObR) expressed in the hypothalamus are well known as an essential regulator of appetite and energy expenditure. Obesity induces abundant leptin production, however, reduced sensitivity to leptin leads to the development of metabolic disorders, so called leptin resistance. The stomach has been identified as an organ that simultaneously expresses leptin and ObR. Accumulating evidence has shown gastric leptin to perform diverse functions, such as those in nutrient absorption and carcinogenesis in the gastrointestinal system, independent of its well-known role in appetite regulation and obesity. Overexpression of leptin and phosphorylated ObR is implicated in gastric cancer in humans and in murine model, and diet-induced obesity causes precancerous lesions in the stomach in mice. While the underlying pathomechanisms remain unclear, leptin signaling can affect gastric mucosal milieu. In this review, we focus on the significant role of the gastric leptin signaling in neoplasia and tumorigenesis in stomach in the context of hereditary and diet-induced obesity.

Topics: Animals; Carcinogenesis; Humans; Leptin; Obesity; Receptors, Leptin; Stomach Neoplasms

Recent research strongly supports the hypothesis that posttraumatic stress disorder (PTSD) can be accompanied by obesity and related metabolic disturbances. The mechanisms of these associations are however still not well defined, although disturbed functions in the sympathetic-adrenergic nervous system together with the disturbed release of hormones via the endocrine HPA (hypothalamic-pituitary-adrenal) axis apparently play a role. Leptin resistance and ghrelin excesses might contribute to a disturbed hypothalamic function, and also disturb other cerebral functions, leading to dysfunctional reward signaling and uncontrolled appetite combined with a tendency to alcohol abuse. Secondarily, cortisol stimulation will contribute to the development of central obesity which is known to facilitate the development of metabolic syndrome, including slightly increased levels of inflammatory biomarkers such as C-reactive protein and fibrinogen. While previous therapeutic strategies have focused on early psychotherapeutic interventions in PTSD, the present review emphasizes the importance of better therapeutic approaches regarding the somatic correlates of the syndrome. Strict regulation of dietary meals and food composition with minimal intake of sweets and saturated fat, as well as alcohol avoidance, can provide a basic therapeutic framework. A cognitive psychotherapeutic approach with graduated desensitization toward trigging factors, combined with pharmacotherapy, is discussed in the present review.

Topics: Anxiety; Cytokines; Humans; Leptin; Obesity; Stress Disorders, Post-Traumatic

We discuss how potentially modifiable factors including obesity, the microbiome, diet, and exercise may impact melanoma development, progression, and therapeutic response.. Obesity is unexpectedly associated with improved outcomes with immune and targeted therapy in melanoma, with early mechanistic data suggesting leptin as one mediator. The gut microbiome is both a biomarker of response to immunotherapy and a potential target. As diet is a major determinant of the gut microbiome, ongoing studies are examining the interaction between diet, the gut microbiome, and immunity. Data are emerging for a potential role of exercise in reducing hypoxia and enhancing anti-tumor immunity, though this has not yet been well-studied in the context of contemporary therapies. Recent data suggests energy balance may play a role in the outcomes of metastatic melanoma. Further studies are needed to demonstrate mechanism and causality as well as the feasibility of targeting these factors.

Topics: Animals; Diet; Energy Metabolism; Exercise; Gastrointestinal Microbiome; Humans; Immunotherapy; Leptin; Melanoma; Obesity

Psoriasis is a common chronic inflammatory multisystemic disease with a complex pathogenesis consisting of genetic, immunological, and environmental components. It is associated with a number of comorbidities, including diabetes, metabolic syndrome, obesity, and myocardial infarction. In addition, the severity of psoriasis seems to be related to the severity of obesity. Patients with higher levels of obesity show poorer response to systemic treatments of psoriasis. Several studies have demonstrated that white adipose tissue is a crucial site of the formation of proinflammatory adipokines such as leptin, adiponectin, and resistin and classical cytokines such as interleukin- (IL-) 6 and tumour necrosis factor-

Topics: Biomarkers; Humans; Inflammation; Leptin; Obesity; Psoriasis; Resistin

Renal cell carcinoma (RCC) is the commonest from of renal neoplasm. Although surgery is a successful curative treatment for localized RCC, most patients are diagnosed with advanced or metastatic RCC, which has poor prognosis. RCC is classified by stage and grade using tissue samples. Whilst these provide good prognostic information, they are not very useful for early detection. Proteins that are dysregulated in patient's serum can be a valuable alternative and less invasive biomarker for early detection of the disease. For this reason, a hypothesis was formed that leptin is a possible biomarker for early detection and prognostication of RCC. The literature has disparate results on the usefulness of leptin as a biomarker for the early detection of RCC. Hence, a systematic review and a meta-analysis was carried out to investigate whether serum leptin could be a reliable diagnostic and prognostic factor in RCC patients. Literature on the available cohort and case-control studies on serum leptin in RCC was searched in electronic databases and included to evaluate this adipokine in the progression of RCC. The relevant studies were evaluated for the diagnostic and prognostic value of leptin in RCC patients. Overall, only 6 original research studies matched selection criteria and were included for meta-analysis. This study was hypothesised that; leptin might be a useful biomarker for early detection and prognostication of RCC. However, the data were presented in this study did not support our hypothesis. Serum leptin levels in RCC patients do not strongly associate with the development or progression of RCC, thus cannot act as a biomarker for early detection in RCC in patients. Extending our hypothesis further to include levels of obesity and RCC development may be worthwhile, but studies are currently limited.

Topics: Adipokines; Adipose Tissue; Biomarkers, Tumor; Carcinoma, Renal Cell; Early Detection of Cancer; Humans; Kidney Neoplasms; Leptin; Models, Theoretical; Obesity; Prognosis

Obesity is a severe medical problem endangering the health of individuals worldwide. Sleeve gastrectomy (SG), one of the most commonly performed bariatric procedures, has been widely applied to the treatment of such patients. Currently, the potential mechanisms underlying the significant weight loss and metabolic improvement after SG have been well studied. First, and most importantly, by removing a large volume of stomach, the SG directly or indirectly restricts food intake. Then, there are alterations in the absorption and metabolism of both macro- and micronutrients, which may benefit or worsen the patients' well-being. Another profound change is enhanced secretion of the satiety gut hormone and reduced secretion of the hunger hormone as a consequence of the operation. Additionally, adjustment of gastrointestinal motility, alteration in the gut microbial community, and an inflammatory response were found after surgery. Therefore, the purpose of the present review was focused on such hypotheses and to compile the accumulated facts on the physiologic mechanism of bariatric surgery so that these results can help improve the understanding of how SG produces substantial weight loss and a significant improvement in the metabolism of patients with metabolic syndrome.

Topics: Animals; Bariatric Surgery; Eating; Gastrectomy; Gastrointestinal Microbiome; Gastrointestinal Motility; Ghrelin; Humans; Leptin; Mice; Obesity; Rats; Signal Transduction; Weight Loss

Multiple sclerosis (MS) is a multifactorial, inflammatory, and neurodegenerative disease of the central nervous system, where environmental factors interact with genetic susceptibility. The role of diet on MS has not been comprehensively elucidated; therefore, through an extensive search of relevant literature, this review reports the most significant evidence regarding nutrition as a possible co-factor influencing the inflammatory cascade by acting on both its molecular pathways and gut microbiota. Since nutritional status and dietary habits in MS patients have not been extensively reported, the lack of a scientific-based consensus on dietary recommendation in MS could encourage many patients to experiment alternative dietetic regimens, increasing the risk of malnutrition. This work investigates the health implications of an unbalanced diet in MS, and collects recent findings on nutrients of great interest among MS patients and physicians. The aim of this review is to elucidate the role of an accurate nutritional counseling in MS to move toward a multidisciplinary management of the disease and to encourage future studies demonstrating the role of a healthy diet on the onset and course of MS.

Topics: Animals; Antioxidants; Body Composition; Complementary Therapies; Diet; Disease Models, Animal; Dysbiosis; Fatty Acids; Fatty Acids, Unsaturated; Humans; Inflammation; Leptin; Lipopolysaccharides; Malnutrition; Micronutrients; Multiple Sclerosis; Nutritional Status; Obesity; Osteoporosis; Randomized Controlled Trials as Topic; Recommended Dietary Allowances; Risk Factors; Vitamin D

Several peripheral and central signals are involved in the sophisticated regulation of food intake. Women with polycystic ovary syndrome (PCOS) are prone to consume a diet higher in saturated fat and foods with high glycemic index and show impaired appetite regulation and measures of satiety. As a consequence, obesity, mostly of the central type, is prevalent in the syndrome and worsens the endocrine and metabolic profile of the affected patients. This review article briefly analyzes the current knowledge about the neuroendocrine mechanisms underlying the interplay between feeding behavior, obesity, and reproductive abnormalities in PCOS.

Topics: Animals; Appetite Regulation; Female; Ghrelin; Humans; Insulin; Leptin; Neurosecretory Systems; Obesity; Polycystic Ovary Syndrome

The purpose of this study was to conduct a meta-analysis of randomized controlled trials (RCTs) to assess the effect of green tea on serum leptin and ghrelin concentrations.. We searched PubMed, ISI Web of Science, Scopus, and Google scholar databases up to December 2016. The searches included RCTs conducted in human adults, and studies on the effect of green tea and green tea extract on serum leptin and ghrelin concentrations as outcome variables. Weighted mean differences (WMDs) and standard errors (SEs) of changes in serum ghrelin and leptin levels were calculated. The random effects model was used to derive the summary mean estimates with their corresponding SEs.. Eleven RCTs were eligible to be included in the systematic review and the meta-analysis. Our analysis indicated that green tea did not significantly affect leptin and ghrelin concentrations in comparison to placebo (WMD = 1.28 ng/mL, 95% confidence interval: -0.49 to 3.05; P = 0.156, and WMD = 21.49 pg/mL, 95% confidence interval: -40.86 to 83.84; P = 0.499, respectively). However, green tea was associated with an increase in leptin concentration in studies that lasted for more than 12 wk and an increase in ghrelin in women and non-Asians.. Green tea or green tea extract might not be able to change circulatory leptin and ghrelin levels, especially with short-term interventions. More RCTs with longer duration of treatment and higher doses are necessary to assess green tea's effect on fat mass and obesity hormones.

Topics: Catechin; Ghrelin; Humans; Leptin; Obesity; Plant Extracts; Randomized Controlled Trials as Topic; Sensitivity and Specificity; Tea

The gut microbiota has emerged as an environmental factor that modulates the host's energy balance. It increases the host's ability to harvest energy from the digested food, and produces metabolites and microbial products such as short-chain fatty acids, secondary bile acids, and lipopolysaccharides. These metabolites and microbial products act as signaling molecules that modulate appetite, gut motility, energy uptake and storage, and energy expenditure. Several findings suggest that the gut microbiota can affect the development of obesity. Germ-free mice are leaner than conventionally raised mice and they are protected against diet-induced obesity. Furthermore, obese humans and rodents have an altered gut microbiota composition with less phylogeneic diversity compared to lean controls, and transplantation of the gut microbiota from obese subjects to germ-free mice can transfer the obese phenotype. Taken together, these findings indicate a role for the gut microbiota in obesity and suggest that the gut microbiota could be targeted to improve metabolic diseases like obesity. This review focuses on the role of the gut microbiota in energy balance regulation and its potential role in obesity.

Topics: Animals; Energy Metabolism; Gastrointestinal Microbiome; Humans; Hypothalamus; Leptin; Obesity; Signal Transduction; Symbiosis

Although it has been known for some time that increases in body mass enhance aldosterone secretion, particularly in women, the origin of this elevation in aldosterone production is not well defined. Adipocyte-derived factors have emerged as potential candidates to increase aldosterone production in obesity.. Emerging evidence suggests the presence of a mechanistic link in which the adipocyte-derived hormone leptin stimulates aldosterone production in obesity, thereby creating a positive feedback loop for obesity-associated cardiovascular disease. In addition, recent reports give credence to the concept that this leptin-aldosterone stimulation pathway in obesity is an underlying mechanism for sex-discrepancies in obesity-associated cardiovascular disease.. Leptin appears as a new direct regulator of adrenal aldosterone production and leptin-mediated aldosterone production is a novel candidate mechanism underlying obesity-associated hypertension, particularly in females.

Topics: Adipocytes; Aldosterone; Animals; Cardiovascular Diseases; Humans; Leptin; Obesity; Sex Factors

The understanding of adipose tissue role has evolved from that of a depot energy storage organ to a dynamic endocrine organ. While genetics, sexual phenotype and sex steroids can impact the mass and distribution of adipose tissue, there is a counter-influence of white adipocytes on reproduction. This primarily occurs via the secretion of adipokines, the most studied of which- leptin and adiponectin- are highlighted in this article. Leptin, the "satiety hormone" primarily acts on the hypothalamus via pro-opiomelanocortin (POMC), neuropeptide Y (NPY), and agouti-related peptide (AgRP) neurons to translate acute changes in nutrition and energy expenditure, as well as chronic adipose accumulation into changes in appetite and potentially mediate insulin resistance via shared pathway and notably impacting reproductive health via influence on GnRH secreting neurons. Meanwhile, adiponectin is notable for its action in mediating insulin sensitivity, with receptors found at every level of the reproductive axis. Both have been examined in the context of physiologic and pathologic reproductive conditions. Leptin has been shown to influence puberty, pregnancy, hypothalamic amenorrhea, and lipodystrophy, and with a potential therapeutic role for both metabolic and reproductive health. Adiponectin mediates the relative state of insulin resistance in pregnancy, and has been implicated in conditions such as polycystic ovary syndrome and reproductive malignancies. There are numerous other adipokines, including resistin, visfatin, chemerin and retinol binding protein-4, which may also play roles in reproductive health and disease states. The continued examination of these and other adipokines in both normal reproduction and reproductive pathologies represents an important avenue for continued study. Here, we seek to provide a broad, yet comprehensive overview of many facets of these relationships and highlight areas of consideration for clinicians and future study.

Topics: Adipose Tissue; Animals; Female; Humans; Leptin; Obesity; Pregnancy; Reproduction; Reproductive Health; Sexual Maturation

Excess adiposity can induce adverse sequelae in multiple cell types and organ systems. The transition from the lean to the obese state is characterized by fundamental cellular changes at the level of the adipocyte. These changes affect the local microenvironment within the respective adipose tissue but can also affect nonadipose systems. Adipocytes within fat pads respond to chronic nutrient excess through hyperplasia or hypertrophy, which can differentially affect interorgan crosstalk between various adipose depots and other organs. This crosstalk is dependent on the unique ability of the adipocyte to coordinate metabolic adjustments throughout the body and to integrate responses to maintain metabolic homeostasis. These actions occur through the release of free fatty acids and metabolites during times of energy need - a process that is altered in the obese state. In addition, adipocytes release a wide array of signalling molecules, such as sphingolipids, as well as inflammatory and hormonal factors (adipokines) that are critical for interorgan crosstalk. The interactions of adipose tissue with the kidney - referred to as the adipo-renal axis - are important for normal kidney function as well as the response of the kidney to injury. Here, we discuss the mechanistic basis of this interorgan crosstalk, which clearly has great therapeutic potential given the increasing rates of chronic kidney disease secondary to obesity and type 2 diabetes mellitus.

Topics: Adipokines; Adiponectin; Adipose Tissue; AMP-Activated Protein Kinases; Angiotensin II; Angiotensinogen; Ceramidases; Diabetes Mellitus, Type 2; Humans; Inflammation; Kidney Diseases; Leptin; Macrophages; Obesity; Receptors, Adiponectin; Signal Transduction

Obesity is currently the most extended metabolic disturbance worldwide favoring the development of cardiometabolic alterations such as type 2 diabetes, hypertension, and dyslipidemia. Obesity and the metabolic syndrome (MS) are characterized by an increase in circulating leptin concentrations, in parallel to a decrease in blood levels of adiponectin. Consequently, the adiponectin/leptin ratio has been suggested as a maker of adipose tissue dysfunction. This emerging biomarker correlates with insulin resistance better than adiponectin or leptin alone, or even HOMA and is decreased with increasing number of metabolic risk factors having been proposed as a predictive marker for the MS. Moreover, the adiponectin/leptin ratio is negatively correlated with markers of low-grade chronic inflammation. In this sense, an increase in this ratio has been related with reduced atherosclerosis risk as well as with a decreased risk of some types of cancer in epidemiological studies. In this commentary we propose new cutoffs to estimate obesity- and MS-associated cardiometabolic risk according to the adiponectin/leptin ratio and discuss different therapeutic strategies to increase this promising biomarker of metabolic risk.

Topics: Adiponectin; Adipose Tissue; Animals; Humans; Inflammation; Leptin; Metabolic Syndrome; Obesity

Leptin has central importance in the global obesity and cardiovascular disease problem. Leptin is principally secreted by adipocytes and acts in the hypothalamus to suppress appetite and food intake, increase energy expenditure, and regulate body weight. Based on clinical translation of specific and networked actions, leptin affects the cardiovascular system and may be a marker and driver of cardiometabolic risk factors with interventions that are actionable by cardiologists. Leptin subnetwork analysis demonstrates a statistically significant role for ethnoculturally and socioeconomically appropriate lifestyle intervention in cardiovascular disease. Emergent mechanistic components and potential diagnostic or therapeutic targets include hexokinase 3, urocortins, clusterin, sialic acid-binding immunoglobulin-like lectin 6, C-reactive protein, platelet glycoprotein VI, albumin, pentraxin 3, ghrelin, obestatin prepropeptide, leptin receptor, neuropeptide Y, and corticotropin-releasing factor receptor 1. Emergent associated symptoms include weight change, eating disorders, vascular necrosis, chronic fatigue, and chest pain. Leptin-targeted therapies are reported for lipodystrophy and leptin deficiency, but they are investigational for leptin resistance, obesity, and other chronic diseases.

Topics: Adipokines; Biomarkers; Body Weight; Energy Metabolism; Global Health; Humans; Leptin; Morbidity; Obesity

Obesity represents the single most important risk factor for early disability and death in developed societies, and the incidence of obesity remains at staggering levels. CNS systems that modulate energy intake and expenditure in response to changes in body energy stores serve to maintain constant body adiposity; the adipocyte-derived hormone leptin and its receptor (LEPR) represent crucial regulators of these systems. As in the case of insulin resistance, a variety of mechanisms (including feedback inhibition, inflammation, gliosis and endoplasmic reticulum stress) have been proposed to interfere with leptin action and impede the systems that control body energy homeostasis to promote or maintain obesity, although the relative importance and contribution of each of these remain unclear. However, LEPR signalling may be increased (rather than impaired) in common obesity, suggesting that any obesity-associated defects in leptin action must result from lesions somewhere other than the initial LEPR signal. It is also possible that increased LEPR signalling could mediate some of the obesity-associated changes in hypothalamic function.

Topics: Animals; Body Weight; Energy Metabolism; Homeostasis; Humans; Leptin; Obesity; Receptors, Leptin; Signal Transduction

Sodium-glucose co-transporter-2 (SGLT2) inhibitors reduce the risk of serious heart failure events in patients with type 2 diabetes, but little is known about mechanisms that might mediate this benefit. The most common heart failure phenotype in type 2 diabetes is obesity-related heart failure with a preserved ejection fraction (HFpEF). It has been hypothesized that the synthesis of leptin in this disorder leads to sodium retention and plasma volume expansion as well as to cardiac and renal inflammation and fibrosis. Interestingly, leptin-mediated neurohormonal activation appears to enhance the expression of SGLT2 in the renal tubules, and SGLT2 inhibitors exert natriuretic actions at multiple renal tubular sites in a manner that can oppose the sodium retention produced by leptin. In addition, SGLT2 inhibitors reduce the accumulation and inflammation of perivisceral adipose tissue, thus minimizing the secretion of leptin and its paracrine actions on the heart and kidneys to promote fibrosis. Such fibrosis probably contributes to the impairment of cardiac distensibility and glomerular function that characterizes obesity-related HFpEF. Ongoing clinical trials with SGLT2 inhibitors in heart failure are positioned to confirm or refute the hypothesis that these drugs may favourably influence the course of obesity-related HFpEF by their ability to attenuate the secretion and actions of leptin.

Topics: Animals; Diabetes Mellitus, Type 2; Diabetic Cardiomyopathies; Diabetic Nephropathies; Heart; Heart Failure; Humans; Hypoglycemic Agents; Intra-Abdominal Fat; Kidney Tubules; Leptin; Models, Biological; Myocardium; Obesity; Renal Insufficiency; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors; Stroke Volume

　The antihyperglycemic activities of extracts of boiogito (BOT) and bofutsushosan (BTS) were investigated in streptozotocin-induced (STZ)-diabetic mice. BOT extract containing Stephania tetrandra S. MOORE root (stephania), has more potent antihyperglycemic activity than BOT extract containing sinomenium stem (sinomenium). Extracts of stephania and astragalus root (astragalus) exert combined effects in the antihyperglycemic and insulinotropic activities of BOT extract. Fangchinoline, but not tetrandrine, in stephania plays a role in its activity. Formononetin in astragalus potentiates the actions of fangchinoline. Tetrandrine has antiangiogenic effects on choroidal vessels in STZ-diabetic rats, which are associated with the inhibition of tumor necrosis factor (TNF)-α-induced nuclear factor (NF)-κB activation. BTS extract has shown antihyperglycemic and insulinotropic activities whereas gardenia fruit (gardenia) extract in BTS has antihyperglycemic, but not insulinotropic, activity in the diabetic mice. Gardenia extract decreased the HOMA-IR level and increased insulin-stimulated 2-deoxyglucose (2-DG) uptake to skeletal muscle. The effects of gardenia extract on 2-DG uptake were associated with the upregulation of glucose transporter type 4 and Akt phosphorylation. Gardenia extract was also shown to have antihyperglycemic and insulinotropic actions in high-fat diet (HFD)-fed and STZ-diabetic mice. In addition, gardenia extract decreased the production of TNF-α and leptin, and increased the production of adiponectin in the visceral adipose tissues. In the early administration period, BTS extract increased mRNA expression levels of leptin, adiponectin, and UCP1 in brown adipose tissues in HFD-fed obese mice. With a longer duration of administration, BTS extract improved insulin resistance and subsequently reduced serum leptin and triglyceride levels in parallel with visceral adipose tissue volume and size.

Topics: Animals; Deoxyglucose; Diabetes Mellitus, Experimental; Disease Models, Animal; Drugs, Chinese Herbal; Gardenia; Humans; Hypoglycemic Agents; Insulin; Insulin Resistance; Leptin; Mice; Muscle, Skeletal; NF-kappa B; Obesity; Phytotherapy; Stephania; Streptozocin; Tumor Necrosis Factor-alpha

Obesity is an epidemic disease that is increasing worldwide and is a major risk factor for many metabolic diseases. However, effective agents for the prevention or treatment of obesity remain limited. Therefore, it is urgent to clarify the pathophysiological mechanisms underlying the development and progression of obesity and exploit potential agents to cure and prevent this disease. According to a recent study series, obesity is associated with the development of endoplasmic reticulum stress and the activation of its stress responses (unfolded protein response) in metabolically active tissues, which contribute to the development of obesity-related insulin and leptin resistance, inflammation and energy imbalance. Hypothalamic endoplasmic reticulum stress is the central mechanism underlying the development of obesity-associated leptin resistance and disruption of energy homeostasis; thus, targeting endoplasmic reticulum stress offers a promising therapeutic strategy for improving leptin sensitivity, increasing energy expenditure and ultimately combating obesity. In this review, we highlight the relationship between and mechanism underlying hypothalamic endoplasmic reticulum stress and obesity-associated leptin resistance and energy imbalance and provide new insight regarding strategies for the treatment of obesity.

Topics: Endoplasmic Reticulum Stress; Energy Metabolism; Humans; Hypothalamus; Insulin; Leptin; Obesity; Signal Transduction

The proportion to which genetic and environmental factors contribute to the etiology of multiple sclerosis (MS) is still incompletely understood. An interesting association between MS etiology and obesity has recently been shown although the mechanisms underlying this association are still unknown. We propose deregulated gut microbiota and increased leptin levels as possible mechanisms underlying MS etiology in obese individuals.. Alterations in the human gut microbiota and leptin levels have recently been established as immune modulators in both MS patients and obese individuals. A resemblance between pro-inflammatory bacterial profiles in MS and obese individuals was observed. Furthermore, elevated leptin levels push the immune system towards a more pro-inflammatory state and inhibit the regulatory immune response. Deregulated gut microbiota and elevated leptin levels may explain the increased risk of developing MS in obese individuals. Further research to confirm causality is warranted.

Topics: Animals; Gastrointestinal Microbiome; Humans; Leptin; Mice; Multiple Sclerosis; Obesity; Risk Factors

Myeloid-derived suppressor cells (MDSC) are present in most individuals with cancer where they inhibit adaptive and innate antitumor immunity and are an obstacle to cancer immunotherapies. Chronic inflammation is characteristic of adipose tissue and is a risk factor for the onset and progression of cancer in obese individuals. Because MDSC accumulate in response to inflammation, it has been hypothesized that one of the mechanisms by which obesity promotes malignancy is through the induction of MDSC. This article reviews the data supporting this hypothesis, the role of leptin and fatty acid metabolism in the induction of MDSC, and the surprising finding that although MDSC promote tumor progression, they are protective against some of the metabolic dysfunction associated with obesity.

Topics: Adipokines; Adipose Tissue; Animals; Cell Communication; Cellular Microenvironment; Chronic Disease; Disease Progression; Disease Susceptibility; Fatty Acids; Humans; Immune System; Immunomodulation; Inflammation; Leptin; Myeloid-Derived Suppressor Cells; Neoplasms; Obesity

The pathogenesis of osteoarthritis (OA) is not clear; leptin may be related to its pathogenesis.. We reviewed articles on leptin in OA, chondrocytes, and in vitro experiments. It is concluded that leptin may lead to OA via some signaling pathways. At the same time, the concentration of leptin in vitro experiments and OA/rheumatoid arthritis (RA) patients was summarized.. Leptin levels in serum and synovial fluid of OA/RA patients were higher than normal person. In the condition of infection and immunity, serum leptin levels in the peripheral blood significantly increase. Because of the close relationship between obesity, leptin, and OA, it is crucial to study the effects of weight loss and exercise intervention on serum leptin levels to improve the symptoms of OA patients.. Treatment for leptin-increased obesity may be a treatment for OA. The role of leptin in OA cannot be ignored and needs to be further studied.

Topics: Arthritis, Rheumatoid; Chondrocytes; Humans; Leptin; Obesity; Osteoarthritis; Risk Factors; Signal Transduction; Synovial Fluid; Weight Loss

Obesity (especially visceral adiposity) can be associated with 3 different phenotypes of heart failure: heart failure with a reduced ejection fraction, heart failure with a preserved ejection fraction, and high-output heart failure. All 3 phenotypes are characterized by an excessive secretion of aldosterone and sodium retention. In addition, obesity is accompanied by increased signaling through the leptin receptor, which can promote activation of both the sympathetic nervous system and the renin-angiotensin system and can directly stimulate the secretion of aldosterone. The deleterious interaction of leptin and aldosterone is potentiated by the simultaneous action of adiposity and the renal sympathetic nerves to cause overactivity of neprilysin; the loss of the counterbalancing effects of natriuretic peptides is exacerbated by an additional effect of both obesity and heart failure to interfere with adiponectin signaling. This intricate neurohormonal interplay leads to plasma volume expansion as well as to adverse ventricular remodeling and cardiac fibrosis. Furthermore, the activity of aldosterone and neprilysin is not only enhanced by obesity, but these mechanisms can also promote adipogenesis and adipocyte dysfunction, thereby enhancing the positive feedback loop. Last, in elderly obese women, changes in quantity and biology of epicardial adipose tissue further enhances the release of leptin and other proinflammatory adipokines, thereby leading to cardiac and systemic inflammation, end-organ fibrosis, and multiple comorbidities. Regardless of the phenotypic expression, activation of the leptin-aldosterone-neprilysin axis appears to contribute importantly to the evolution and progression of heart failure in people with obesity. Efforts to interfere with the detrimental interactions of this distinctive neurohormonal ecosystem with existing or novel therapeutic agents are likely to yield unique clinical benefits.

Topics: Adipose Tissue; Adiposity; Aldosterone; Heart Failure; Heart Ventricles; Humans; Leptin; Neprilysin; Obesity; Phenotype; Prognosis; Risk Factors; Signal Transduction; Stroke Volume; Sympathetic Nervous System; Ventricular Function, Left

The rates of obesity are increasing worldwide and this condition is now recognized as a leading preventable cause of cancer. Several diseases are directly related to obesity, including diabetes, hypertension, atherosclerosis, stroke, musculoskeletal disorders, and a diverse range of malignances-such as breast cancer. Obesity is associated with an increased risk of postmenopausal estrogen receptor-positive breast cancer and worse cancer-related outcomes for all breast tumor subtypes. Several mechanisms have been proposed to contribute to the obesity-cancer link, including high levels of circulating and local estrogens, altered amounts of adipokines (leptin and adiponectin), disrupted insulin/IGF signaling, modifications within the microbiome, and local and systemic effects of inflammation. Here we will review recent advances in our understanding of the complex signaling pathways underlying the obesity-cancer link. An improved understanding of these processes is anticipated to propel novel and effective intervention strategies to reduce the global obesity-cancer burden.

Topics: Adipokines; Adiponectin; Breast Neoplasms; Estrogens; Female; Humans; Inflammation; Leptin; Metabolic Networks and Pathways; Obesity; Receptors, Estrogen; Risk Factors

Obesity-related sleep breathing disorders such as obstructive sleep apnea (OSA) and obesity hypoventilation syndrome (OHS) cause intermittent hypoxia (IH) during sleep, a powerful trigger of oxidative stress. Obesity also leads to dramatic increases in circulating levels of leptin, a hormone produced in adipose tissue. Leptin acts in the hypothalamus to suppress food intake and increase metabolic rate. However, obese individuals are resistant to metabolic effects of leptin. Leptin also activates the sympathetic nervous system without any evidence of resistance, possibly because these effects occur peripherally without a need to penetrate the blood-brain barrier. IH is a potent stimulator of leptin expression and release from adipose tissue. Hyperleptinemia and leptin resistance may upregulate generation of reactive oxygen species, increasing oxidative stress and promoting inflammation. The current review summarizes recent data on a possible link between leptin and oxidative stress in the pathogenesis of sleep breathing disorders.

Topics: Humans; Hypoxia; Leptin; Obesity; Oxidative Stress; Sleep Apnea, Obstructive

Obesity is strongly associated with leptin resistance. It is unclear whether leptin resistance results from the (over)consumption of energy-dense diets or if reduced leptin sensitivity is also a pre-existing factor in rodent models of diet-induced obesity (DIO). We here tested whether leptin sensitivity on a chow diet predicts subsequent weight gain and leptin sensitivity on a free choice high-fat high-sucrose (fcHFHS) diet.. Based upon individual leptin sensitivity on chow diet, rats were grouped in leptin sensitive (LS, n = 22) and leptin resistant (LR, n = 19) rats (P = 0.000), and the development of DIO on a fcHFHS diet was compared. The time-course of leptin sensitivity was measured over weeks in individual rats.. Both on a chow and a fcHFHS diet, high variability in leptin sensitivity was observed between rats, but not over time per individual rat. Exposure to the fcHFHS diet revealed that LR rats were more prone to develop DIO (P = 0.013), which was independent of caloric intake (p ≥ 0.320) and the development of diet-induced leptin resistance (P = 0.769). Reduced leptin sensitivity in LR compared with LS rats before fcHFHS diet exposure, was associated with reduced leptin-induced phosphorylated signal transducer and activator of transcription 3 (pSTAT3) levels in the dorsomedial and ventromedial hypothalamus (P ≤ 0.049), but not the arcuate nucleus (P = 0.558).. A pre-existing reduction in leptin sensitivity determines the susceptibility to develop excessive DIO after fcHFHS diet exposure. Rats with a pre-existing reduction in leptin sensitivity develop excessive DIO without eating more calories or altering their leptin sensitivity.

Topics: Animals; Diet; Dietary Fats; Leptin; Metabolic Diseases; Obesity; Rats; Sucrose

One-third of men with obesity or type 2 diabetes have subnormal free testosterone concentrations. The lower free testosterone concentrations are observed in obese men at all ages, including adolescents at completion of puberty. The gonadotropin concentrations in these males are inappropriately normal; thus, these patients have hypogonadotropic hypogonadism (HH). The causative mechanism of diabesity-induced HH is yet to be defined but is likely multifactorial. Decreased insulin and leptin signaling in the central nervous system are probably significant contributors. Contrary to popular belief, estrogen concentrations are lower in men with HH. Men with diabesity and HH have more fat mass and are more insulin resistant than eugonadal men. In addition, they have a high prevalence of anemia and higher mortality rates than eugonadal men. Testosterone replacement therapy results in a loss of fat mass, gain in lean mass, and increase in insulin sensitivity in men with diabesity and HH. This is accompanied by an increase in insulin-signaling genes in adipose tissue and a reduction in inflammatory mediators that interfere with insulin signaling. There is also an improvement in sexual symptoms, anemia, LDL cholesterol, and lipoprotein (a). However, testosterone therapy does not consistently affect HbA

Topics: Diabetes Mellitus, Type 2; Humans; Hypogonadism; Insulin; Insulin Resistance; Leptin; Male; Metabolic Syndrome; Obesity; Prevalence; Testosterone

Leptin and its receptor are widely distributed in several tissues, mainly in white adipose tissue. The serum leptin is highly correlated with body mass index in rodents and humans, being documented that leptin levels reduces in the fasting state and increase during refeeding, similarly to insulin release by pancreatic islets. Insulin appears to increase leptin mRNA and protein expression and its release by adipocytes. Some studies have suggested that insulin acts through the activation of the transcription factors: sterol regulatory element binding protein 1 (SREBP1), CCAAT enhancer binding protein-α (C/EBP-α) and specificity protein 1 (Sp1). Insulin stimulates the release of preformed and newly synthesized leptin by adipocytes through its signaling cascade. Its effects are blocked by inhibitors of the insulin signaling pathway, as well as by inhibitors of protein synthesis and agents that increase the intracellular cAMP. The literature data suggest that chronic hyperinsulinemia increases serum leptin levels in humans and rodents. In this review, we summarized the most updated knowledge on the effects of insulin on serum leptin levels, presenting the cell mechanisms that control leptin synthesis and release by the white adipose tissue.

Topics: Adipose Tissue, White; Animals; Glucose; Humans; Insulin; Insulin-Like Growth Factor I; Leptin; Mechanistic Target of Rapamycin Complex 1; Mice, Obese; Obesity; Phosphatidylinositol 3-Kinases; Rats, Sprague-Dawley; Sterol Regulatory Element Binding Protein 1

It is well established that obesity increases the incidence and worsens the prognosis of women's cancer. For breast cancer, women with obesity exhibit more than a twofold increase in the odds of being diagnosed with cancer, with a greater risk of advanced stage at diagnosis, and ≤40% greater risk of recurrence and death than their normal-weight counterparts. These findings are similar in gynecologic cancers, where women who are obese with a body mass index (BMI) >40 kg/m2 have up to six times greater risk of developing endometrial cancer and a 9.2% increase in mortality with every 10% increase in BMI. Likewise, patients with obesity exhibit a twofold higher risk of premenopausal ovarian cancer, and patients who are obese with advanced stage ovarian cancer have shown a shorter time to recurrence and poorer overall survival. Obesity is accompanied by changes in expression of adipose factors that act on local tissues and systemically. Once obesity was recognized as a factor in cancer incidence and progression, the adipose cytokine (adipokine) leptin became the focus of intense investigation as a putative link, with nearly 3000 publications on the topic. Leptin has been shown to increase cell proliferation, inhibit apoptosis, promote angiogenesis, and increase therapeutic resistance. These characteristics are associated with a subset of cells in both liquid and solid tumors known as cancer stem cells (CSCs), or tumor initiating cells. We will review the literature discussing leptin's role in breast and gynecologic cancer, focusing on its role in CSCs, and consider goals for targeting future therapy in this arena to disrupt tumor initiation and progression in women's cancer.

Topics: Body Mass Index; Breast Neoplasms; Female; Genital Neoplasms, Female; Humans; Leptin; Mortality; Neoplastic Stem Cells; Obesity; Prognosis

Many studies have indicated that leptin is correlated with breast cancer occurrence and tumor behavior. However, this issue remains controversial. Therefore, we conducted an updated meta-analysis to investigate the role of leptin in breast cancer.. We performed a systematic literature search and identified relevant papers up to 1 September 2017. Standardized mean differences (SMDs) with 95% confidence intervals (CIs) were used to evaluate effect sizes.. Thirty-five eligible studies were included in the current meta-analysis. Serum leptin levels were related to breast cancer risk as demonstrated by calculations of the overall SMD = 0.46 (95% CI = 0.31-0.60, I = 93.5%). A subgroup analysis of BMI identified an association between breast cancer and serum leptin levels in patients who are overweight and obese (overweight: SMD = 0.35, 95% CI = 0.13-0.57, I = 88.1%; obesity: SMD = 1.38, 95% CI = 0.64-2.12, I = 89.6%). Additionally, menopausal status subgroup analysis revealed a significant association in postmenopausal women (SMD = 0.26, 95% CI = 0.12-0.40, I = 77.9%). Furthermore, we identified a significant association between breast cancer and serum leptin levels in Chinese women (SMD = 0.61, 95% CI = 0.44-0.79, I = 40.6%).. The results of this meta-analysis suggested that leptin could be a potential biomarker for breast cancer risk in women, especially overweight/obese or postmenopausal women. Therefore, it may be useful for identifying subjects with a high risk for breast cancer who may benefit from preventive treatments.

Topics: Biomarkers, Tumor; Breast Neoplasms; Female; Humans; Leptin; Menopause; Obesity; Overweight; Risk Factors

Breastfed infants have a growth pattern that is different from formula-fed infants, which is regarded as the optimal growth pattern. Breastfed infants increase more in weight, length, and BMI during the first 2-3 months of life and then have a slower growth velocity up to 12 months. They also have a higher accumulation of fat during early infancy. Breastfed infants have lower levels of circulating IGF-I and insulin, which could be part of the explanation of their growth pattern. Many studies and meta-analyses have examined the association between breastfeeding and later obesity. Most find a moderate reduction in the risk of later obesity, but it has been argued that this could be biased due to residual confounding and reverse causation. From studies in low- and middle-income countries randomizing women to breastfeeding promotion, there was only little effect on early growth. Recent studies have found associations between breast milk composition (total fat, protein, human milk oligosaccharides, adiponectin, leptin, and insulin) and growth. However, the studies are few, and the results are inconsistent. More studies, including studies of maternal factors influencing breast milk composition, are needed to better understand how breastfeeding influences current and later growth and thereby short- and long-term health.

Topics: Adiponectin; Body Composition; Body Height; Body Mass Index; Body Weight; Breast Feeding; Child; Child, Preschool; Fats; Female; Humans; Infant; Infant Formula; Infant Nutritional Physiological Phenomena; Infant, Newborn; Insulin; Insulin-Like Growth Factor I; Leptin; Milk Proteins; Milk, Human; Obesity; Oligosaccharides; Poverty; Somatomedins; Weight Gain

Leptin levels may affect mortality through its link to inflammation and obesity. However, data are inconclusive. This meta-analysis was performed to investigate the association of leptin with mortality. The PubMed, Scopus, Google scholar, and reference lists of the included studies were searched for all published prospective observational studies that described the associations of serum leptin and mortality up to August 2017. Two reviewers independently assessed all potentially relevant studies for inclusion and methodological quality using standardized abstraction forms. Of 518 studies identified, 19 studies considered the association of leptin with all-cause mortality (16 208 subjects) and 12 studies evaluated the association of leptin with disease-specific mortality (13 680 subjects). In the overall analysis, no significant association was found between leptin and all-cause mortality (HR=1.028; 95% CI: 0.908-1.165; p=0.659), with a high between study heterogeneity (p˂0.001, I

Topics: Biomarkers; Humans; Leptin; Obesity; Observational Studies as Topic; Prospective Studies

This study aimed to investigate the comparison of G1359A variant of cannabinoid receptor gene (rs1049353) with obesity-related traits including body mass index (BMI), fat mass (FM), fat-free mass (FFM), food-related traits, and leptin among healthy and non-healthy adults.. We searched PubMed, Cochrane, Scopus, Web of Science, and EMBASE until December 2016 for observational studies assessing each of the anthropometric measurements, food-related traits, and leptin of 1359 G/A polymorphism of CNR1 gene. A total of 22 studies were included in the meta-analysis comparing mean and SD differences of the anthropometric measurements, leptin, and dietary intake between GA/AA and GG genotypes.. The results showed that subjects with GA/AA genotype had significantly lower BMI (weighted mean difference = -0.59 kg/m2, p < 0.001) compared to those with the GG genotype. Dietary intake of fat, carbohydrate, and protein as well as serum levels of leptin was not significantly different between GA/AA and GG genotypes.. It was revealed that subjects with mutant polymorphism (GA/AA) of CNR1, compared to the wild-type group (GG), had lower BMI (although there was unexplained heterogeneity).

Topics: Body Mass Index; Diet; Endophenotypes; Genotype; Humans; Leptin; Obesity; Receptor, Cannabinoid, CB1

This review aims to present current information on genes underlying severe obesity, with the main emphasis on the three genes LEP, LEPR and MC4R.. There is a substantial amount of evidence that variants in at least ten different genes are the cause of severe monogenic obesity. The majority of these are involved in the leptin-melanocortin signalling pathway. Due to the frequency of some of the identified variants, it is clear that monogenic variants also make a significant contribution to common obesity. The artificial distinction between rare monogenic obesity and common polygenic obesity is now obsolete with the identification of MC4R variants of strong effect in the general population.

Topics: Body Mass Index; Genetic Predisposition to Disease; Humans; Leptin; Obesity; Receptor, Melanocortin, Type 4; Receptors, Leptin

Obesity has become a major health concern in modern times, as it significantly increases the risk for the development of cardiovascular diseases, type 2 diabetes mellitus, and some types of cancer. The obesity epidemic has brought considerable attention to the molecular mechanisms through which adipocyte-secreted adipokines regulate physiological processes involved in metabolic and inflammatory diseases. Among them, leptin is considered as one of the principal regulators of a variety of physiological processes, including appetite and energy metabolism, through its binding to a variety of receptors and in particular by signaling through the long isoform receptor ObRb. Leptin signaling in the brain via ObRb plays an important role in the regulation of appetite and food intake, and involves several signaling pathways that either upregulate or attenuate leptin's anorexigenic response. This review describes ObRb-dependent, leptin-induced signaling pathways implicated in the control of appetite and energy metabolism in the organism, based on current information from animal models.

Topics: Animals; Appetite Regulation; Humans; Leptin; Obesity; Signal Transduction

Leptin ingested as a component of breast milk is increasingly recognized to play a role in the postnatal programming of a healthy phenotype in adulthood. Besides its primary function in controlling body weight, leptin may be an essential nutrient required during lactation to ensure that the system controlling fat accumulation and body composition is well organized from the early stages of development. This review delves into the following topics: (1) the imprinted protective function of adequate leptin intake during lactation in future metabolic health; (2) the consequences of a lack of leptin intake or of alterations in leptin levels; and (3) the mechanisms described for the effects of leptin on postnatal programming. Furthermore, it highlights the importance of breastfeeding and the need to establish optimal or reference intake values for leptin during lactation to design patterns of personalized nutrition from early childhood.

Topics: Adipose Tissue; Adult; Body Composition; Body Weight; Breast Feeding; Child; Diet; Eating; Female; Humans; Lactation; Leptin; Milk, Human; Obesity

Receptors are the master regulators conveying the information provided by the hormone from the extracellular environment to the intracellular milieu. As a result, the level of receptors at the cell surface can determine the signaling strength. Regulation of receptor trafficking to the cell surface or receptor retention processes in intracellular compartments are key mechanisms for leptin receptor (ObR) activity. An alteration of these mechanisms leads to the development of obesity. However, the canonical mechanism of plasma membrane receptors activation is challenged by the discovery that intracellular receptors also have their own signaling activity inside specific intracellular compartments. These intracellular receptors can trigger signaling that regulates a particular function, different from, or in continuity with, surface receptor signaling. We will address both these aspects by focusing particularly on the case of the leptin receptor (ObR), i.e., i) the regulation of its level of exposure to the cell surface and its impact on the development of obesity, and ii) the discovery of its location and signaling in some intracellular compartments.

Topics: Animals; Cell Membrane; Humans; Leptin; Obesity; Organelles; Protein Transport; Receptors, Leptin; Signal Transduction; Subcellular Fractions

Obesity stands as one of the greatest healthcare challenges of the 21

Topics: Animals; Female; Humans; Infertility, Male; Leptin; Male; Obesity; Reproductive Health; Spermatogenesis; Testis

Obesity is a major public health problem. The prevalence of obesity has significantly increased in developed countries, particularly in France with an overall increase of 76% over the last 15 years. In pregnant women, obesity is associated with alterations in the quality of labor, such as delayed onset of labor, a higher rate of prolonged pregnancies, prolonged labor, and higher oxytocin requirements. There is also an increased prevalence of Cesarean sections, particularly during the active phase of labor, and perinatal complications (postpartum hemorrhage). It seems that some of these functional changes and their consequences can be attributed to a disruption of hormonal balance encountered in obese women and involving adipokines (apelin, ghrelin, visfatin, leptin), but also to the interactions between adipose tissue and the "oxytocin (OT) - oxytocin receptor (OTR)". In this review, we detailed mechanisms to understand the impact of specific metabolic alterations in obesity on uterine contractility. Better knowledge of the impact of obesity on labor and delivery pathophysiology should strengthen the prevention of obesity in women of childbearing age and provide a suitable and effective management. The beneficial effect of weight loss and exercise in non-pregnant women on the correction of metabolic disorders secondary to obesity should be studied in populations of overweight women to demonstrate its effectiveness.

Topics: Adipokines; Adolescent; Adult; Apelin; Delivery, Obstetric; Female; Humans; Labor, Obstetric; Leptin; Muscle Contraction; Obesity; Oxytocin; Pregnancy; Pregnancy Complications; Uterine Contraction; Young Adult

Obesity is a global health problem even among pregnant women. Obesity alters quality of labor, such as preterm labor, prolonged labor, and higher oxytocin requirements in pregnant women. The most important factors to play a role in the altered gestational period and serve as drug targets to treat the consequences are female sexual hormones, calcium channels, adrenergic system, oxytocin, and prostaglandins. However, we have limited information about the impact of obesity on the pregnant uterine contractility and gestation time. Adipose tissue, which is the largest endocrine and paracrine organ, especially in obesity, is responsible for the production of adipokines and various cytokines and chemokines, and there are no reliable data available describing the relation between body mass index, glucose intolerance, and adipokines during pregnancy. Recent data suggest that the dysregulation of leptin, adiponectin, and kisspeptin during pregnancy contributes to gestational diabetes mellitus and pre-eclampsia. A preclinical method for obese pregnancy should be developed to clarify the action of adipokines and assess their impact in obesity. The deeper understanding of the adipokines-induced processes in obese pregnancy may be a step closer to the prevention and therapy of preterm delivery or prolonged pregnancy. Gestational weight gain is one of the factors that could influence the prenatal development, birth weight, and adiposity of newborn.

Topics: Adipokines; Adiponectin; Birth Weight; Body Mass Index; Female; Gestational Age; Humans; Infant, Newborn; Kisspeptins; Leptin; Obesity; Pregnancy; Uterus; Weight Gain

Overweight is believed to be associated with colorectal cancer risk. Adipose tissue is loose connective tissue composed of adipocytes. It is now recognized as a major endocrine organ, secreting humoral factors collectively called adipokines. Aberrant hormonal systems consisting of modulated adipokines and their receptors are thought to play a role in colorectal carcinogenesis and cancer progression in obese conditions. However, it is still unclear whether and how each adipokine relates to colorectal carcinogenesis. Notably, a couple of molecules that were initially proposed to be obesity-related adipokines were disqualified by subsequent studies. The adipokines, adiponectin, and intelectin-1 (also known as omentin-1), whose levels are decreased in obesity, act as tumor suppressor factors in various cancers. Numerous studies have demonstrated a link between the insufficient expression and function of adiponectin and its receptor, T-cadherin, in colorectal carcinogenesis. Moreover, our recent study indicated that loss of TMEM207, which is critical for the proper processing of intelectin-1 in the colon mucosa, leads to insufficient intelectin-1 production, thus participating in colorectal carcinogenesis. Here, we discuss the recent understanding of the role of adipokines in colorectal carcinogenesis and subsequently describe the potent tumor suppressor roles of intelectin-1 and TMEM207 in colorectal cancer.

Topics: Adipokines; Adiponectin; Animals; Carrier Proteins; Cell Transformation, Neoplastic; Colorectal Neoplasms; Cytokines; GPI-Linked Proteins; Humans; Lectins; Leptin; Membrane Proteins; Obesity; Overweight; Receptors, Adipokine

Obesity is metabolic disorder that increases the risk of diabetes, heart disease, and other metabolic syndromes in human beings. One sign of diabetes is increased blood glucose levels in the body. Glucose levels increase due to problems with insulin secretion or insulin resistance. Maturity onset of diabetes of the young is more common in adults and occurs due to insulin resistance. Both diabetes and obesity are major problems that are responsible for the death of millions of individuals every year, worldwide. Leptin, a 164-KDa hormone that is secreted by white adipose tissue, is a product of the lep gene. Mutation in lep decreases leptin concentration and increases obesity and type-2 diabetes mellitus. Leptin has been shown to produce positive effects on hunger, energy expenditure, and behavior and is thus useful in the treatment of obesity and type-2 diabetes. Leptin controls appetite through its effect on the hypothalamus in the brain. Both leptin and insulin regulate appetite, body weight, and glucose levels in the body.

Topics: Diabetes Mellitus, Type 2; Humans; Insulin Resistance; Leptin; Obesity

Metabolic adaptations occur with weight loss that result in increased hunger with discordant simultaneous reductions in energy requirements-producing the so-called

Topics: Appetite; Basal Metabolism; Diet, Reducing; Energy Intake; Energy Metabolism; Ghrelin; Humans; Hunger; Leptin; Life Style; Obesity; Thermodynamics; Weight Gain; Weight Loss

The major health issue of being overweight or obese relates to the development of hypertension, insulin resistance and diabetic complications. One of the major underlying factors influencing the elevated blood pressure in obesity is increased activity of the sympathetic nerves to particular organs such as the kidney.. There is now convincing evidence from animal studies that major signals such as leptin and insulin have a sympathoexcitatory action in the hypothalamus to cause hypertension. Recent studies suggest that this may involve 'neural plasticity' within hypothalamic signalling driven by central actions of leptin mediated via activation of melanocortin receptor signalling and activation of brain neurotrophic factors. This review describes the evidence to support the contribution of the SNS to obesity related hypertension and the major metabolic and adipokine signals.

Topics: Animals; Humans; Hypertension; Hypothalamus; Leptin; Obesity; Risk Factors; Signal Transduction; Sympathetic Nervous System

Obesity-related co-morbidities decrease life quality, reduce working ability and lead to early death. The total amount of dietary fat consumption may be the most potent food-related risk factor for weight gain. In this respect, dietary intake of high-caloric, high-fat diets due to chronic over-eating and sedentary lifestyle lead to increased storage of triglycerides not only in adipose tissue but also ectopically in other tissues . Increased plasma concentrations of non-esterified free fatty acids and lipid-overloaded hypertrophic adipocytes may cause insulin resistance in an inflammation-independent manner. Even in the absence of metabolic disorders, mismatch between fatty acid uptake and utilization leads to the accumulation of toxic lipid species resulting in organ dysfunction. Lipid-induced apoptosis, ceramide accumulation, reactive oxygen species overproduction, endoplasmic reticulum stress, and mitochondrial dysfunction may play role in the pathogenesis of lipotoxicity. The hypothalamus senses availability of circulating levels of glucose, lipids and amino acids, thereby modifies feeding according to the levels of those molecules. However, the hypothalamus is also similarly vulnerable to lipotoxicity as the other ectopic lipid accumulated tissues. Chronic overnutrition most likely provides repetitive and persistent signals that up-regulate inhibitor of nuclear factor kappa B kinase beta subunit/nuclear factor kappa B (IKKβ/NF-κB) in the hypothalamus before the onset of obesity. However, the mechanisms by which high-fat diet induced peripheral signals affect the hypothalamic arcuate nucleus remain largely unknown. In this chapter, besides lipids and leptin, the role of glucose and insulin on specialized fuel-sensing neurons of hypothalamic neuronal circuits has been debated.

Topics: Death; Feeding Behavior; Glucose; Humans; Hyperphagia; Hypothalamus; Insulin; Leptin; Lipid Metabolism; Obesity; Signal Transduction

Obesity is associated with low-grade inflammation. Leptin, a hormone made by fat cells regulates appetite and hunger and thus food intake behavior. Interestingly, , food preservatives like sodium sulfite and sodium benzoate and also natural colorant and spice compounds such as curcumin were found to decrease the release of leptin in murine 3T3-L1 adipocytes, after co-incubation with LPS, which was added to mimic the pro-inflammatory status in obesity. Several of these compounds are well known food antioxidants.Whilst reducing oxidation events is beneficial in states of elevated oxidative stress, overexposure to food antioxidant can lead to adverse effects. There are hints from in vivo data, that antioxidant stress in younger age plays a role in the development of adiposity in later life. The insufficient exposure to oxidizing compounds like reactive oxygen species (ROS) cannot only cause an insufficient burning of calories but there is also a link to the regulation of food intake behavior. If the in vitro findings can be extrapolated to the in vivo situation, consumption of antioxidant supplemented food could lead to decreased leptin release and contribute to an obesogenic environment. This aspect sheds some new critical light on the potential role of an antioxidant-enriched nutrition in the obesity epidemic during the past few centuries. Doing sports could represent not only a proper strategy to initiate physiological ROS production and burning of calories, but also may shift the hormone milieu towards a reduction of hunger feelings and thus reduce appetite and food intake.

Topics: Adipocytes; Animals; Antioxidants; Humans; Inflammation; Leptin; Obesity; Oxidative Stress

Leptin signaling blockade by chronic overstimulation of the leptin receptor or hypothalamic pro-inflammatory responses due to elevated levels of saturated fatty acid can induce leptin resistance by activating negative feedback pathways. Although, long form leptin receptor (Ob-Rb) initiates leptin signaling through more than seven different signal transduction pathways, excessive suppressor of cytokine signaling-3 (SOCS-3) activity is a potential mechanism for the leptin resistance that characterizes human obesity. Because the leptin-responsive metabolic pathways broadly integrate with other neurons to control energy balance, the methods used to counteract the leptin resistance has extremely limited effect. In this chapter, besides the impairment of central and peripheral leptin signaling pathways, limited access of leptin to central nervous system (CNS) through blood-brain barrier, mismatch between high leptin and the amount of leptin receptor expression, contradictory effects of cellular and circulating molecules on leptin signaling, the connection between leptin signaling and endoplasmic reticulum (ER) stress and self-regulation of leptin signaling has been discussed in terms of leptin resistance.

Topics: Animals; Diet; Eating; Feeding Behavior; Humans; Hypothalamus; Leptin; Obesity; Receptors, Leptin; Signal Transduction

Several studies show that a significantly stronger association is obvious between increased body mass index (BMI) and higher breast cancer incidence. Furthermore, obese women are at higher risk of all-cause and breast cancer specific mortality when compared to non-obese women with breast cancer. In this context, increased levels of estrogens due to excessive aromatization activity of the adipose tissue, overexpression of pro-inflammatory cytokines, insulin resistance, hyperactivation of insulin-like growth factors (IGFs) pathways, adipocyte-derived adipokines, hypercholesterolemia and excessive oxidative stress contribute to the development of breast cancer in obese women. While higher breast cancer risk with hormone replacement therapy is particularly evident among lean women, in postmenopausal women who are not taking exogenous hormones, general obesity is a significant predictor for breast cancer. Moreover, increased plasma cholesterol leads to accelerated tumor formation and exacerbates their aggressiveness. In contrast to postmenopausal women, premenopausal women with high BMI are inversely associated with breast cancer risk. Nevertheless, life-style of women for breast cancer risk is regulated by avoiding the overweight and a high-fat diet. Estrogen-plus-progestin hormone therapy users for more than 5 years have elevated risks of both invasive ductal and lobular breast cancer. Additionally, these cases are more commonly node-positive and have a higher cancer-related mortality. Collectively, in this chapter, the impacts of obesity-related estrogen, cholesterol, saturated fatty acid, leptin and adiponectin concentrations, aromatase activity, leptin and insulin resistance on breast cancer patients are evaluated. Obesity-related prognostic factors of breast cancer also are discussed at molecular basis.

Topics: Breast Neoplasms; Cholesterol; Female; Humans; Insulin Resistance; Leptin; Obesity; Risk Factors

This meta-analysis provides an updated and comprehensive estimate of the effects of obesity on metabolic disorders in adolescent polycystic ovary syndrome (PCOS). Relevant articles consistent with the search terms published up to 31 January 2014 were retrieved from PubMed, EMBASE, PsycINFO and CENTRAL. Thirteen articles (16 independent studies) conformed to the inclusion criteria. The evaluated outcomes were the metabolic parameters of obese adolescents with PCOS (case group) relative to normal-weight adolescents with PCOS, or obese adolescents without PCOS. Compared with normal-weight adolescents with PCOS, the case group had significantly lower sex hormone-binding globulin and high-density lipoprotein cholesterol, and significantly higher triglycerides, leptin, fasting insulin, low-density lipoprotein cholesterol and free testosterone levels. Relative to obese adolescents without PCOS, the case group had significantly higher fasting insulin, low-density lipoprotein cholesterol, free testosterone levels and 2-h glucose during the oral glucose tolerance test. These results indicate that metabolic disorders in adolescent PCOS are worsened by concomitant obesity. This study highlights the importance of preventing obesity during the management of adolescent PCOS. Impact statement What is already known about this subject: Obesity and PCOS share many of the same metabolic disorders, for example, hyperandrogenism and hyperinsulinemia with subsequent insulin resistance. Knowledge regarding metabolic features in obese adolescents with PCOS is limited, and there is concern whether obesity and PCOS are related. What do the results of this study add: Relative to PCOS adolescents of normal weight, obese adolescents with PCOS (the case group) had significantly lower SHBG and HDL-C, and significantly higher triglycerides, leptin, fasting insulin, LDL-C and free testosterone levels. The results indicate that metabolic disorders in adolescent PCOS are worsened by concomitant obesity. What are the implications of these findings for clinical practice and/or further research: Obesity, metabolic disorders and PCOS in adolescents are associated. Obesity exacerbates metabolic disorders in adolescent PCOS. This study highlights the importance of preventing obesity during the management of adolescent PCOS. Therapeutic intervention combined with lifestyle modification may provide better treatment for adolescent PCOS. The aetiologies of PCOS combined with obesity in adolescents re

Topics: Adolescent; Blood Glucose; Body Mass Index; Cholesterol, HDL; Cholesterol, LDL; Female; Glucose Tolerance Test; Humans; Insulin; Leptin; Metabolic Diseases; Obesity; Polycystic Ovary Syndrome; Sex Hormone-Binding Globulin; Testosterone; Triglycerides

Leptin has been implicated in bone metabolism, but the association with parathyroid gland function has not been fully clarified. This review aimed to summarize evidence of the association between leptin and hyperparathyroidism, both primary and secondary, elucidating the potential pathophysiologic and therapeutic consequences between leptin and parathyroid hormone, hopefully prompting the design of new studies.. Experimental studies indicate a positive loop between leptin and parathyroid hormone in primary hyperparathyroidism. Dissimilar, parathyroid hormone seems to inhibit leptin expression in severe secondary hyperparathyroidism. Data from clinical studies indicate higher leptin levels in patients with primary hyperparathyroidism than controls, but no association between parathyroid hormone and leptin levels, as well as a minimal or neutral effect of parathyroidectomy on leptin levels in patients with primary hyperparathyroidism. Clinical data on secondary hyperparathyroidism, mainly derived from patients with chronic kidney disease, indicate a potential inverse association between leptin and parathyroid hormone in some, but not all studies. This relationship may be affected by the diversity of morbidity among these patients.. Data from experimental studies suggest a different association between leptin and parathyroid hormone in primary and secondary hyperparathyroidism. Data from clinical studies are conflicting and potentially affected by confounders. More focused, well-designed studies are warranted to elucidate a potential association between leptin and parathyroid hormone, which may have specific clinical implications, i.e., targeting obesity and hyperleptinemia in patients with hyperparathyroidism.

Topics: Adipose Tissue, White; Animals; Anti-Obesity Agents; Chief Cells, Gastric; Hormone Replacement Therapy; Humans; Hyperparathyroidism, Primary; Hyperparathyroidism, Secondary; Insulin Resistance; Leptin; Models, Biological; Obesity; Parathyroid Glands; Parathyroid Hormone; Recombinant Proteins; Reproducibility of Results; Severity of Illness Index

Accumulating evidence links obesity with low-grade inflammation which may originate from adipose tissue that secretes a plethora of pro- and anti-inflammatory cytokines termed adipokines. Adiponectin and leptin have evolved as crucial signals in many obesity-related pathologies including non-alcoholic fatty liver disease (NAFLD). Whereas adiponectin deficiency might be critically involved in the pro-inflammatory state associated with obesity and related disorders, overproduction of leptin, a rather pro-inflammatory mediator, is considered of equal relevance. An imbalanced adipokine profile in obesity consecutively contributes to metabolic inflammation in NAFLD, which is associated with a substantial risk for developing hepatocellular carcinoma (HCC) also in the non-cirrhotic stage of disease. Both adiponectin and leptin have been related to liver tumorigenesis especially in preclinical models. This review covers recent advances in our understanding of some adipokines in NAFLD and associated HCC.

Topics: Adiponectin; Animals; Carcinoma, Hepatocellular; Humans; Leptin; Liver Neoplasms; Neoplasm Proteins; Non-alcoholic Fatty Liver Disease; Obesity

Leptin is a peptide hormone produced mainly in white adipose tissue. It is known to regulate energy homeostasis, inflammation, metabolism, and sympathetic nerve activity. Increasing evidence suggests it has a role in ventilatory function and upper airway obstruction. Leptin levels correlate positively with measurements of adiposity and can potentially provide important insights into the pathophysiology of diseases associated with obesity. Obesity is a strong risk factor for obstructive sleep apnea, a disease characterized by periodic upper airway occlusion during sleep. The neuromuscular activity that maintains upper airway patency during sleep and the anatomy of upper airway are key factors involved in its pathogenesis. Experimental studies using animal models of a low leptin state such as leptin deficiency have shown that leptin regulates sleep architecture, upper airway patency, ventilatory function, and hypercapnic ventilatory response. However, findings from human studies do not consistently support the data from the animal models. The effect of leptin on the pathophysiology of obstructive sleep apnea is being investigated, but the results of studies have been confounded by leptin's diurnal variation and the short-term effects of feeding, adiposity, age, and sex. Improved study design and methods of assessing functional leptin levels, specifically their central versus peripheral effects, will improve understanding of the role of leptin in sleep apnea.

Topics: Animals; Biomarkers; Disease Models, Animal; Humans; Leptin; Mice; Obesity; Rats; Sleep; Sleep Apnea, Obstructive

Leptin is one of the major adipokines in obesity that indicates the severity of fat accumulation. It is also an important etiological factor of consequent cardiometabolic and autoimmune disorders. Aging has been demonstrated to aggravate obesity and to induce leptin resistance and hyperleptinemia. Hyperleptinemia, on the other hand, may promote the development of age-related abnormalities. While major weight loss has been demonstrated to ameliorate hyperleptinemia, obese people show a poor tendency to achieve lasting success in this field. The question arises whether training intervention per se is able to reduce the level of this adipokine.. We aimed to review the literature on the effects of training intervention on peripheral leptin level in obesity during aging, in order to evaluate the independent efficacy of this method. In the studies that were included in our analysis, changes of adiponectin levels (when present) were also evaluated.. 3481 records were identified through searching of PubMed, Embase and Cochrane Library Database. Altogether 19 articles were suitable for analyses.. Empirical research papers were eligible provided that they reported data of middle-aged or older (above 45 years of age) overweight or obese (body mass index above 25) individuals and included physical training intervention or at least fitness status of groups together with corresponding blood leptin values.. We used random effect models in each of the meta-analyses calculating with the DerSimonian and Laird weighting methods. I-squared indicator and Q test were performed to assess heterogeneity. To assess publication bias Egger's test was applied. In case of significant publication bias, the Duval and Tweedie's trim and fill algorithm was used.. Training intervention leads to a decrease in leptin level of middle-aged or older, overweight or obese male and female groups, even without major weight loss, indicated by unchanged serum adiponectin levels. Resistance training appears to be more efficient in reducing blood leptin level than aerobic training alone.. Physical training, especially resistance training successfully reduces hyperleptinemia even without diet or major weight loss.

Topics: Adult; Aged; Aging; Exercise; Female; Humans; Leptin; Male; Middle Aged; Obesity; Resistance Training

Obesity has been an epidemic worldwide over the past decades and significantly increases the risk of developing a variety of deadly diseases including type 2 diabetes, cardiovascular diseases and many cancers. The relationship between obesity and type 2 diabetes and cardiovascular disease has been well documented. The drastically increased frequency of a number of cancers in obesity has attracted growing interest. On one hand, how increased adiposity promotes cancer development remains poorly understood, despite the fact that considerable epidemiological evidence has suggested links between them. On the other hand, however, numerous studies have shown that tumorigenesis leads to substantial weight loss in a large portion of cancer patients. Here, we summarize the recent advances on our understanding of the link between obesity and cancer development with a focus on the molecular mechanisms accounting for the rising cancer incidence in the context of obesity. In addition, we also discuss how cancer-associated anorexia and cachexia causes weight loss. © 2017 IUBMB Life, 69(10):776-784, 2017.

Topics: Anorexia; Body Mass Index; Cachexia; Cytokines; Energy Metabolism; Gene Expression Regulation, Neoplastic; Humans; Insulin Resistance; Leptin; Neoplasms; NF-kappa B; Obesity; Receptors, Leptin; Risk Factors; Signal Transduction; STAT3 Transcription Factor

Food intake and energy expenditure are closely regulated by several mechanisms which involve peripheral organs and nervous system, in order to maintain energy homeostasis.Short-term and long-term signals express the size and composition of ingested nutrients and the amount of body fat, respectively. Ingested nutrients trigger mechanical forces and gastrointestinal peptide secretion which provide signals to the brain through neuronal and endocrine pathways. Pancreatic hormones also play a role in energy balance exerting a short-acting control regulating the start, end, and composition of a meal. In addition, insulin and leptin derived from adipose tissue are involved in long-acting adiposity signals and regulate body weigh as well as the amount of energy stored as fat over time.This chapter focuses on the gastrointestinal-, pancreatic-, and adipose tissue-derived signals which are integrated in selective orexigenic and anorexigenic brain areas that, in turn, regulate food intake, energy expenditure, and peripheral metabolism.

Topics: Adipose Tissue; Adiposity; Appetite Regulation; Body Weight; Brain; Eating; Energy Intake; Energy Metabolism; Gastrointestinal Hormones; Gastrointestinal Tract; Humans; Insulin; Insulin-Secreting Cells; Leptin; Obesity; Pancreas; Pancreatic Hormones

The hypothalamus is the brain region responsible for the maintenance of energetic homeostasis. The regulation of this process arises from the ability of the hypothalamus to orchestrate complex physiological responses such as food intake and energy expenditure, circadian rhythm, stress response, and fertility. Metabolic alterations such as obesity can compromise these hypothalamic regulatory functions. Alterations in circadian rhythm, stress response, and fertility further contribute to aggravate the metabolic dysfunction of obesity and contribute to the development of chronic disorders such as depression and infertility.At cellular level, obesity caused by overnutrition can damage the hypothalamus promoting inflammation and impairing hypothalamic neurogenesis. Furthermore, hypothalamic neurons suffer apoptosis and impairment in synaptic plasticity that can compromise the proper functioning of the hypothalamus. Several factors contribute to these phenomena such as ER stress, oxidative stress, and impairments in autophagy. All these observations occur at the same time and it is still difficult to discern whether inflammatory processes are the main drivers of these cellular dysfunctions or if the hypothalamic hormone resistance (insulin, leptin, and ghrelin) can be pinpointed as the source of several of these events.Understanding the mechanisms that underlie the pathophysiology of obesity in the hypothalamus is crucial for the development of strategies that can prevent or attenuate the deleterious effects of obesity.

Topics: Animals; Autophagy; Circadian Rhythm; Eating; Energy Metabolism; Fertility; Ghrelin; Homeostasis; Humans; Hypothalamus; Inflammation; Insulin; Leptin; Metabolic Diseases; Neuronal Plasticity; Obesity; Overnutrition; Oxidative Stress; Stress, Physiological

Despite the well-known global impact of overweight and obesity in the incidence of cerebrovascular disease, many aspects of this association are still inconsistently defined. In this chapter we aim to present a critical review on the links between obesity and both ischemic and hemorrhagic stroke and discuss its influence on functional outcomes, survival, and current treatments to acute and chronic stroke. The role of cerebrovascular endothelial function and respective modulation is also described as well as its laboratory and clinical assessment. In this context, the major contributing mechanisms underlying obesity-induced cerebral endothelial function (adipokine secretion, insulin resistance, inflammation, and hypertension) are discussed. A special emphasis is given to the participation of adipokines in the pathophysiology of stroke, namely adiponectin, leptin, resistin, apelin, and visfatin.

Topics: Adipokines; Adiponectin; Apelin; Brain Ischemia; Cerebrovascular Disorders; Endothelium, Vascular; Humans; Hypertension; Inflammation; Insulin Resistance; Intracranial Hemorrhages; Leptin; Nicotinamide Phosphoribosyltransferase; Obesity; Resistin; Stroke

In moderately or morbidly obese patients, bariatric surgery has been proven to be an effective therapeutic approach to control body weight and comorbidities. Surgery-mediated modulation of brain function via modified postoperative secretion of gut peptides and vagal nerve stimulation was identified as an underlying mechanism in weight loss and improvement of weight-related diseases. Increased basal and postprandial plasma levels of gastrointestinal hormones like glucagon-like peptide 1 and peptide YY that act on specific areas of the hypothalamus to reduce food intake, either directly or mediated by the vagus nerve, are observed after surgery while suppression of meal-induced ghrelin release is increased. Hormones released from the adipose tissue like leptin and adiponectin are also affected and leptin plasma levels are reduced in treated patients. Besides homeostatic control of body weight, surgery also changes hedonistic behavior in regard to food intake and cognitive performance involving the limbic system and prefrontal areas.

Topics: Adiponectin; Bariatric Surgery; Brain; Cognition; Eating; Energy Metabolism; Feeding Behavior; Ghrelin; Glucagon-Like Peptide 1; Homeostasis; Humans; Hypothalamus; Leptin; Limbic System; Obesity; Peptide YY; Prefrontal Cortex; Vagus Nerve

The adipocyte-released hormone-like cytokine/adipokine leptin behaves differently in obesity compared to its functions in the normal healthy state. In obese individuals, elevated leptin levels act as a pro-inflammatory adipokine and are associated with certain types of cancers. Further, a growing body of evidence suggests that higher circulating leptin concentrations and/or elevated expression of leptin receptors (Ob-R) in tumors may be poor prognostic factors. Although the underlying pathological mechanisms of leptin's association with poor prognosis are not clear, leptin can impact the tumor microenvironment in several ways. For example, leptin is associated with a number of biological components that could lead to tumor cell invasion and distant metastasis. This includes interactions with carcinoma-associated fibroblasts, tumor promoting effects of infiltrating macrophages, activation of matrix metalloproteinases, transforming growth factor-β signaling, etc. Recent studies also have shown that leptin plays a role in the epithelial-mesenchymal transition, an important phenomenon for cancer cell migration and/or metastasis. Furthermore, leptin's potentiating effects on insulin-like growth factor-I, epidermal growth factor receptor and HER2/neu have been reported. Regarding unfavorable prognosis, leptin has been shown to influence both adenocarcinomas and squamous cell carcinomas. Features of poor prognosis such as tumor invasion, lymph node involvement and distant metastasis have been recorded in several cancer types with higher levels of leptin and/or Ob-R. This review will describe the current scenario in a precise manner. In general, obesity indicates poor prognosis in cancer patients.

Topics: Animals; Cell Movement; Humans; Leptin; Neoplasm Metastasis; Neoplasms; Obesity; Signal Transduction

Leptin, the adipocyte-derived hormone identified in 1994 for its major role in the control of satiety and body weight regulation, is an adipokine secreted in a sex-specific manner. Although it has clearly been established that females secrete three to four times more leptin than males and that this sexual dimorphism in leptin secretion is exacerbated with overweight and obesity, the origin and the physiological consequences of this sexual dimorphism remain ill-defined. The adipose tissue is the major site of leptin secretion; however, leptin receptors are ubiquitously expressed, conferring to leptin, and indirectly to the adipose tissue, a potential role in the control of numerous physiological functions. Besides its major role in the control of food intake and energy expenditure, leptin has been shown to contribute to the control of immune, bone, reproductive, and cardiovascular functions. The goal of the present chapter is to review and discuss the current knowledge on the contribution of leptin to the control of cardiovascular function while focusing on the impact of the sexual dimorphism in leptin secretion and of the pathological increases in leptin levels induced by overweight and obesity.

Topics: Adipose Tissue; Animals; Biomarkers; Cardiovascular Diseases; Cardiovascular System; Female; Health Status Disparities; Humans; Leptin; Male; Metabolic Diseases; Obesity; Risk Factors; Sex Characteristics; Sex Factors

Adipose tissue has long been identified as the major site of vitamin D storage. Recent studies have demonstrated that VDR and vitamin D metabolizing enzymes are expressed in adipocytes. Furthermore, it has been shown that vitamin D regulates adipogenic gene expression as well as adipocyte apoptosis. Vitamin D is active in adipocytes at all levels. It interacts with membrane receptors, adaptor molecules, and nuclear coregulator proteins. Several functions of unliganded nVDR were discovered by studying human samples from patients having hereditary vitamin D resistant rickets, transgenic mice overexpressing the VDR and VDR knockout mice. Through its genomic action, vitamin D participates in the regulation of energy metabolism by controlling the expression of uncoupling proteins. In vitro, vitamin D stimulates lipogenesis and inhibits lipolysis by interacting with mVDR. mVDR is present in caveolae of the plasma membrane and is the same as the classic nVDR. In addition, vitamin D affects directly the expression of the appetite regulating hormone, leptin. Some researchers reported also that vitamin D regulates the expression of the insulin sensitizing hormone, adiponectin. Vitamin D reduced cytokine release and adipose tissue inflammation through the inhibition of NF-κB signaling. Scientific research investigating the role of adipose tissue resident immune cells in the pathogenesis of obesity-associated inflammation is scarce. Obesity is associated with vitamin D deficiency. However there is no scientific evidence to prove that vitamin D deficiency predispose to obesity. Vitamin D supplementation may prevent obesity but it does not lead to weight loss in obese subjects.

Topics: Active Transport, Cell Nucleus; Adipocytes; Adipogenesis; Adipose Tissue; Adolescent; Adult; Aged; Animals; Apoptosis; Calcitriol; Cell Membrane; Female; Gene Expression Regulation; Genomics; Humans; Inflammation; Leptin; Male; Mice; Middle Aged; Mitochondrial Uncoupling Proteins; Obesity; Receptors, Calcitriol; Vitamin D; Young Adult

With the still-growing prevalence of obesity worldwide, major efforts are made to understand the various behavioral, environmental, and genetic factors that promote excess fat gain. Obesity results from an imbalance between energy intake and energy expenditure, which emphasizes the importance of deciphering the mechanisms behind energy balance regulation to understand its physiopathology. The control of energy balance is assured by brain systems/circuits capable of generating adequate ingestive and thermogenic responses to maintain the stability of energy reserves, which implies a proper integration of the homeostatic signals that inform about the status of the energy stores. In this article, we overview the organization and functionality of key neuronal circuits or pathways involved in the control of food intake and energy expenditure. We review the role of the corticolimbic (executive and reward) and autonomic systems that integrate their activities to regulate energy balance. We also describe the mechanisms and pathways whereby homeostatic sensing is achieved in response to variations of homeostatic hormones, such as leptin, insulin, and ghrelin, while putting some emphasis on the prominent importance of the mechanistic target of the rapamycin signaling pathway in coordinating the homeostatic sensing process.

Topics: Animals; Eating; Energy Metabolism; Ghrelin; Homeostasis; Humans; Insulin; Leptin; Obesity; Thermogenesis

The vagal link between the gastrointestinal tract and the central nervous system (CNS) has numerous vital functions for maintaining homeostasis. The regulation of energy balance is one which is attracting more and more attention due to the potential for exploiting peripheral hormonal targets as treatments for conditions such as obesity. While physiologically, this system is well tuned and demonstrated to be effective in the regulation of both local function and promoting/terminating food intake the neural connection represents a susceptible pathway for disruption in various disease states. Numerous studies have revealed that obesity in particularly is associated with an array of modifications in vagal afferent function from changes in expression of signaling molecules to altered activation mechanics. In general, these changes in vagal afferent function in obesity further promote food intake instead of the more desirable reduction in food intake. It is essential to gain a comprehensive understanding of the mechanisms responsible for these detrimental effects before we can establish more effective pharmacotherapies or lifestyle strategies for the treatment of obesity and the maintenance of weight loss.

Topics: Animals; Cholecystokinin; Dipeptides; Eating; Gastrointestinal Tract; Ghrelin; Glucagon-Like Peptide 1; Humans; Leptin; Microbiota; Neuronal Plasticity; Obesity; Satiation; Signal Transduction; Vagus Nerve

Cardiovascular diseases (CVDs) are the number one cause of death globally. The risk for the development of CVDs is significantly increased in obesity. Leptin, the product of white adipose tissue, appears to contribute to the development of CVDs in obesity. Here, we discuss the premise that leptin engages the sympathetic nervous system and contributes to elevated blood pressure (BP) developing in obesity.. The long-term regulation of BP is dependent on the activity of the autonomic nervous system and specifically the sympathetic nervous system. Sympathetic nerve activity is significantly increased in obese rodents and humans. Leptin increases sympathetic nerve activity in rodents and humans; however, leptin only consistently increases BP chronically in rodents. The ability of leptin to increase BP in rodents is via both hypothalamic and extrahypothalamic regions. In leptin-deficient and leptin receptor-deficient humans, leptin appears to be the key reason for decreased systolic BP. However, in other research conducted in humans, chronic administration of leptin does not elevate BP.. Further research into the role of leptin in the development of CVDs, especially in humans, needs to be conducted.

Topics: Animals; Blood Pressure; Humans; Hypertension; Hypothalamus; Leptin; Obesity; Receptors, Leptin; Sympathetic Nervous System

Obesity and obstructive sleep apnea (OSA) have a reciprocal relationship. Sleep disruptions characteristic of OSA may promote behavioral, metabolic, and/or hormonal changes favoring weight gain and/or difficulty losing weight. The regulation of energy balance (EB), i.e., the relationship between energy intake (EI) and energy expenditure (EE), is complex and multi-factorial, involving food intake, hormonal regulation of hunger/satiety/appetite, and EE via metabolism and physical activity (PA). The current systematic review describes the literature on how OSA affects EB-related parameters. OSA is associated with a hormonal profile characterized by abnormally high leptin and ghrelin levels, which may encourage excess EI. Data on actual measures of food intake are lacking, and not sufficient to make conclusions. Resting metabolic rate appears elevated in OSA vs.. Findings on PA are inconsistent, but may indicate a negative relationship with OSA severity that is modulated by daytime sleepiness and body weight. A speculative explanation for the positive EB in OSA is that the increased EE via metabolism induces an overcompensation in the drive for hunger/food intake, which is larger in magnitude than the rise in EI required to re-establish EB. Understanding how OSA affects EB-related parameters can help improve weight loss efforts in these patients.

Topics: Eating; Energy Metabolism; Exercise; Humans; Leptin; Obesity; Polysomnography; Sleep Apnea, Obstructive

After its discovery as a key controller of metabolic function, leptin has been later extensively implicated in additional functions including important modulatory activities on the innate and adaptive immune response. This review analyzes the known implications of leptin in multiple inflammatory conditions, including autoimmune diseases, and how this knowledge could be instrumental in the design of leptin-based manipulation strategies to help restoration of abnormal immune responses.

Topics: Adaptive Immunity; Animals; Autoimmunity; Humans; Immunity, Innate; Inflammation; Leptin; Mice; Obesity

The incidence of obesity is rapidly escalating and has reached epidemic proportions. In all species, including rodents, humans, and sheep, there is large variation in the degree of weight gain across individuals in response to an obesogenic environment. This individual variation is, at least in part, determined by innate differences in energy expenditure, of which adaptive thermogenesis is a key component. The hypothalamus is essential to the control of body weight and adiposity. Appetite-regulating peptides within the hypothalamus exert reciprocal effects on food intake and energy expenditure, such that neuropeptides that stimulate food intake inhibit thermogenesis and vice versa. This review discusses the role of the hypothalamic neuropeptides in determining innate predisposition to obesity in 3 animal models being obesity-prone and obesity-resistant rodents, genetically lean and obese sheep, and animals selected for high/low cortisol responsiveness. In rodents, leptin resistance is a primary feature of the propensity to become obese. This contrasts that of larger mammals, such as sheep, where altered susceptibility to obesity manifests within the melanocortin and/or orexin pathways. This review highlights fundamental species differences within the hypothalamus that lead to altered susceptibility to weight gain and increased propensity to become obese.

Topics: Animals; Disease Models, Animal; Energy Metabolism; Humans; Hypothalamus; Leptin; Melanocortins; Models, Biological; Obesity; Orexins; Species Specificity; Thermogenesis

Aging is associated with dysregulation of glucose and lipid metabolism. Various factors that contribute to the dysregulation include both modifiable (e.g. obesity, insulin resistance) and non-modifiable risk factors (age-associated physiologic changes). Although there is no linear relationship between aging and prevalence of non-alcoholic fatty liver disease, current data strongly suggests that advanced age leads to more severe histological changes and poorer clinical outcomes. Hepatic lipid accumulation could lead to significant hepatic and systemic consequences including steatohepatitis, cirrhosis, impairment of systemic glucose metabolism and metabolic syndrome, thereby contributing to age-related diseases. Insulin, leptin and adiponectin are key regulators of the various physiologic processes that regulate hepatic lipid metabolism. Recent advances have expanded our understanding in this field, highlighting the role of novel mediators such as FGF 21, and mitochondria derived peptides. In this review, we will summarize the mediators of hepatic lipid metabolism and how they are altered in aging.

Topics: Adiponectin; Aging; Fibroblast Growth Factors; Gene Expression Regulation, Developmental; Glucose; Humans; Insulin; Insulin Resistance; Leptin; Lipid Metabolism; Liver; Liver Cirrhosis; Metabolic Syndrome; Non-alcoholic Fatty Liver Disease; Obesity; Signal Transduction

T cells are highly influenced by nutrient uptake from their environment, and changes in overall nutritional status, such as malnutrition or obesity, can result in altered T-cell metabolism and behavior. In states of severe malnutrition or starvation, T-cell survival, proliferation, and inflammatory cytokine production are all decreased, as is T-cell glucose uptake and metabolism. The altered T-cell function and metabolism seen in malnutrition is associated with altered adipokine levels, most particularly decreased leptin. Circulating leptin levels are low in malnutrition, and leptin has been shown to be a key link between nutrition and immunity. The current view is that leptin signaling is required to upregulate activated T-cell glucose metabolism and thereby fuel T-cell activation. In the setting of obesity, T cells have been found to have a key role in promoting the recruitment of inflammatory macrophages to adipose depots along with the production of inflammatory cytokines that promote the development of insulin resistance leading to diabetes. Deletion of T cells, key T-cell transcription factors, or pro-inflammatory T-cell cytokines prevents insulin resistance in obesity and underscores the importance of T cells in obesity-associated inflammation and metabolic disease. Altogether, T cells have a critical role in nutritional immunometabolism.

Topics: Animals; Cytokines; Food; Glucose; Humans; Inflammation; Insulin Resistance; Leptin; Lymphocyte Activation; Malnutrition; Nutritional Status; Obesity; Signal Transduction; T-Lymphocytes

Stroke is a multifactorial disease contributing to significant noncommunicable disease burden in developing countries. Risk of stroke is largely a consequence of morbidities of diabetes, obesity, hypertension, and heart diseases. Incidence of stroke is directly proportional to body mass index. Adipose tissue stores energy as well as acts as an active endocrine organ, which secretes numerous humoral factors. Adiponectin and leptin are the commonest adipocytokines and have been invariably linked to the development of coronary heart disease and may be involved in the underlying biological mechanism of stroke. Leptin and adiponectin mediate proatherogenic and antiatherogenic responses, respectively, and hence, determining the plasma or serum levels of leptin and adiponectin alone or in combination may act as a novel prognostic biomarker for inflammation and atherosclerosis in stroke. This review addresses leptin- and adiponectin-mediated inflammatory mechanism in ischemic stroke and their potential as therapeutic targets.

Topics: Adiponectin; Animals; Humans; Inflammation; Ischemia; Leptin; Obesity; Stroke

The central link between obesity and type 2 diabetes is the development of insulin resistance. To date, it is still not clear whether hyperinsulinemia causes insulin resistance, which underlies the pathogenesis of obesity-associated type 2 diabetes, owing to the sophisticated regulatory mechanisms that exist in the periphery and in the brain. In recent years, accumulating evidence has demonstrated the existence of insulin resistance within the hypothalamus. In this review, we have integrated the recent discoveries surrounding both central and peripheral insulin resistance to provide a comprehensive overview of insulin resistance in obesity and the regulation of systemic glucose homeostasis. In particular, this review will discuss how hyperinsulinemia and hyperleptinemia in obesity impair insulin sensitivity in tissues such as the liver, skeletal muscle, adipose tissue, and the brain. In addition, this review highlights insulin transport into the brain, signaling pathways associated with hypothalamic insulin receptor expression in the regulation of hepatic glucose production, and finally the perturbation of systemic glucose homeostasis as a consequence of central insulin resistance. We also suggest future approaches to overcome both central and peripheral insulin resistance to treat obesity and type 2 diabetes.

Topics: Animals; Diabetes Mellitus, Type 2; Glucose; Homeostasis; Humans; Hypothalamus; Insulin Resistance; Leptin; Obesity; Signal Transduction

Childhood obesity is a major public health problem that has grown to epidemic proportions throughout the world. Obesity is influenced by genetic and environmental factors. The nutritional status plays an important role in growth and body weight regulation. Excess adiposity during childhood can affect the process of growth and puberty. Obese children are frequently tall for their age, with accelerated epiphyseal growth plate maturation despite low growth hormone levels. Several regulatory hormones may affect the process of linear growth in the constellation of obesity, as high levels of insulin and leptin are observed in obese children. Leptin can act as a skeletal growth factor, with a direct effect on skeletal growth centers. The finding that overweight children, especially girls, tend to mature earlier than lean children has led to the hypothesis that the degree of body fatness may trigger the neuroendocrine events that lead to the onset of puberty. Leptin receptors have been identified in the hypothalamus, as well as in gonadotrope cells, ovarian follicular cells, and Leydig cells. The increased leptin and androgen levels seen in obese children may be implicated in their earlier onset of puberty and accelerated pubertal growth. This review is focused on the interaction between childhood obesity and growth and pubertal processes.
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Topics: Adiposity; Adolescent; Adolescent Development; Androgens; Body Height; Body Weight; Child; Child Development; Humans; Leptin; Obesity; Puberty

Obesity, a major risk factor for the development of diabetes mellitus, cardiovascular diseases and certain types of cancer, arises from a chronic positive energy balance that is often due to unlimited access to food and an increasingly sedentary lifestyle on the background of a genetic and epigenetic vulnerability. Our understanding of the humoral and neuronal systems that mediate the control of energy homeostasis has improved dramatically in the past few decades. However, our ability to develop effective strategies to slow the current epidemic of obesity has been hampered, largely owing to the limited knowledge of the mechanisms underlying resistance to the action of metabolic hormones such as leptin and ghrelin. The development of resistance to leptin and ghrelin, hormones that are crucial for the neuroendocrine control of energy homeostasis, is a hallmark of obesity. Intensive research over the past several years has yielded tremendous progress in our understanding of the cellular pathways that disrupt the action of leptin and ghrelin. In this Review, we discuss the molecular mechanisms underpinning resistance to leptin and ghrelin and how they can be exploited as targets for pharmacological management of obesity.

Topics: Animals; Cyclic AMP; Drug Resistance; Energy Metabolism; Ghrelin; Homeostasis; Humans; Hypothalamus; Leptin; Obesity; Receptors, Ghrelin; Receptors, Leptin; Signal Transduction

Hypothalamic resistance to adipostatic actions of leptin is a hallmark of obesity. Studies have revealed that hypothalamic inflammation, triggered in response to the consumption of large amounts of dietary fat, is an important mechanism in the development of leptin resistance. In this chapter, we will review the work that paved the way linking neuroinflammation of the hypothalamus and defective leptin action in obesity.

Topics: Animals; Humans; Hypothalamus; Inflammation; Leptin; Neuroimmunomodulation; Obesity

Previous reports have shown that exercise improves serum leptin and adiponectin abnormalities in overweight and obese individuals; however, results to date are controversial. Here we performed a systematic review and meta-analysis of the available randomized controlled trials (RCTs) of the possible beneficial action of exercise on serum leptin and adiponectin levels in overweight and obese individuals. We searched PubMed, EMbase, The Cochrane Library, and the Clinicaltrial.gov databases for relevant studies published between January 1980 and September 2015. Two independent reviewers extracted relevant data and assessed study quality and risk of bias. Data were pooled using a random-effects model for leptin and a fixed-effects model for adiponectin. Effect of size was expressed as mean difference (MD) with 95% confidence interval (CI). Heterogeneity was assessed (Cochran Q-statistic) and quantified (I

Topics: Adiponectin; Exercise Therapy; Female; Humans; Leptin; Male; Obesity; Randomized Controlled Trials as Topic

Leptin is an adipocyte-derived hormone not only with an important role in the central control of energy metabolism, but also with many pleiotropic effects in different physiological systems. One of these peripheral functions of leptin is a regulatory role in the interplay between energy metabolism and the immune system, being a cornerstone of the new field of immunometabolism. Leptin receptor is expressed throughout the immune system and the regulatory effects of leptin include cells from both the innate and adaptive immune system. Leptin is one of the adipokines responsible for the inflammatory state found in obesity that predisposes not only to type 2 diabetes, metabolic syndrome and cardiovascular disease, but also to autoimmune and allergic diseases. Leptin is an important mediator of the immunosuppressive state in undernutrition status. Placenta is the second source of leptin and it may play a role in the immunomodulation during pregnancy. Finally, recent work has pointed to the participation of leptin and leptin receptor in the pathophysiology of inflammation in oral biology. Therefore, leptin and leptin receptor should be considered for investigation as a marker of inflammation and immune activation in the frontier of innate-adaptive system, and as possible targets for intervention in the immunometabolic mediated pathophysiology.

Topics: Adaptive Immunity; Animals; Biomarkers; Diabetes Mellitus, Type 2; Energy Metabolism; Humans; Immune System; Immunity, Innate; Immunomodulation; Inflammation; Leptin; Mice; Obesity; Receptors, Leptin

With the global epidemic of obesity, breathing disorders associated with excess body weight have markedly increased. Respiratory dysfunctions caused by obesity were originally attributed to mechanical factors; however, recent studies have suggested a pathophysiological component that involves the central nervous system (CNS) and hormones such as leptin produced by adipocytes as well as other cells. Leptin is suggested to stimulate breathing and leptin deficiency causes an impairment of the chemoreflex, which can be reverted by leptin therapy. This facilitation of the chemoreflex may depend on the action of leptin in the hindbrain areas involved in the respiratory control such as the nucleus of the solitary tract (NTS), a site that receives chemosensory afferents, and the ventral surface of the medulla that includes the retrotrapezoid nucleus (RTN), a central chemosensitive area, and the rostral ventrolateral medulla (RVLM). Although the mechanisms and pathways activated by leptin to facilitate breathing are still not completely clear, evidence suggests that the facilitatory effects of leptin on breathing require the brain melanocortin system, including the POMC-MC4R pathway, a mechanism also activated by leptin to modulate blood pressure. The results of all the studies that have investigated the effect of leptin on breathing suggest that disruption of leptin signalling as caused by obesity-induced reduction of central leptin function (leptin resistance) is a relevant mechanism that may contribute to respiratory dysfunctions associated with obesity.

Topics: Animals; Central Nervous System; Humans; Leptin; Obesity; Respiration

The increasing prevalence of both obesity and depression is becoming a significant health concern throughout the world. Evidence suggests a positive and bidirectional association between obesity and depression. It is now well established that central serotonergic system is involved in the elicitation of satiety signal and elevation of mood. Drugs that increase serotonin neurotransmission are commonly recommended for the treatment of depression. But many patients are not benefitted by these drugs, while remission rate is also not satisfactory. Serotonin based antiobesity drugs have been either withdrawn from the market or disapproved for long term use. In view of critical need for novel therapeutic targets for obesity and depression, the role of leptin is becoming increasingly important. The peptide hormone secreted by adipocytes can cross blood brain barriers to elicit satiety signal via its receptors in the hypothalamus. Emerging evidence suggests that the peptide hormone has a role in responses to stress and produces antidepressant like effects. On the other hand, both obesity and depression are often associated with higher levels of leptin in circulation suggesting insensitivity to leptin. The aim of the present article is to draw research interest towards exploring mechanism involved in leptin resistance. These studies may facilitate the development of alternative treatment strategies, beyond serotonin based drugs, for obesity depression and their comorbid condition.

Topics: Animals; Anti-Obesity Agents; Antidepressive Agents; Depression; Drug Design; Humans; Leptin; Molecular Targeted Therapy; Obesity; Serotonin

Obesity is rising to unprecedented numbers, affecting a growing number of children, adolescents and young adult men. These individuals face innumerous health problems, including subfertility or even infertility. Overweight and obese men present severe alterations in their body composition and hormonal profile, particularly in ghrelin, leptin and glucagon-like peptide-1 (GLP-1) levels. It is well known that male reproductive health is under the control of the individual's nutritional status and also of a tight network of regulatory signals, particularly hormonal signaling. However, few studies have been focused on the effects of ghrelin, leptin and GLP-1 in male reproduction and how energy homeostasis and male reproductive function are linked. These hormones regulate body glucose homeostasis and several studies suggest that they can serve as targets for anti-obesity drugs. In recent years, our understanding of the mechanisms of action of these hormones has grown significantly. Curiously, their effect on male reproductive potential, that is highly dependent of the metabolic cooperation established between testicular cells, remains a matter of debate. Herein, we review general concepts of male fertility and obesity, with a special focus on the effects of ghrelin, leptin and GLP-1 on male reproductive health. We also discuss the possible pharmacological relevance of these hormones to counteract the fertility problems that overweight and obese men face.

Topics: Adolescent; Child; Fertility; Ghrelin; Glucagon-Like Peptide 1; Humans; Infertility, Male; Leptin; Male; Obesity; Overweight; Young Adult

Leptin, an adipose hormone, has been shown to control energy homeostasis and food intake, and exert many actions on female reproductive function. Consequently, this adipokine is a pivotal factor in studies conducted on animal models and humans to decipher the mechanisms behind the infertility often observed in obese women.. A systematic PubMed search was conducted on all articles, published up to January 2015 and related to leptin and its actions on energy balance and reproduction, using the following key words: leptin, reproduction, infertility, IVF and controlled ovarian stimulation. The available literature was reviewed in order to provide an overview of the current knowledge on the physiological roles of leptin, its involvement in female reproductive function and its potential interest as a prognostic marker in IVF cycles.. Animal and human studies show that leptin communicates nutritional status to the central nervous system and emerging evidence has demonstrated that leptin is involved in the control of reproductive functions by acting both directly on the ovaries and indirectly on the central nervous system. With respect to the clinical use of leptin as a biomarker in IVF cycles, a systematic review of the literature suggested its potential interest as a predictor of IVF outcome, as high serum and/or follicular fluid leptin concentrations have correlated negatively with cycle outcome. However, these preliminary results remain to be confirmed.. Leptin regulates energy balance and female reproductive function, mainly through its action on hypothalamic-pituitary-ovarian function, whose molecular and cellular aspects are progressively being deciphered. Preliminary studies evaluating leptin as a biomarker in human IVF seem promising but need further confirmation.

Topics: Animals; Biomarkers; Energy Metabolism; Female; Fertilization in Vitro; Follicular Fluid; Humans; Infertility, Female; Leptin; Obesity; Ovary; Ovulation Induction; Reproduction

Over the past century, overwhelming evidence has emerged pointing to the hypothalamus of the central nervous system (CNS) as a crucial regulator of systemic control of metabolism, including appetite and feeding behavior. Appetite (or hunger) is a fundamental driver of survival, involving complex behaviors governed by various parts of the brain, including the cerebral cortex. Here, we provide an overview of basic metabolic principles affecting the CNS and discuss their relevance to physiological and pathological conditions of higher brain functions. These novel perspectives may well provide new insights into future research strategies to facilitate the development of novel therapies for treating mental illness.

Topics: Antidepressive Agents; Cerebral Cortex; Depression; Feeding and Eating Disorders; Feeding Behavior; Gene Expression Regulation; Ghrelin; Humans; Hypothalamus; Insulin; Kruppel-Like Factor 4; Kruppel-Like Transcription Factors; Leptin; Obesity; Serotonin; Signal Transduction; Synaptic Transmission

Leptin is the most critical hormone in the homeostatic regulation of energy balance among those so far discovered. Leptin primarily acts on the neurons of the mediobasal part of hypothalamus to regulate food intake, thermogenesis, and the blood glucose level. In the hypothalamic neurons, leptin binding to the long form leptin receptors on the plasma membrane initiates multiple signaling cascades. The signaling pathways known to mediate the actions of leptin include JAK-STAT signaling, PI3K-Akt-FoxO1 signaling, SHP2-ERK signaling, AMPK signaling, and mTOR-S6K signaling. Recent evidence suggests that leptin signaling in hypothalamic neurons is also linked to primary cilia function. On the other hand, signaling molecules/pathways mitigating leptin actions in hypothalamic neurons have been extensively investigated in an effort to treat leptin resistance observed in obesity. These include SOCS3, tyrosine phosphatase PTP1B, and inflammatory signaling pathways such as IKK-NFκB and JNK signaling, and ER stress-mitochondrial signaling. In this review, we discuss leptin signaling pathways in the hypothalamus, with a particular focus on the most recently discovered pathways.

Topics: Animals; Cilia; Endoplasmic Reticulum Stress; Humans; Hypothalamus; Leptin; Mitochondria; Obesity; Receptors, Leptin; Signal Transduction

This review discusses current and future pharmacological approaches to the treatment of obesity, with a focus on the biological control of energy balance.

Topics: Adipose Tissue; Animals; Anti-Obesity Agents; Bile Acids and Salts; Body Weight; Diabetes Mellitus, Type 2; Drug Discovery; Energy Metabolism; Feeding Behavior; Homeostasis; Humans; Hypothalamus; Inflammation; Leptin; Obesity; Oxidative Phosphorylation; Pediatric Obesity

Leptin is mainly secreted by white adipose tissue and regulates energy homeostasis by inhibiting food intake and stimulating energy expenditure through its action in neuronal circuits in the brain, particularly in the hypothalamus. However, hyperleptinemia coexists with the loss of responsiveness to leptin in common obese conditions. This phenomenon has been defined as leptin resistance and the restoration of leptin sensitivity is considered to be a useful strategy to treat obesity. This review summarizes the existing literature on potentially valuable nutrients and food components to reverse leptin resistance. Notably, several food compounds, such as teasaponins, resveratrol, celastrol, caffeine, and taurine among others, are able to restore the leptin signaling in neurons by overexpressing anorexigenic peptides (proopiomelanocortin) and/or repressing orexigenic peptides (neuropeptide Y/agouti-related peptide), thus decreasing food intake. Additionally, some nutrients, such as vitamins A and D, can improve leptin transport through the blood-brain barrier. Therefore, food components can improve leptin resistance by acting at different levels of the leptin pathway; moreover, some compounds are able to target more than one feature of leptin resistance. However, systematic studies are necessary to define the actual effectiveness of each compound.

Topics: Agouti-Related Protein; Animals; Blood-Brain Barrier; Caffeine; Eating; Food; Hypothalamus; Leptin; Low Density Lipoprotein Receptor-Related Protein-2; Neurons; Neuropeptide Y; Obesity; Pentacyclic Triterpenes; Pro-Opiomelanocortin; Protein Tyrosine Phosphatase, Non-Receptor Type 1; Receptors, Leptin; Resveratrol; Saponins; Stilbenes; Taurine; Triterpenes

Topics: Abdominal Fat; Adiponectin; Body Composition; Body Mass Index; Breast Feeding; Child; Child, Preschool; Dietary Proteins; Growth; Humans; Infant; Infant Formula; Infant Nutritional Physiological Phenomena; Infant, Newborn; Leptin; Maternal Health; Milk, Human; Obesity; Pediatric Obesity; Risk Factors; Weight Gain; Young Adult

Hypothyroidism is a condition in which the serum levels of thyroid hormones are below that necessary to carry out physiological functions in the body. Hypothyroidism is related to obesity as an increase in body weight gain is seen in hypothyroid patients. Moreover, an inverse correlation between free thyroxine values and body mass index has been reported. Leptin, a polypeptide hormone produced by adipocytes, was originally thought to be an antiobesity hormone due its anorexic effects on hypothalamic appetite regulation. However, nowadays it is known that leptin conveys information about the nutritional status to the brain being considered a crucial endocrine factor for regulating several physiological processes including reproduction. Since the identification of thyroid hormone and leptin receptors on the testes, these hormones are being recognized as having important roles in male reproductive functions. A clear link exists among thyroid hormones, leptin and reproduction. Both hormones can negatively affect spermatogenesis and consequently may cause male infertility. The World Health Organization (WHO) estimates the overall prevalence of primary infertility ranging from 8 to 15%. The fact that 30% of couples' inability to conceive is related to a male factor and that the longer hypothyroidism persisted, the greater the damage to the testes, strongly suggest that more studies attempting to clarify both hormones actions directly in the testes need to be conducted specially in cases of congenital hypothyroidism. Therefore, the goal of this review is to highlight the relationship of such hormones in the reproductive system.

Topics: Animals; Humans; Hypothyroidism; Infertility, Male; Leptin; Male; Obesity; Reproduction; Thyroid Hormones

The incidence of obesity, a leading modifiable risk factor for common solid tumors, is increasing. Effective interventions are needed to minimize the public health implications of obesity. Although the mechanisms linking increased adiposity to malignancy are incompletely understood, growing evidence points to complex interactions among multiple systemic and tissue-specific pathways including inflamed white adipose tissue. The metabolic and inflammatory consequences of white adipose tissue dysfunction collectively provide a plausible explanation for the link between overweight/obesity and carcinogenesis. Gaining a better understanding of these underlying molecular pathways and developing risk assessment tools that identify at-risk populations will be critical in implementing effective and novel cancer prevention and management strategies.

Topics: Adiponectin; Adipose Tissue, White; Androgens; Estrogens; Humans; Inflammation; Insulin Resistance; Leptin; Lipid Metabolism; Neoplasms; Obesity

Diet-induced obesity and its metabolic comorbidities constitute an overwhelming health crisis and there is an urgent need for safe and effective pharmacological interventions. Being largely shelved for decades, scientists are now revisiting the anti-obesity virtues of leptin. Whereas it remains evident that leptin as a stand-alone therapy is not an effective approach, the potential for employing sensitising pharmacology to unleash the weight-lowering properties of leptin has injected new hope into the field. Fascinatingly, these leptin-sensitising agents seem to act via distinct metabolic pathways and may thus, in parallel with their clinical development, serve as important research tools to progress our understanding of the molecular, physiological and behavioural pathways underlying energy homeostasis and obesity pathophysiology. This review summarises a presentation given at the 'Is leptin coming back?' symposium at the 2015 annual meeting of the EASD. It is accompanied by two other reviews on topics from this symposium (by Thomas Meek and Gregory Morton, DOI: 10.1007/s00125-016-3898-3 , and by Gerald Shulman and colleagues, DOI: 10.1007/s00125-016-3909-4 ) and an overview by the Session Chair, Ulf Smith (DOI: 10.1007/s00125-016-3894-7 ).

Topics: Animals; Body Weight; Energy Metabolism; Homeostasis; Humans; Leptin; Obesity; Signal Transduction

Obesity and its major comorbidities, including type 2 diabetes mellitus, nonalcoholic fatty liver disease (NAFLD), obesity cardiomyopathy, and certain cancers, have caused life expectancy in the United States to decline in recent years. Obesity is the increased accumulation of triglycerides (TG), which are synthesized from glycerol and long-chain fatty acids (LCFA) throughout the body. LCFA enter adipocytes, hepatocytes, and cardiomyocytes via specific, facilitated transport processes. Metabolism of increased cellular TG content in obesity may lead to comorbidities such as NAFLD and cardiomyopathy. Better understanding of LCFA transport processes may lead to successful treatment of obesity and NAFLD.

Topics: Animals; Disease Models, Animal; Fatty Acids; Humans; Insulin Resistance; Leptin; Non-alcoholic Fatty Liver Disease; Obesity; Peptide Hormones; Triglycerides

This narrative review examines six important non-nutritive substances in breast milk, many of which were thought to have little to no biological significance. The overall objective is to provide background on key bioactive factors in breast milk believed to have an effect on infant outcomes (growth and body composition).. The evidence for the effects of the following six bioactive compounds in breast milk on infant growth outcomes are reviewed: insulin, leptin, adiponectin, ghrelin, interleukin-6, and tumor necrosis factor-α.. The existing literature on the effects of breast milk insulin, ghrelin, interleukin-6, and tumor necrosis factor-α and their associations with infant growth and adiposity is sparse. Of the bioactive compounds reviewed, leptin and adiponectin are the most researched. Data reveal that breast milk adiponectin has negative associations with growth in infancy.. There is a need for innovative, well-designed studies to improve causal inference and advance our understanding in the effects of breast milk and its components on offspring growth and body composition. The recommendations provided, along with careful consideration of both known and unknown factors that affect breast milk composition, will help improve, standardize, and ultimately advance this emergent field.

Topics: Adiposity; Body Mass Index; Breast Feeding; Child Development; Female; Glucose; Humans; Infant; Insulin; Interleukin-6; Leptin; Maternal Nutritional Physiological Phenomena; Milk, Human; Obesity; Tumor Necrosis Factor-alpha

In high-, middle- and low-income countries, the rising prevalence of obesity is the underlying cause of numerous health complications and increased mortality. Being a complex and heritable disorder, obesity results from the interplay between genetic susceptibility, epigenetics, metagenomics and the environment. Attempts at understanding the genetic basis of obesity have identified numerous genes associated with syndromic monogenic, non-syndromic monogenic, oligogenic and polygenic obesity. The genetics of leanness are also considered relevant as it mirrors some of obesity's aetiologies. In this report, we summarize ten genetically elucidated obesity syndromes, some of which are involved in ciliary functioning. We comprehensively review 11 monogenic obesity genes identified to date and their role in energy maintenance as part of the leptin-melanocortin pathway. With the emergence of genome-wide association studies over the last decade, 227 genetic variants involved in different biological pathways (central nervous system, food sensing and digestion, adipocyte differentiation, insulin signalling, lipid metabolism, muscle and liver biology, gut microbiota) have been associated with polygenic obesity. Advances in obligatory and facilitated epigenetic variation, and gene-environment interaction studies have partly accounted for the missing heritability of obesity and provided additional insight into its aetiology. The role of gut microbiota in obesity pathophysiology, as well as the 12 genes associated with lipodystrophies is discussed. Furthermore, in an attempt to improve future studies and merge the gap between research and clinical practice, we provide suggestions on how high-throughput '-omic' data can be integrated in order to get closer to the new age of personalized medicine.

Topics: Epigenesis, Genetic; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Leptin; Metagenomics; Obesity

Obesity is one of the major risk factors of metabolic syndrome, such as hypertension, hyperlipidemia, and diabetes. Leptin exerts an anti-obesity effect through the Ob-Rb leptin receptor, which is mainly expressed on hypothalamic neuronal cells. Recent evidence indicated that one of the mechanisms of obesity may be the development of leptin resistance. In the present review, we discuss the mechanisms of leptin resistance in obesity, focusing on endoplasmic reticulum (ER) stress. We previously found that flurbiprofen is a candidate drug for attenuating ER stress and the subsequent development of leptin resistance. We will discuss a possible pharmacological strategy for treating obesity by ameliorating ER stress.

Topics: Drug Discovery; Endoplasmic Reticulum Stress; Flurbiprofen; Humans; Hypothalamus; Leptin; Metabolic Syndrome; Obesity; Receptors, Leptin; Risk Factors

Obesity is a serious health hazard with rapidly increasing prevalence in the United States. In 2014, the World Health Organization estimated that nearly 2 billion people worldwide were overweight with an estimated 600 million of these obese. Obesity is associated with many chronic diseases, including cardiovascular disease and hypertension. Data from the Framingham Heart study suggest that approximately 78% of the risk for hypertension in men and 65% in women is related to excess body weight, a relationship that is further supported by studies showing increases in blood pressure with weight gain and decreases with weight loss. However, the exact mechanism by which excess body fat induces hypertension remains poorly understood. Several clinical studies have demonstrated elevated plasma aldosterone levels in obese individuals, especially those with visceral adiposity, with decreased aldosterone levels measured in concert with reduced blood pressure following weight loss. Since aldosterone is a mineralocorticoid hormone that regulates blood volume and pressure, serum aldosterone levels may link obesity and hypertension. Nevertheless, the mechanism by which obesity induces aldosterone production is unclear. A recent study by Belin de Chantemele and coworkers suggests that one adipose-released factor, leptin, is a direct agonist for aldosterone secretion; other adipose-related factors may also contribute to elevated aldosterone levels in obesity, such as very low-density lipoprotein (VLDL), the levels of which are elevated in obesity and which also directly stimulates aldosterone biosynthesis. This focused review explores the possible roles of leptin and VLDL in modulating aldosterone secretion to underlie obesity-associated hypertension.

Topics: Adipose Tissue; Aldosterone; Blood Pressure; Female; Humans; Hypertension; Leptin; Male; Obesity

Leptin protein consists of 167 amino acids, which is mainly secreted from the white adipose tissue. This protein acts on the hypothalamic regions of the brain which control eating behavior, thus playing a significant role in maintaining body's metabolism. Leptin receptors belong to glycoprotein 130 (gp130) family of cytokine receptors and exist in six isoforms (LEPR a-f), and all the isoforms are encoded by LEPR gene; out of these isoforms, the LEPR-b receptor is the 'longest form,' and in most of the cases, mutations in this isoform cause severe obesity. Also, mutations in the leptin gene (LEP) or its receptors gene can lead to obesity. Some biochemical pathways affect the bioactivity of leptin and/or its receptors. To date, eleven pathogenic mutations have been reported in the LEP which are p.L72S, p.N103K, p.R105W, p.H118L, p.S141C, p.W121X c.104_106delTCA, c.135del3bp, c.398delG, c.481_482delCT, and c.163C>T. Different mutations in the LEPR have also been reported as c.2396-1 G>T, c.1675 G>A, p.P316T, etc. In some studies, where leptin was deficient, leptin replacement therapy has shown positive impact by preventing weight gain and obesity.

Topics: Genetic Predisposition to Disease; Humans; Leptin; Mutation; Obesity; Receptors, Leptin; Weight Gain

This review article introduces the research advances in the pathophysiological mechanism of obesity in inducing pediatric bronchial asthma, including the role of leptin in obesity and asthma, the association of plasminogen activator inhibitor-1 with obesity and asthma, the association of adiponectin and interleukins with obesity and asthma, and the influence of neurotransmitter on asthma. In particular, this article introduces the latest research on the inhibition of allergic asthma through targeting at the nociceptor of dorsal root ganglion and blocking the signaling pathway of the nociceptor.

Topics: Asthma; Humans; Leptin; Nerve Growth Factor; Neurotransmitter Agents; Obesity; Plasminogen Activator Inhibitor 1

Children with Down syndrome (DS) are more likely to be overweight or obese than the general population of youth without DS.. To review the prevalence of overweight and obesity and their determinants in youth with DS. The health consequences and the effectiveness of interventions were also examined.. A search using MEDLINE, Embase, Web of Science, Scopus, CINAHL, PsycINFO, SPORTDiscus, LILACS, and COCHRANE was conducted. From a total of 4280 studies, we included 45 original research articles published between 1988 and 2015.. The combined prevalence of overweight and obesity varied between studies from 23% to 70%. Youth with DS had higher rates of overweight and obesity than youths without DS. Likely determinants of obesity included increased leptin, decreased resting energy expenditure, comorbidities, unfavorable diet, and low physical activity levels. Obesity was positively associated with obstructive sleep apnea, dyslipidemia, hyperinsulinemia, and gait disorder. Interventions for obesity prevention and control were primarily based on exercise-based programs, and were insufficient to achieve weight or fat loss.. Population-based research is needed to identify risk factors and support multi-factorial strategies for reducing overweight and obesity in children and adolescents with DS.

Topics: Adolescent; Child; Diet; Down Syndrome; Dyslipidemias; Energy Metabolism; Exercise; Exercise Therapy; Humans; Hyperinsulinism; Leptin; Obesity; Overweight; Prevalence; Risk Factors; Sleep Apnea, Obstructive

Energy balance is not a simple algebraic sum of energy expenditure and energy intake as often depicted in communications. Energy balance is a dynamic process and there exist reciprocal effects between food intake and energy expenditure. An important distinction is that of metabolic and behavioural components of energy expenditure. These components not only contribute to the energy budget directly, but also by influencing the energy intake side of the equation. It has recently been demonstrated that resting metabolic rate (RMR) is a potential driver of energy intake, and evidence is accumulating on the influence of physical activity (behavioural energy expenditure) on mechanisms of satiety and appetite control. These effects are associated with changes in leptin and insulin sensitivity, and in the plasma levels of gastrointestinal (GI) peptides such as glucagon-like peptide-1 (GLP-1), ghrelin and cholecystokinin (CCK). The influence of fat-free mass on energy expenditure and as a driver of energy intake directs attention to molecules emanating from skeletal tissue as potential appetite signals. Sedentariness (physical inactivity) is positively associated with adiposity and is proposed to be a source of overconsumption and appetite dysregulation. The molecular signals underlying these effects are not known but represent a target for research.

Topics: Animals; Appetite Regulation; Body Composition; Energy Metabolism; Ghrelin; Glucagon-Like Peptide 1; Humans; Leptin; Obesity

Obesity is a risk factor for asthma, and obese asthmatics have lower disease control and increased symptom severity. Several putative links have been proposed, including genetics, mechanical restriction of the chest and the intake of corticosteroids. The most consistent evidence, however, comes from studies of cytokines produced by the adipose tissue called adipokines. Adipokine imbalance is associated with both proinflammatory status and asthma. Although reverse causation has been proposed, it is now acknowledged that obesity precedes asthma symptoms. Nevertheless, prenatal origins of both conditions complicate the search for causality. There is a confirmed role of neuro-immune cross-talk mediating obesity-induced asthma, with leptin playing a key role in these processes. Obesity-induced asthma is now considered a distinct asthma phenotype. In fact, it is one of the most important determinants of asthma phenotypes. Two main subphenotypes have been distinguished. The first phenotype, which affects adult women, is characterised by later onset and is more likely to be non-atopic. The childhood obesity-induced asthma phenotype is characterised by primary and predominantly atopic asthma. In obesity-induced asthma, the immune responses are shifted towards T helper (Th) 1 polarisation rather than the typical atopic Th2 immunological profile. Moreover, obese asthmatics might respond differently to environmental triggers. The high cost of treatment of obesity-related asthma, and the burden it causes for the patients and their families call for urgent intervention. Phenotype-specific approaches seem to be crucial for the success of prevention and treatment.

Topics: Adipokines; Adult; Asthma; Female; Humans; Hypersensitivity, Immediate; Leptin; Male; Obesity; Pediatric Obesity

Maternal obesity, usually associated with the adverse birth outcomes, has been a serious public health concern. Studies examining its effect on the physical and cognitive development of children have only recently emerged and the findings are inconsistent. This review aimed to systematically examine the role of maternal obesity on children's physical and cognitive development using the available evidence.. The CINAHL, EMBASE, PSYCINFO, PUBMED and SCOPUS databases were searched. Studies addressing children's (⩽12 years) physical and cognitive development as outcome and maternal pre-pregnancy body mass index as an exposure were included. Data were extracted and evaluated for quality by two independent reviewers.. A total of 17 articles were eligible for this systematic review; 10 of them were birth cohorts from the USA. Nine of the 14 studies supported an adverse association between maternal pre-pregnancy obesity and childhood cognitive development. A few studies also demonstrated a negative association between the maternal obesity and gross motor function in children (5 of 10), but not with fine motor function (none out of five studies). Whether the observed negative association between the maternal obesity and children's cognitive and gross motor abilities is casual or due to residual confounding effects is unclear. The current evidence is based on a limited number of studies with heterogeneous measurement scales and obesity definition.. From the available evidence, it seems that exposure to maternal pre-pregnancy obesity in the intrauterine environment has a detrimental effect on children's cognitive development. However, evidence of the association between the maternal obesity and physical development of children is too scarce to offer a conclusion. More research work is required to delineate the intrauterine effect of the maternal obesity from the residual confounding effects.

Topics: Blood Glucose; Body Mass Index; Child; Child Development; Cognition; Fatty Acids; Female; Fetal Development; Humans; Inflammation; Leptin; Obesity; Observational Studies as Topic; Pregnancy; Pregnancy Complications; Prenatal Exposure Delayed Effects; Risk Factors; Women's Health

Obesity continues to be a major global problem. Various cancers are related to obesity and proper understanding of their aetiology, especially their molecular tumour biology is important for early diagnosis and better treatment. Genes play an important role in the development of obesity. Few genes such as leptin, leptin receptor encoded by the db (diabetes), pro-opiomelanocortin, AgRP and NPY and melanocortin-4 receptors and insulin-induced gene 2 were linked to obesity. MicroRNAs control gene expression via mRNA degradation and protein translation inhibition and influence cell differentiation, cell growth and cell death. Overexpression of miR-143 inhibits tumour growth by suppressing B cell lymphoma 2, extracellular signal-regulated kinase-5 activities and KRAS oncogene. Cancers of the breast, uterus, renal, thyroid and liver are also related to obesity. Any disturbance in the production of sex hormones and insulin, leads to distortion in the balance between cell proliferation, differentiation and apoptosis. The possible mechanism linking obesity to cancer involves alteration in the level of adipokines and sex hormones. These mediators act as biomarkers for cancer progression and act as targets for cancer therapy and prevention. Interestingly, many anti-cancerous drugs are also beneficial in treating obesity and vice versa. We also reviewed the possible link in the mechanism of few drugs which act both on cancer and obesity. The present review may be important for molecular biologists, oncologists and clinicians treating cancers and also pave the way for better therapeutic options.

Topics: Adipokines; Agouti-Related Protein; Animals; Brain-Derived Neurotrophic Factor; Extracellular Signal-Regulated MAP Kinases; Female; Gonadal Steroid Hormones; Humans; Intracellular Signaling Peptides and Proteins; Leptin; Male; Membrane Proteins; Mice; MicroRNAs; Neoplasms; Neuropeptide Y; Obesity; Pro-Opiomelanocortin; Receptor, Melanocortin, Type 4; Receptors, Leptin

Sleep is important for regulating many physiologic functions that relate to metabolism. Because of this, there is substantial evidence to suggest that sleep habits and sleep disorders are related to diabetes risk. In specific, insufficient sleep duration and/or sleep restriction in the laboratory, poor sleep quality, and sleep disorders such as insomnia and sleep apnea have all been associated with diabetes risk. This research spans epidemiologic and laboratory studies. Both physiologic mechanisms such as insulin resistance, decreased leptin, and increased ghrelin and inflammation and behavioral mechanisms such as increased food intake, impaired decision-making, and increased likelihood of other behavioral risk factors such as smoking, sedentary behavior, and alcohol use predispose to both diabetes and obesity, which itself is an important diabetes risk factor. This review describes the evidence linking sleep and diabetes risk at the population and laboratory levels.

Topics: Diabetes Mellitus; Energy Intake; Ghrelin; Humans; Insulin Resistance; Leptin; Obesity; Risk Factors; Sleep; Sleep Wake Disorders

Hypertension and associated cardiovascular diseases represent the most common health complication of obesity and the leading cause of morbidity and mortality in overweight and obese patients. Emerging evidence suggests a critical role for the central nervous system particularly the brain action of the adipocyte-derived hormone leptin in linking obesity and hypertension. The preserved ability of leptin to cause cardiovascular sympathetic nerve activation despite the resistance to the metabolic actions of the hormone appears essential in this pathological process. This review describes the evidence supporting the neurogenic bases for obesity-associated hypertension with a particular focus on the neuronal and molecular signaling pathways underlying leptin's effects on sympathetic nerve activity and blood pressure.

Topics: Adipocytes; Humans; Hypertension; Leptin; Obesity; Signal Transduction; Sympathetic Nervous System

Multiple Sclerosis (MS) is an autoimmune disorder of the Central Nervous System that has been associated with several environmental factors, such as diet and obesity. The possible link between MS and obesity has become more interesting in recent years since the discovery of the remarkable properties of adipose tissue. Once MS is initiated, obesity can contribute to increased disease severity by negatively influencing disease progress and treatment response, but, also, obesity in early life is highly relevant as a susceptibility factor and causally related risk for late MS development. The aim of this review was to discuss recent evidence about the link between obesity, as a chronic inflammatory state, and the pathogenesis of MS as a chronic autoimmune and inflammatory disease. First, we describe the main cells involved in MS pathogenesis, both from neural tissue and from the immune system, and including a new participant, the adipocyte, focusing on their roles in MS. Second, we concentrate on the role of several adipokines that are able to participate in the mediation of the immune response in MS and on the possible cross talk between the latter. Finally, we explore recent therapy that involves the transplantation of adipocyte precursor cells for the treatment of MS.

Topics: Adipocytes; Adipokines; Adiponectin; Adipose Tissue; Animals; Astrocytes; Autoimmune Diseases; CD8-Positive T-Lymphocytes; Complement Factor D; Disease Models, Animal; Encephalomyelitis, Autoimmune, Experimental; Humans; Immune System; Inflammation; Interleukin-17; Leptin; Mesenchymal Stem Cells; Mice; Microglia; Multiple Sclerosis; Nicotinamide Phosphoribosyltransferase; Obesity; Oligodendroglia; Prevalence; Resistin; Risk; Th1 Cells; Th2 Cells

Obesity has a complicated connection to both breast cancer risk and the clinical behaviour of the established disease. The obese setting provides a unique adipose tissue microenvironment that, in association with systemic endocrine modifications, promotes tumor initiation, primary growth, invasion, and metastatic progression. This review presents an overview of the clinical and experimental evidences highlighting the adipokine leptin as the most important molecular mediator of obesity-breast cancer axis. The research of leptin network operating in this context could launch a new field not only in the knowledge of risk factors for breast cancer but also in the development of leptin targeting drugs as promising anticancer agents.

Topics: Adipose Tissue; Animals; Antineoplastic Agents; Breast Neoplasms; Disease Progression; Drug Design; Female; Humans; Leptin; Neoplasm Invasiveness; Neoplasm Metastasis; Obesity; Risk Factors

Obesity is both a cause and a possible consequence of obstructive sleep apnoea (OSA), as OSA seems to affect parameters involved in energy balance regulation, including food intake, hormonal regulation of hunger/satiety, energy metabolism and physical activity. It is known that weight loss improves OSA, yet it remains unclear why continuous positive airway pressure (CPAP) often results in weight gain.The goal of this systematic review is to explore if and how CPAP affects the behaviour and/or metabolism involved in regulating energy balance.CPAP appears to correct for a hormonal profile characterised by abnormally high leptin and ghrelin levels in OSA, by reducing the circulating levels of each. This is expected to reduce excess food intake. However, reliable measures of food intake are lacking, and not yet sufficient to make conclusions. Although studies are limited and inconsistent, CPAP may alter energy metabolism, with reports of reductions in resting metabolic rate or sleeping metabolic rate. CPAP appears to not have an appreciable effect on altering physical activity levels. More work is needed to characterise how CPAP affects energy balance regulation.It is clear that promoting CPAP in conjunction with other weight loss approaches should be used to encourage optimal outcomes in OSA patients.

Topics: Continuous Positive Airway Pressure; Eating; Energy Metabolism; Ghrelin; Humans; Leptin; Obesity; Randomized Controlled Trials as Topic; Sleep Apnea, Obstructive

β-cell failure coupled with insulin resistance plays a key role in the development of type 2 diabetes mellitus (T2DM). Changed adipokines in circulating level form a remarkable link between obesity and both β-cell failure and insulin resistance. Some adipokines have beneficial effects,whereas others have detrimental properties. The overall contribution of adipokines to β-cell failure mainly depends on the interactions among adipokines. This article reviews the role of individual adipokines such as leptin,adiponectin,and resistin in the function,proliferation,death,and failure of β-cells. Future studies focusing on the combined effects of adipokines on β-cells failure may provide new insights in the treatment of T2DM.

Topics: Adipokines; Adiponectin; Diabetes Mellitus, Type 2; Humans; Insulin Resistance; Insulin-Secreting Cells; Leptin; Obesity; Resistin

Leptin is an adipose tissue hormone that functions as an afferent signal in a negative feedback loop that maintains homeostatic control of adipose tissue mass. This endocrine system thus serves a critical evolutionary function by protecting individuals from the risks associated with being too thin (starvation) or too obese (predation and temperature dysregulation). Mutations in leptin or its receptor cause massive obesity in mice and humans, and leptin can effectively treat obesity in leptin-deficient patients. Leptin acts on neurons in the hypothalamus and elsewhere to elicit its effects, and mutations that affect the function of this neural circuit cause Mendelian forms of obesity. Leptin levels fall during starvation and elicit adaptive responses in many other physiologic systems, the net effect of which is to reduce energy expenditure. These effects include cessation of menstruation, insulin resistance, alterations of immune function, and neuroendocrine dysfunction, among others. Some or all of these effects are also seen in patients with constitutively low leptin levels, such as occur in lipodystrophy. Leptin is an approved treatment for generalized lipodystrophy, a condition associated with severe metabolic disease, and has also shown potential for the treatment of other types of diabetes. In addition, leptin restores reproductive capacity and increases bone mineral density in patients with hypothalamic amenorrhea, an infertility syndrome in females. Most obese patients have high endogenous levels of leptin, in some instances as a result of mutations in the neural circuit on which leptin acts, though in most cases, the pathogenesis of leptin resistance is not known. Obese patients with leptin resistance show a variable response to exogenous leptin but may respond to a combination of leptin plus amylin. Overall, the identification of leptin has provided a framework for studying the pathogenesis of obesity in the general population, clarified the nature of the biologic response to starvation, and helped to advance our understanding of the neural mechanisms that control feeding.

Topics: Adipose Tissue; Animals; Diabetes Mellitus; Humans; Hypothalamus; Leptin; Lipodystrophy; Mice; Neurons; Obesity; Receptors, Leptin; Starvation

Aging leads to a number of physiological alterations, specifically changes in circulating hormone levels, increases in fat deposition, decreases in metabolism, changes in inflammatory responses, and reductions in growth factors. These progressive changes in physiology and metabolism are exacerbated by modern culture and Western diet and give rise to diseases such as obesity, metabolic syndrome, and type 2 (non-insulin-dependent) diabetes (T2D). These age and lifestyle-related metabolic diseases are often accompanied by insulin and leptin resistance, as well as aberrant amylin production and signaling. Many of these alterations in hormone production and signaling are directly influenced by an increase in both oxidative stress and inflammation. Importantly, changes in hormone production and signaling have direct effects on brain function and the development of age-related neurologic disorders. Therefore, this review aims to present evidence on the effects that diet and metabolic disease have on age-related cognitive decline and the development of cognitive diseases, particularly Alzheimer disease. This review will focus on the metabolic hormones insulin, leptin, and amylin and their role in cognitive decline, as well as the therapeutic potential of these hormones in treating cognitive disease. Future investigations targeting the long-term effects of insulin and leptin treatment may reveal evidence to reduce risk of cognitive decline and Alzheimer disease.

Topics: Aging; Alzheimer Disease; Cognition; Cognitive Dysfunction; Diabetes Mellitus, Type 2; Humans; Insulin; Islet Amyloid Polypeptide; Leptin; Obesity

Leptin is secreted by adipose tissue and regulates energy homeostasis, neuroendocrine function, metabolism, immune function and other systems through its effects on the central nervous system and peripheral tissues. Leptin administration has been shown to restore metabolic and neuroendocrine abnormalities in individuals with leptin-deficient states, including hypothalamic amenorrhea and lipoatrophy. In contrast, obese individuals are resistant to leptin. Recombinant leptin is beneficial in patients with congenital leptin deficiency or generalized lipodystrophy. However, further research on molecular mediators of leptin resistance is needed for the development of targeted leptin sensitizing therapies for obesity and related metabolic diseases.

Topics: Animals; Energy Metabolism; Homeostasis; Humans; Leptin; Metabolic Diseases; Neurosecretory Systems; Obesity

Metabolic homeostasis requires integration of complex signaling networks which, when deregulated, contribute to metabolic syndrome and related disorders. Protein-tyrosine phosphatase 1B (PTP1B) has emerged as a key regulator of signaling networks that are implicated in metabolic diseases such as obesity and type 2 diabetes. In this review, we examine mechanisms that regulate PTP1B-substrate interaction, enzymatic activity and experimental approaches to identify PTP1B substrates. We then highlight findings that implicate PTP1B in metabolic regulation. In particular, insulin and leptin signaling are discussed as well as recently identified PTP1B substrates that are involved in endoplasmic reticulum stress response, cell-cell communication, energy balance and vesicle trafficking. In summary, PTP1B exhibits exquisite substrate specificity and is an outstanding pharmaceutical target for obesity and type 2 diabetes.

Topics: Animals; Diabetes Mellitus, Type 2; Endoplasmic Reticulum Stress; Humans; Leptin; Obesity; Protein Tyrosine Phosphatase, Non-Receptor Type 1; Signal Transduction; Thermodynamics

There is a growing focus on links between obesity and cognitive decline in adulthood, including Alzheimer's disease. It is also increasingly recognized that obesity in youth is associated with poorer cognitive function, specifically executive functioning skills such as inhibitory control and working memory, which are critical for academic achievement. Emerging literature provides evidence for possible biological mechanisms driven by obesity; obesity-associated biomarkers such as adipokines, obesity-associated inflammatory cytokines, and obesity-associated gut hormones have been associated with learning, memory, and general cognitive function. To date, examination of obesity-associated biology with brain function has primarily occurred in animal models. The few studies examining such biologically mediated pathways in adult humans have corroborated the animal data, but this body of work has gone relatively unrecognized by the pediatric literature. Despite the fact that differences in these biomarkers have been found in association with obesity in children, the possibility that obesity-related biology could affect brain development in children has not been actively considered. We review obesity-associated biomarkers that have shown associations with neurocognitive skills, specifically executive functioning skills, which have far-reaching implications for child development. Understanding such gut-brain associations early in the lifespan may yield unique intervention implications.

Topics: Adipokines; Biomarkers; Brain; Child; Child Development; Cytokines; Executive Function; Humans; Leptin; Obesity

Hypothalamic obesity represents a rare diagnosis applicable to only a small subset of obese patients. It is important to identify, diagnose, and treat these patients. This article reviews the physiology of the hypothalamus, focusing on its role in regulation of hunger, feeding, and metabolism. The causes of hypothalamic obesity are discussed including genetic, anatomic, and iatrogenic etiologies. The complex hormonal environment leading to obesity is explored for each etiology and treatment strategies are discussed. Reproductive consequences are also reviewed.

Topics: Appetite; Appetite Depressants; Bariatric Surgery; Craniopharyngioma; Energy Metabolism; Feeding Behavior; Humans; Hyperphagia; Hypogonadism; Hypothalamic Diseases; Hypothalamic Hormones; Hypothalamus; Iatrogenic Disease; Infertility; Leptin; Nerve Tissue Proteins; Obesity; Pituitary Neoplasms; Postoperative Complications; Pro-Opiomelanocortin; Puberty, Delayed; Receptors, Leptin; Receptors, Melanocortin; Sedentary Behavior

Obesity is a growing health risk with few successful treatment options and fewer still that target both obesity and obesity-associated comorbidities. Despite ongoing scientific efforts, the most effective treatment option to date was not developed from basic research but by surgeons observing outcomes in the clinic. Bariatric surgery is the most successful treatment for significant weight loss, resolution of type 2 diabetes and the prevention of future weight gain. Recent work with animal models has shed considerable light on the molecular underpinnings of the potent effects of these 'metabolic' surgical procedures. Here we review data from animal models and how these studies have evolved our understanding of the critical signalling systems that mediate the effects of bariatric surgery. These insights could lead to alternative therapies able to accomplish effects similar to bariatric surgery in a less invasive manner.

Topics: Animals; Disease Models, Animal; Energy Intake; Energy Metabolism; Feeding Behavior; Gastrectomy; Gastric Bypass; Homeostasis; Leptin; Lipids; Mice; Obesity; Paracrine Communication; Peptide Hormones; Rats; Weight Loss

Obesity causes dysfunction of adipose tissue, with resultant chronic inflammation and adverse interplay of various adipokines, sex steroids and endocrine hormones. All these drive tumourigenesis and explain the epidemiological link between obesity and cancer. Over the past decade, the associations among obesity, adipokines and cancer have been increasingly recognized. Adipokines and their respective signalling pathways have drawn much research attention in the field of oncology and cancer therapeutics. This review will discuss the recent advances in the understanding of the association of several adipokines with common obesity-related cancers and the clinical therapeutic implications.

Topics: Adipokines; Adiponectin; Adipose Tissue; Animals; Female; Hormones; Humans; Inflammation; Interleukin-6; Leptin; Male; Neoplasms; Obesity; Signal Transduction; Tumor Necrosis Factor-alpha

Obesity is a major risk factor for asthma. Likewise, obesity is known to increase disease severity in asthmatic subjects and also to impair the efficacy of first-line treatment medications for asthma, worsening asthma control in obese patients. This concept is in agreement with the current understanding that some asthma phenotypes are not accompanied by detectable inflammation, and may not be ameliorated by classical anti-inflammatory therapy. There are growing evidences suggesting that the obesity-related asthma phenotype does not necessarily involve the classical T(H)2-dependent inflammatory process. Hormones involved in glucose homeostasis and in the pathogeneses of obesity likely directly or indirectly link obesity and asthma through inflammatory and non-inflammatory pathways. Furthermore, the endocrine regulation of the airway-related pre-ganglionic nerves likely contributes to airway hyperreactivity (AHR) in obese states. In this review, we focused our efforts on understanding the mechanism underlying obesity-related asthma by exploring the T(H)2-independent mechanisms leading to this disease.

Topics: Adiponectin; Adipose Tissue; Adiposity; Airway Resistance; Animals; Asthma; Humans; Leptin; Models, Biological; Obesity; Th2 Cells

The past twenty years of research on leptin has provided crucial information on the link between metabolic state and immune system function. Adipocytes influence not only the endocrine system but also the immune response, through several cytokine-like mediators known as adipokines, which include leptin. Initially described as an antiobesity hormone, leptin has subsequently been shown also to influence hematopoiesis, thermogenesis, reproduction, angiogenesis, and more importantly immune homeostasis. As a cytokine, leptin can affect thymic homeostasis and the secretion of acute-phase reactants such as interleukin-1 (IL-1) and tumor-necrosis factor-alpha (TNF-α). Leptin links nutritional status and proinflammatory T helper 1 (Th1) immune responses and the decrease in leptin plasma concentration during food deprivation leads to impaired immune function. Conversely, elevated circulating leptin levels in obesity appear to contribute to the low-grade inflammatory background which makes obese individuals more susceptible to increased risk of developing cardiovascular diseases, diabetes, or degenerative disease including autoimmunity and cancer. In this review, we provide an overview of recent advances on the role of leptin in the pathogenesis of several autoimmune disorders that may be of particular relevance in the modulation of the autoimmune attack through metabolic-based therapeutic approaches.

Topics: Animals; Autoimmune Diseases; Autoimmunity; Humans; Leptin; Obesity

The genes encoding adipose-derived hormone leptin and its receptor (LEPR) are increasingly deemed as hypertension-susceptibility genes. In this meta-analysis, we summarized the association of the II/I polymorphism in leptin gene and Gln223Arg polymorphism in LEPR gene with hypertension and circulating leptin.. PubMed and Embase were systematically searched. Data extraction and study quality were assessed in duplicate. Statistical analyses were carried out with the STATA software (v. 11.2).. A total of 11 articles written in English were eligible. Overall analysis identified a significant association between II/I polymorphism I allele and increased risk of hypertension under allelic (odds ratio; 95% confidence interval; P: 1.48; 1.06-2.08; 0.022) and homozygous genotypic (2.27; 1.20-4.29; 0.012) models. The magnitude of the association for II/I polymorphism I allele with hypertension was substantiated in Asians and for essential hypertension under both genetic models. Overall and subgroup analyses failed to reveal any significance for the association between the Gln223Arg polymorphism and hypertension risk. Carriers of Gln223Arg polymorphism Gln/Gln genotype had significantly higher circulating leptin than the Arg/Arg genotype carriers (weighted mean difference; 95% confidence interval; P: 1.61 ng/mL; 0.02-3.20; 0.047), and this significance persisted in essential hypertension subgroup (1.69 ng/mL; 0.02-3.35; 0.047). There were low probabilities of publication bias for the above comparisons.. Our findings support the contributory role of the II/I polymorphism in leptin gene in the pathogenesis of hypertension, and this role was more evident in Asians and for essential hypertension.

Topics: Alleles; Asian People; Essential Hypertension; Gene Frequency; Genetic Predisposition to Disease; Genotype; Humans; Hypertension; Leptin; Obesity; Odds Ratio; Polymorphism, Single Nucleotide; Receptors, Leptin; White People

Obesity is a chronic disease that represents one of the most serious global health burdens associated to an excess of body fat resulting from an imbalance between energy intake and expenditure, which is regulated by environmental and genetic interactions. The adipose-derived hormone leptin acts via a specific receptor in the brain to regulate energy balance and body weight, although this protein can also elicit a myriad of actions in peripheral tissues. Obese individuals, rather than be leptin deficient, have in most cases, high levels of circulating leptin. The failure of these high levels to control body weight suggests the presence of a resistance process to the hormone that could be partly responsible of disturbances on body weight regulation. Furthermore, leptin resistance can impair physiological peripheral functions of leptin such as lipid and carbohydrate metabolism and nutrient intestinal utilization. The present document summarizes those findings regarding leptin resistance development and the role of this hormone in the development and maintenance of an obese state. Thus, we focused on the effect of the impaired leptin action on adipose tissue, liver, skeletal muscle and intestinal function and the accompanying relationships with diet-induced obesity. The involvement of some inflammatory mediators implicated in the development of obesity and their roles in leptin resistance development are also discussed.

Topics: Animals; Body Weight; Central Nervous System; Diet; Humans; Leptin; Obesity; Peripheral Nervous System

This year marks the 20th anniversary of the discovery of leptin, which has tremendously stimulated translational obesity research. The discovery of leptin has led to realizations that have established adipose tissue as an endocrine organ, secreting bioactive molecules including hormones now termed adipokines. Through adipokines, the adipose tissue influences the regulation of several important physiological functions including but not limited to appetite, satiety, energy expenditure, activity, insulin sensitivity and secretion, glucose and lipid metabolism, fat distribution, endothelial function, hemostasis, blood pressure, neuroendocrine regulation, and function of the immune system. Adipokines have a great potential for clinical use as potential therapeutics for obesity, obesity related metabolic, cardiovascular and other diseases. After 20 years of intense research efforts, recombinant leptin and the leptin analog metreleptin are already available for the treatment of congenital leptin deficiency and lipodystrophy. Other adipokines are also emerging as promising candidates for urgently needed novel pharmacological treatment strategies not only in obesity but also other disease states associated with and influenced by adipose tissue size and activity. In addition, prediction of reduced type 2 diabetes risk by high circulating adiponectin concentrations suggests that adipokines have the potential to be used as biomarkers for individual treatment success and disease progression, to monitor clinical responses and to identify non-responders to anti-obesity interventions. With the growing number of adipokines there is an increasing need to define their function, molecular targets and translational potential for the treatment of obesity and other diseases. In this review we present research data on adipose tissue secreted hormones, the discovery of which followed the discovery of leptin 20 years ago pointing to future research directions to unravel mechanisms of action for adipokines.

Topics: Adipokines; Adipose Tissue; Animals; Diabetes Mellitus, Type 2; Humans; Leptin; Obesity

Adipokines are hormones produced by adipocytes and have been involved in multiple pathologic pathways, including inflammatory and cardiovascular complications in essential hypertension. Arterial stiffness is a frequent vascular complication that represents increased cardiovascular risk in hypertensive patients. Adipokines, such as adiponectin, leptin and resistin, might be implicated in hypertension, as well as in vascular alterations associated with this condition. Arterial stiffness has proven to be a predictor of cardiovascular events. Obesity and target-organ damage such as arterial stiffness are features associated with hypertension. This review aims to update the association between adipokines and arterial stiffness in essential and resistant hypertension (RHTN).

Topics: Adipocytes; Adipokines; Adiponectin; Essential Hypertension; Humans; Hypertension; Leptin; Obesity; Resistin; Risk Factors; Vascular Stiffness

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality, affecting both developed and developing countries. Whilst it is well recognized that our risk of CVD can be determined by the interaction between our genetics and lifestyle, this only partly explains the variability at the population level. Based on these well-known risk factors, for many years, intervention and primary prevention strategies have focused on modifying lifestyle factors in adulthood. However, research shows that our risk of CVD can be pre-determined by our early life environment and this area of research is known as the Developmental Origins of Health and Disease. The aim of this review is to evaluate our current understanding of mechanisms underlying the programming of CVD. This article is part of a special issue entitled CV Aging.

Topics: Aging; Animals; Cardiovascular Diseases; Disease Models, Animal; Epigenesis, Genetic; Female; Heart; Humans; Insulin; Kidney; Leptin; Obesity; Oxidative Stress; Pregnancy; Renin-Angiotensin System; Risk Factors; Signal Transduction

With the steady rise in the incidence of obesity and its associated comorbidities, in the last decades research aimed at understanding molecular mechanisms that control body weight has gained new interest. Fat gain is frequently associated with chronic adipose tissue inflammation and with peripheral as well as central metabolic derangements, resulting in an impaired hypothalamic regulation of energy homeostasis. Recent attention has focused on the role of phosphatidylinositol 3-kinase (PI3K) in both immune and metabolic response pathways, being involved in the pathophysiology of obesity and its associated metabolic diseases. In this review, we focus on distinct PI3K isoforms, especially class I PI3Ks, mediating inflammatory cells recruitment to the enlarged fat as well as intracellular responses to key hormonal regulators of fat storage, both in adipocytes and in the central nervous system. This integrated view of PI3K functions may ultimately help to develop new therapeutic interventions for the treatment of obesity.

Topics: Adipocytes; Adipose Tissue; Animals; Class I Phosphatidylinositol 3-Kinases; Energy Metabolism; Gene Expression Regulation; Homeostasis; Humans; Hypothalamus; Immunity, Innate; Inflammation; Insulin Resistance; Leptin; Obesity; Receptor, Melanocortin, Type 4; Signal Transduction

Obesity and diabetes represent a significant healthcare concern. In contrast to genome-wide association studies that, some exceptions notwithstanding, have offered modest clues about pathomechanism, the dissection of rare disorders in which obesity represents a core feature have highlighted key molecules and structures critical to energy regulation. Here we focus on the primary cilium, an organelle whose roles in energy homeostasis have been underscored by the high incidence of obesity and type II diabetes in patients and mouse mutants with compromised ciliary function. We discuss recent evidence linking ciliary dysfunction to metabolic defects and we explore the contribution of neuronal and nonneuronal cilia to these phenotypes.

Topics: Animals; Cilia; Diabetes Mellitus, Type 2; Energy Metabolism; Hypothalamus; Leptin; Microtubule-Associated Proteins; Obesity; Receptors, Leptin; STAT3 Transcription Factor

The objective of this study was to investigate whether the response to periodontal treatment differs among obese, overweight or normal-weight patients.. Both randomized and non-randomized studies were identified from searches up to July 2013. Risk of bias was assessed with the Downs-Black checklist, the Cochrane tool and the GRADE framework. Quantitative synthesis was conducted with random-effects meta-analyses in subgroups for systemically healthy and diabetic patients.. A total of 15 studies including 867 patients were included. No significant difference was found for any clinical periodontal parameter between overweight/obese and normal-weight patients. Periodontal treatment in systemically healthy overweight/obese patients was associated with higher decrease in TNFα levels (1 study) and higher decrease in HbA1c levels (1 study) compared to systemically healthy normal-weight patients. Contrary to diabetic normal-weight patients, periodontal treatment in diabetic overweight/obese patients was associated with an increase in adiponectin levels (2 studies) and a decrease in leptin levels (2 studies). However, the quality of existing evidence is low due to inconsistency, imprecision and lack of studies.. Whereas no difference was found in clinical periodontal parameters, significant differences in inflammatory or metabolic parameters were found between overweight/obese and normal-weight patients, but existing evidence is weak.

Topics: Adiponectin; Body Weight; Diabetes Complications; Glycated Hemoglobin; Humans; Leptin; Obesity; Overweight; Periodontal Diseases; Tumor Necrosis Factor-alpha

Global levels of obesity are reaching epidemic proportions, leading to a dramatic increase in incidence of secondary diseases and the significant economic burden associated with their treatment. These comorbidities include diabetes, cardiovascular disease, and some psychopathologies, which have been linked to a low-grade inflammatory state. Obese individuals exhibit an increase in circulating inflammatory mediators implicated as the underlying cause of these comorbidities. A number of these molecules are also manufactured and released by white adipose tissue (WAT), in direct proportion to tissue mass and are collectively known as adipokines. In the current review we focused on the role of two of the better-studied members of this family namely, leptin and adiponectin, with particular emphasis on their role in neuro-immune interactions, neuroinflammation and subsequent brain diseases. This article is part of a Special Issue entitled 'Neuroimmunology and Synaptic Function'.

Topics: Adipokines; Adiponectin; Animals; Encephalitis; Humans; Inflammation; Leptin; Obesity

The consumption of Western diets, high in sugar and saturated fat, is a crucial contributor to the alarming incidence of obesity and its associated morbidities. These diets have been reported to induce an inflammatory response in the hypothalamus, which promotes the development of central leptin resistance and obesity. This inflammatory signalling involves dynamic changes in the expression and activity of several mediators of the innate immune system, including toll-like receptor 4, IκB kinase-β/nuclear factor-κB, c-Jun N-terminal kinase, suppressor of cytokine signalling 3 and pro-inflammatory cytokines, as well as the induction of endoplasmic reticulum stress and autophagy defect. Although the exact cellular mechanisms remain incompletely understood, recent evidence suggests that the inflammatory response is at least mediated by interactions between neurons and non-neuronal cells such as microglia and astrocytes. Current evidence of the contribution of each inflammatory mediator to leptin resistance and diet-induced obesity (DIO), including their reciprocal interactions and cell-type-specific effects, is reviewed and integrated in a conceptual model. Based upon this model and pharmacological intervention studies, several inflammatory mediators are proposed to be promising therapeutic targets for the treatment of DIO.

Topics: Animals; Diet, High-Fat; Energy Metabolism; Humans; Hypothalamus; Inflammation; Leptin; Mice; Obesity; Oxidative Stress; Rats; Signal Transduction

Obesity is among the most pressing health concerns in the world since it is increasingly common even in the developing world, and is clearly associated with increased risk for chronic debilitating diseases and death. Furthermore, obesity can influence the pathogenesis of infectious diseases by affecting the balance of pathogen clearance and pathological inflammation. The mechanisms that result in enhanced inflammation in obese individuals are poorly understood. Clostridium difficile is a major cause of nosocomial infections worldwide. Recent studies have shown that obesity is associated with increased risk of C. difficile infections. In this review, we will discuss our current knowledge of the role of obesity in determining risk of C. difficile infections, and focus on the role of the adipose tissue-derived cytokine leptin in C. difficile infections.

Topics: Adipose Tissue; Clostridioides difficile; Clostridium Infections; Host-Pathogen Interactions; Humans; Leptin; Obesity

Obesity is a major health burden with an increased risk of cardiovascular morbidity and mortality. Endothelial dysfunction is pivotal to the development of cardiovascular disease (CVD). In relation to this, adipose tissue secreted factors termed "adipokines" have been reported to modulate endothelial dysfunction. In this review, we focus on two of the most abundant circulating adipokines, that is, leptin and adiponectin, in the development of endothelial dysfunction. Leptin has been documented to influence a multitude of organ systems, that is, central nervous system (appetite regulation, satiety factor) and cardiovascular system (endothelial dysfunction leading to atherosclerosis). Adiponectin, circulating at a much higher concentration, exists in different molecular weight forms, essentially made up of the collagenous fraction and a globular domain, the latter being investigated minimally for its involvement in proinflammatory processes including activation of NF-κβ and endothelial adhesion molecules. The opposing actions of the two forms of adiponectin in endothelial cells have been recently demonstrated. Additionally, a local and systemic change to multimeric forms of adiponectin has gained importance. Thus detailed investigations on the potential interplay between these adipokines would likely result in better understanding of the missing links connecting CVD, adipokines, and obesity.

Topics: Adipokines; Adiponectin; Animals; Atherosclerosis; Cardiovascular Diseases; Endothelium, Vascular; Humans; Ischemia; Leptin; Mice; Neovascularization, Pathologic; Neovascularization, Physiologic; NF-kappa B; Nitric Oxide; Obesity

Leptin is a hormone with a key role in food intake and body weight homeostasis. Congenital leptin deficiency (CLD) is a rare disease that causes hyperphagia and early severe obesity. However, common obesity conditions are associated with hyperleptinemia and leptin resistance.. The main signaling pathways activated by leptin as well as the mechanisms underlying the regulatory actions of leptin on food intake and on lipid and glucose metabolism are reviewed. The potential mechanisms involving leptin resistance and the main regulatory hormonal and nutritional factors controlling leptin production/functions are also analyzed. The pathophysiology of leptin in human obesity, and especially the trials analyzing effects of leptin replacement therapy in patients with CLD or in subjects with common obesity and in post-obese weight-reduced subjects are also summarized.. The use of drugs or specific bioactive food components with anti-inflammatory properties to reduce the inflammatory state associated with obesity, especially at the hypothalamus, may help to overcome leptin resistance. Research should also be focused on investigating dietary strategies, food supplements or drugs capable of avoiding or reversing the leptin fall during weight management, in order to promote sustained body weight lowering and weight loss maintenance.

Topics: Animals; Anti-Inflammatory Agents; Anti-Obesity Agents; Body Weight; Humans; Hypothalamus; Inflammation; Leptin; Molecular Targeted Therapy; Obesity; Signal Transduction

Several articles have dealt with the importance and mechanisms of the sympathetic nervous system alterations in experimental animal models of hypertension. This review addresses the role of the sympathetic nervous system in the pathophysiology and therapy of human hypertension. We first discuss the strengths and limitations of various techniques for assessing the sympathetic nervous system in humans, with a focus on heart rate, plasma norepinephrine, microneurographic recording of sympathetic nerve traffic, and measurements of radiolabeled norepinephrine spillover. We then examine the evidence supporting the importance of neuroadrenergic factors as promoters and amplifiers of human hypertension. We expand on the role of the sympathetic nervous system in 2 increasingly common forms of secondary hypertension, namely hypertension associated with obesity and with renal disease. With this background, we examine interventions of sympathetic deactivation as a mode of antihypertensive treatment. Particular emphasis is given to the background and results of recent therapeutic approaches based on carotid baroreceptor stimulation and radiofrequency ablation of the renal nerves.

Topics: Animals; Antihypertensive Agents; Clinical Trials as Topic; Diagnostic Techniques, Cardiovascular; Forecasting; Heart Rate; Humans; Hyperinsulinism; Hypertension; Hypertension, Renal; Insulin Resistance; Kidney; Kidney Diseases; Leptin; Melanocortins; Metabolic Syndrome; Multicenter Studies as Topic; Neuroimaging; Norepinephrine; Obesity; Sympathectomy; Sympathetic Fibers, Postganglionic; Sympathetic Nervous System; Vasoconstriction

Excess weight gain, especially when associated with increased visceral adiposity, is a major cause of hypertension, accounting for 65% to 75% of the risk for human primary (essential) hypertension. Increased renal tubular sodium reabsorption impairs pressure natriuresis and plays an important role in initiating obesity hypertension. The mediators of abnormal kidney function and increased blood pressure during development of obesity hypertension include (1) physical compression of the kidneys by fat in and around the kidneys, (2) activation of the renin-angiotensin-aldosterone system, and (3) increased sympathetic nervous system activity. Activation of the renin-angiotensin-aldosterone system is likely due, in part, to renal compression, as well as sympathetic nervous system activation. However, obesity also causes mineralocorticoid receptor activation independent of aldosterone or angiotensin II. The mechanisms for sympathetic nervous system activation in obesity have not been fully elucidated but may require leptin and activation of the brain melanocortin system. With prolonged obesity and development of target organ injury, especially renal injury, obesity-associated hypertension becomes more difficult to control, often requiring multiple antihypertensive drugs and treatment of other risk factors, including dyslipidemia, insulin resistance and diabetes mellitus, and inflammation. Unless effective antiobesity drugs are developed, the effect of obesity on hypertension and related cardiovascular, renal and metabolic disorders is likely to become even more important in the future as the prevalence of obesity continues to increase.

Topics: Aldosterone; Animals; Antihypertensive Agents; Dyslipidemias; Heart Conduction System; Hemodynamics; Humans; Hypertension; Insulin Resistance; Intra-Abdominal Fat; Kidney; Leptin; Metabolic Syndrome; Models, Animal; Models, Cardiovascular; Natriuresis; Obesity; Organ Specificity; Parasympathetic Nervous System; Pressure; Prevalence; Pro-Opiomelanocortin; Receptors, Leptin; Renal Insufficiency, Chronic; Renin-Angiotensin System; Sodium; Sympathetic Nervous System

Adipose tissue has been more accepted as an active contributor to whole body homeostasis, rather than just a fat depot, since leptin, a 16 kDa protein, was discovered as the product of the obese gene in 1994. With more and more studies conducted on this hormone, it has been shown that there is a close relationship between adipose tissue and bone, which have important effects on each other. Bone is the source of many hormones, such as osteocalcin, that can affect energy metabolism and then the anabolism or catabolism of fat tissue. In contrast, the adipose tissue synthesizes and releases a series of adipokines, which are involved in bone metabolism through direct or indirect effects on bone formation and resorption. Interestingly, leptin, one of the most important cytokines derived from fat tissue, seems to account for the largest part of effects on bone, through direct or indirect involvement in bone remodeling and by playing a significant role in many bone diseases, such as osteoporosis, osteoarthritis, rheumatic arthritis, bone tumors and even fractures. In this review, we will discuss the progress in leptin research, particularly focusing on the roles of leptin in bone diseases.

Topics: Adipokines; Adipose Tissue; Animals; Bone and Bones; Bone Diseases; Bone Remodeling; Energy Metabolism; Humans; Leptin; Obesity; Osteocalcin; Osteogenesis

Obesity is a central health issue due to its epidemic prevalence and its association with type 2 diabetes and other comorbidities. Obesity is not just being overweight. It is a metabolic disorder due to the accumulation of excess dietary calories into visceral fat and the release of high concentrations of free fatty acids into various organs. It represents a state of chronic oxidative stress and low-grade inflammation whose intermediary molecules may include leptin, adiponectin and cytokines. It may progress to hyperglycemia, leading to type 2 diabetes. Whether or not dietary antioxidant supplements are useful in the management of obesity and type 2 diabetes is discussed in this review. Only the benefits for obesity and diabetes are examined here. Other health benefits of antioxidants are not considered. There are difficulties in comparing studies in this field because they differ in the time frame, participants' ethnicity, administration of antioxidant supplements, and even in how obesity was measured. However, the literature presents reasonable evidence for marginal benefits of supplementation with zinc, lipoic acid, carnitine, cinnamon, green tea, and possibly vitamin C plus E, although the evidence is much weaker for omega-3 polyunsaturated fatty acids, coenzyme Q10, green coffee, resveratrol, or lycopene. Overall, antioxidant supplements are not a panacea to compensate for a fast-food and video-game way of living, but antioxidant-rich foods are recommended as part of the lifestyle. Such antioxidant foods are commonly available.

Topics: Adipose Tissue; Alpha-Ketoglutarate-Dependent Dioxygenase FTO; Antioxidants; Biomarkers; Body Mass Index; Diabetes Mellitus, Type 2; Dietary Supplements; Fatty Acids, Nonesterified; Genetic Predisposition to Disease; Humans; Inflammation; Leptin; Obesity; Overweight; Oxidative Stress; Proprotein Convertase 1; Proteins; Reactive Oxygen Species; Receptor, Melanocortin, Type 4; Vitamins

The core of the leptin resistance hypothesis promulgated several years ago to explain obesity as a result of environmental causes consists of 2 tenets: the extinction of leptin-induced intracellular signaling downstream of leptin binding to the long form of the neuronal receptor LTRb in the hypothalamus and the impedance to leptin entry imposed at the blood-brain barrier (BBB). A recent comprehensive investigation concluded that a central leptin insufficiency associated with obesity can be attributed to a decreased efficiency of BBB leptin transport and not to leptin insensitivity within the hypothalamus. Interestingly, anorectic leptin's effects are counteracted in some individuals by a natural resistance associated with hyperleptinemia, which is related to changes in hypothalamic sensitivity to leptin (eg, due to malnutrition, obesity, or seasonal variations due to day-length-dependent reproduction changes). In sheep, it has been observed that the hypothalamus is resistant to leptin in some periods, which is related to the adaptation of these animals to annual changes in energy supply and demand. However, a broad range of ambiguities exists regarding the implications that the intracellular signaling of signal transducer and activator of transcription-2/suppressor of cytokine signaling 3 (STAT2/SOCS3) imparts central leptin resistance. Furthermore, several plausible alternative possibilities have been proposed, such as compensatory functional and anatomic reorganizations in the appetite regulating network, rearrangements in the afferent hormonal feedback signaling involved in weight homeostasis, and modifications in leptin transport to the hypothalamus across the BBB. Taken together, these observations suggest that the contention that impaired intracellular signaling downstream of leptin entry into the appetite regulating network expedites environmentally induced obesity remains unsubstantiated and requires further evidence. Furthermore, pregnancy decreases hypothalamic sensitivity to leptin (or other unknown mechanisms), and lactation can also alter the appetite-suppressing central activity of leptin. The objective of this review was to offer an approach to understanding (1) how information regarding nutritional status is transmitted to and interpreted within the hypothalamus in animals, with special attention on seasonally breeding animals and (2) whether central leptin resistance and/or leptin insufficiency in the hypothalamus favors the development o

Topics: Animals; Appetite Regulation; Biological Transport; Blood-Brain Barrier; Brain; Breeding; Drug Resistance; Female; Hypothalamus; Leptin; Mammary Glands, Animal; Nutritional Status; Obesity; Photoperiod; Pregnancy; Prolactin; Receptors, Leptin; RNA, Messenger; Seasons; Sheep; Signal Transduction; STAT2 Transcription Factor; Suppressor of Cytokine Signaling Proteins

Obesity is an established risk factor for postmenopausal breast cancer. The mechanisms through which obesity influences the development and progression of breast cancer are not fully elucidated; however, several factors such as increased oestrogen, concentrations of various members of the insulin family and inflammation that are associated with adiposity are purported to be important factors in this relationship. Emerging research has also begun to focus on the role of adipokines, (i.e. adipocyte secreted factors), in breast cancer. Leptin secretion is directly related to adiposity and is believed to promote breast cancer directly and independently, as well as through involvement with the oestrogen and insulin signalling pathways. As leptin is secreted from white adipose tissue, any intervention that reduces adiposity may be favourable. However, it is also important to consider that energy expenditure through exercise, independent of fat loss, may improve leptin regulation. The purpose of this narrative review was to explore the role of leptin in breast cancer development and progression, identify key interactions with oestrogen and the insulin family, and distinguish the potential effects of exercise on these interactions.

Topics: Adiposity; Animals; Breast Neoplasms; Energy Metabolism; Estrogens; Exercise; Female; Humans; Insulin; Insulin Secretion; Leptin; Models, Biological; Molecular Sequence Data; Obesity; Risk Factors; Signal Transduction

Obesity is a significant risk factor for the development of different cancer types and has been associated with poorer response to oncotherapies and linked to earlier recurrence of the neoplastic disease. While molecular mechanisms of these associations are still under investigation, functional dysregulation of two major fat tissue-derived adipokines, leptin and adiponectin, appears to play an important role. Leptin is known to activate carcinogenic pathways, while adiponectin appears to exert antineoplastic activities and interfere with leptin-induced processes. Because excess body fat is associated with increased leptin expression and adiponectin downregulation, therapeutic rebalancing of these pathways may benefit cancer patients, especially the obese subpopulations. This review focuses on our novel leptin receptor antagonists and adiponectin receptor agonists designed for therapeutic modulation of obesity-associated pathways in cancer.

Topics: Adiponectin; Animals; Antineoplastic Agents; Biomimetics; Humans; Leptin; Metabolic Networks and Pathways; Molecular Targeted Therapy; Neoplasm Recurrence, Local; Neoplasms; Obesity; Peptides; Receptors, Adiponectin; Receptors, Leptin

The prevalence of obesity has increased worldwide at an alarming rate. However, non-invasive pharmacological treatments remain elusive. Leptin resistance is a general feature of obesity, thus strategies aimed at enhancing the sensitivity to this hormone may constitute an excellent therapeutical approach to counteract current obesity epidemics. Nevertheless, the etiology and neuronal basis of leptin resistance remains an enigma. A recent hypothesis gaining substantial experimental support is that hypothalamic endoplasmic reticulum (ER) stress plays a causal role in the development of leptin resistance and obesity. The objective of this review article is to provide an updated view on current evidence connecting hypothalamic ER stress with leptin resistance. We discuss the experimental findings supporting this hypothesis, as well as the potential causes and underlying mechanisms leading to this metabolic disorder. Understanding these mechanisms may provide key insights into the development of novel intervention approaches.

Topics: Endoplasmic Reticulum; Humans; Hypothalamus; Leptin; Obesity

Diabetes and obesity are worldwide health problems. White fat dynamically participates in hormonal and inflammatory regulation. White adipose tissue is recognized as a multifactorial organ that secretes several adipose-derived factors that have been collectively termed "adipokines." Adipokines are pleiotropic molecules that gather factors such as leptin, adiponectin, visfatin, apelin, vaspin, hepcidin, RBP4, and inflammatory cytokines, including TNF and IL-1β, among others. Multiple roles in metabolic and inflammatory responses have been assigned to these molecules. Several adipokines contribute to the self-styled "low-grade inflammatory state" of obese and insulin-resistant subjects, inducing the accumulation of metabolic anomalies within these individuals, including autoimmune and inflammatory diseases. Thus, adipokines are an interesting drug target to treat autoimmune diseases, obesity, insulin resistance, and adipose tissue inflammation. The aim of this review is to present an overview of the roles of adipokines in different immune and nonimmune cells, which will contribute to diabetes as well as to adipose tissue inflammation and insulin resistance development. We describe how adipokines regulate inflammation in these diseases and their therapeutic implications. We also survey current attempts to exploit adipokines for clinical applications, which hold potential as novel approaches to drug development in several immune-mediated diseases.

Topics: Adipokines; Adiponectin; Adipose Tissue; Animals; Diabetes Mellitus; Humans; Inflammation; Interleukin-1beta; Leptin; Mice; Nicotinamide Phosphoribosyltransferase; Obesity; Retinol-Binding Proteins, Plasma; Tumor Necrosis Factor-alpha

Diabetes and obesity are associated with nonalcoholic fatty liver disease (NAFLD) and an increased incidence of hepatocellular carcinoma (HCC). NAFLD is the commonest cause of chronic liver disease. HCC can develop in NAFLD patients even without cirrhosis, suggesting an association between the metabolic process and HCC and raising a concern that many cancers could be missed given high NAFLD prevalence and screening limitations. The increasing prevalence of these conditions and lack of effective treatments necessitate a better understanding of their connection. This article defines the known interrelationships and common pathways between NAFLD, diabetes, obesity and HCC and possible chemoprevention strategies.

Topics: Carcinoma, Hepatocellular; Chemoprevention; Diabetes Mellitus, Type 2; Endoplasmic Reticulum Stress; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypoglycemic Agents; Incidence; Inflammation; Insulin Resistance; JNK Mitogen-Activated Protein Kinases; Leptin; Liver Neoplasms; Metformin; Non-alcoholic Fatty Liver Disease; Obesity; Risk Factors; S-Adenosylmethionine; Toll-Like Receptors

Obesity is a risk factor for infertility and adverse reproductive outcomes. Adipose tissue is an important endocrine gland that secretes a host of endocrine factors, called adipokines, which modulate diverse physiologic processes including appetite, metabolism, cardiovascular function, immunity and reproduction. Altered adipokine expression in obese individuals has been implicated in the pathogenesis of a host of health disorders including diabetes and cardiovascular disease. It remains unclear whether adipokines play a significant role in the pathogenesis of adverse reproductive outcomes in obese individuals and, if so, whether the adipokines are acting directly or indirectly on the peripheral reproductive tissues. Many groups have demonstrated that receptors for the adipokines leptin and adiponectin are expressed in peripheral reproductive tissues and that these adipokines are likely, therefore, to exert direct effects on these tissues. Many groups have tested for direct effects of leptin and adiponectin on reproductive tissues including the testis, ovary, uterus, placenta and egg/embryo. The hypothesis that decreased fertility potential or adverse reproductive outcomes may result, at least in part, from defects in adipokine signaling within reproductive tissues has also been tested. Here, we present a critical analysis of published studies with respect to two adipokines, leptin and adiponectin, for which significant data have been generated. Our evaluation reveals significant inconsistencies and methodological limitations regarding the direct effects of these adipokines on peripheral reproductive tissues. We also observe a pervasive failure to account for in vivo data that challenge observations made in vitro. Overall, while leptin and adiponectin may directly modulate peripheral reproductive tissues, existing data suggest that these effects are minor and non-essential to human or mouse reproductive function. Current evidence suggests that direct effects of leptin or adiponectin on peripheral reproductive tissues are unlikely to factor significantly in the adverse reproductive outcomes observed in obese individuals.

Topics: Adipokines; Animals; Humans; Leptin; Male; Obesity; Reproduction

Leptin (Lep) is emerging as a pivotal molecule involved in both the early events and the terminal phases of Alzheimer's disease (AD). In the canonical pathway, Lep acts as an anorexigenic factor via its effects on hypothalamic nucleus. However, additional functions of Lep in the hippocampus and cortex have been unravelled in recent years. Early events in the sporadic form of AD likely involve cellular level alterations which can have an effect on food intake and metabolism. Thus, AD can be conceivably interpreted as a multiorgan pathology that not only results in a dramatic neuronal loss in brain areas such as the hippocampus and the cortex (ultimately leading to a significant cognitive impairment) but as a disease which also affects body-weight homeostasis. According to this view, body-weight control disruptions are to be expected in both the early- and late-stage AD, concomitant with changes in serum Lep content, alterations in Lep transport across the blood-brain barrier (BBB) and Lep receptor-related signalling abnormalities. Lep is a member of the adipokine family of molecules, while the Lep receptor belongs to the class I cytokine receptors. Since cellular response to adipokine signalling can be either potentiated or diminished as a result of specific ligand-receptor interactions, Lep interactions with other members of the adipokine family including amylin, ghrelin and hormones such as prolactin require further investigation. In this review, we provide a general perspective on the functions of Lep in the brain, with a particular focus on the sporadic AD.

Topics: Alzheimer Disease; Diabetes Mellitus, Type 2; Ghrelin; Humans; Hypothalamus; Islet Amyloid Polypeptide; Leptin; Life Style; Obesity; Prolactin; Protein Binding

Leptin is an adipocyte-secreted hormone that inhibits food intake and stimulates energy expenditure through interactions with neuronal pathways in the brain, particularly pathways involving the hypothalamus. Intact functioning of the leptin route is required for body weight and energy homeostasis. Given its function, the discovery of leptin increased expectations for the treatment of obesity. However, most obese individuals and subjects with a predisposition to regain weight after losing it have leptin concentrations than lean individuals, but despite the anorexigenic function of this hormone, appetite is not effectively suppressed in these individuals. This phenomenon has been deemed leptin resistance and could be the result of impairments at a number of levels in the leptin signalling pathway, including reduced access of the hormone to its receptor due to changes in receptor expression or changes in post-receptor signal transduction. Epigenetic regulation of the leptin signalling circuit could be a potential mechanism of leptin function disturbance. This review discusses the molecular mechanisms, particularly the epigenetic regulation mechanisms, involved in leptin resistance associated with obesity and the therapeutic potential of these molecular mechanisms in the battle against the obesity pandemic.

Topics: Epigenesis, Genetic; Humans; Leptin; Obesity; Signal Transduction

The current concept of the pathogenesis of obesity relates to the inflammation caused by excess of adipose tissue. Regulatory T cells accumulated in visceral adipose tissue (VAT-resident Tregs) are also involved in this pathogenesis. In the present paper the mechanisms responsible for alterations in the number and function of VAT-resident Tregs T in obesity are described. The role of Tregs in inflammation, insulin resistance, atherogenesis, and also the influence on VAT-resident Tregs of adipocytokines and insulin are reviewed.

Topics: Adiponectin; Animals; Humans; Intra-Abdominal Fat; Leptin; Obesity; T-Lymphocytes, Regulatory

Colorectal cancer (CRC) is a worldwide health problem, being the third most commonly detected cancer in males and the second in females. Rising CRC incidence trends are mainly regarded as a part of the rapid 'Westernization' of life-style and are associated with calorically excessive high-fat/low-fibre diet, consumption of refined products, lack of physical activity, and obesity. Most recent epidemiological and clinical investigations have consistently evidenced a significant relationship between obesity-driven inflammation in particular steps of colorectal cancer development, including initiation, promotion, progression, and metastasis. Inflammation in obesity occurs by several mechanisms. Roles of imbalanced metabolism (MetS), distinct immune cells, cytokines, and other immune mediators have been suggested in the inflammatory processes. Critical mechanisms are accounted to proinflammatory cytokines (e.g. IL-1, IL-6, IL-8) and tumor necrosis factor-α (TNF-α). These molecules are secreted by macrophages and are considered as major agents in the transition between acute and chronic inflammation and inflammation-related CRC. The second factor promoting the CRC development in obese individuals is altered adipokine concentrations (leptin and adiponectin). The role of leptin and adiponectin in cancer cell proliferation, invasion, and metastasis is attributable to the activation of several signal transduction pathways (JAK/STAT, mitogen-activated protein kinase (MAPK), phosphatidylinositol 3 kinase (PI3K), mTOR, and 5'AMPK signaling pathways) and multiple dysregulation (COX-2 downregulation, mRNA expression).

Topics: Adiponectin; Carcinogenesis; Chronic Disease; Colorectal Neoplasms; Cytokines; Female; Humans; Inflammation; Leptin; Male; Obesity; Reactive Oxygen Species

Over the past few decades, our understanding of the role of adipose tissue has changed dramatically. Far from simply being a site of energy storage or a modulator of the endocrine system, adipose tissue has emerged as an important regulator of multiple important processes including inflammation. Adipokines are a diverse family of soluble mediators with a range of specific actions on the immune response. Autoimmune diseases are perpetuated by chronic inflammatory responses but the exact etiology of these diseases remains elusive. While researchers continue to investigate these causes, millions of people continue to suffer from chronic diseases. To this end, an increased interest has developed in the connection between adipose tissue-secreted proteins that influence inflammation and the onset and perpetuation of autoimmunity. This review will focus on recent advances in adipokine research with specific attention on a subset of adipokines that have been associated with autoimmune diseases.

Topics: Adipokines; Adiponectin; Adipose Tissue, White; Autoimmunity; Chemokines; Humans; Inflammation; Intercellular Signaling Peptides and Proteins; Leptin; Nicotinamide Phosphoribosyltransferase; Obesity; Resistin

Metreleptin was recently approved by the Food and Drug Administration for the treatment of generalized lipodystrophy, a condition characterized by leptin deficiency. Its efficacy as hormone replacement therapy suggests broader applications in diseases also characterized by leptin abnormalities, such as familial partial lipodystrophy (FPLD), non-alcoholic fatty liver disease (NAFLD), and common obesity. Metreleptin, in conjunction with other pharmacologic interventions, has the potential to address one of the most widespread epidemics of our time, obesity.. This review covers the physiology of leptin, the pharmacologic properties of recombinant methionyl human leptin (R-metHu-Leptin, metreleptin), evidence for metreleptin's efficacy in the treatment of generalized lipodystrophy from both completed and ongoing clinical trials, safety concerns, and future directions in metreleptin research.. Metreleptin's approval for generalized lipodystrophy is the first step in defining and expanding its role to other metabolic diseases. Clinical trials are underway to delineate its efficacy in FPLD, human immunodeficiency virus/highly active anti-retroviral therapy-associated acquired lipodystrophy (HAL), and NAFLD. Additionally, there is growing data that support a therapeutic role in obesity. One of the barriers to development, however, is metreleptin's safety and immunogenicity. Further advances in biologic compatibility are required before metreleptin can be approved for additional indications.

Topics: Autoimmunity; Clinical Trials as Topic; Half-Life; Humans; Leptin; Lipodystrophy; Lipodystrophy, Congenital Generalized; Obesity; Signal Transduction

Recent epidemiological and ecological trends in humans indicate a possible causal relationship between sleep duration and energy balance. We aimed to find experimental evidence that has tested this relationship between sleep duration and measures of body composition, food intake or biomarkers related to food intake. We conducted a systematic literature review using six databases throughout 7 August 2014. We sought reports of randomized controlled trials where sleep duration was manipulated and measured outcomes were body weight or other body composition metrics, food intake, and/or biomarkers related to eating. We found 18 unique studies meeting all criteria: eight studies with an outcome of body weight (4 - increased sleep, 4 - reduced sleep); four studies on food intake; four studies of sleep restriction on total energy expenditure and three of respiratory quotient; and four studies on leptin and/or ghrelin. Few controlled experimental studies have addressed the question of the effect of sleep on body weight/composition and eating. The available experimental literature suggests that sleep restriction increases food intake and total energy expenditure with inconsistent effects on integrated energy balance as operationalized by weight change. Future controlled trials that examine the impact of increased sleep on body weight/energy balance factors are warranted.

Topics: Adiposity; Body Composition; Body Weight; Energy Intake; Energy Metabolism; Female; Humans; Leptin; Male; Obesity; Randomized Controlled Trials as Topic; Sleep; Sleep Deprivation; Weight Gain

Obesity is a disorder that develops from the interaction between genotype and environment involving social, behavioral, cultural, and physiological factors. Obesity increases the risk for type 2 diabetes mellitus, hypertension, cardiovascular disease, cancer, musculoskeletal disorders, chronic kidney and pulmonary disease. Although obesity is clearly associated with an increased prevalence of hypertension, many obese individuals may not develop hypertension. Protecting factors may exist and it is important to understand why obesity is not always related to hypertension. The aim of this review is to highlight the knowledge gap for the association between obesity, hypertension, and potential genetic and racial differences or environmental factors that may protect obese patients against the development of hypertension and other co-morbidities. Specific mutations in the leptin and the melaninocortin receptor genes in animal models of obesity without hypertension, the actions of α-melanocyte stimulating hormone, and SNS activity in obesity-related hypertension may promote recognition of protective and promoting factors for hypertension in obesity. Furthermore, gene-environment interactions may have the potential to modify gene expression and epigenetic mechanisms could also contribute to the heritability of obesity-induced hypertension. Finally, differences in nutrition, gut microbiota, exposure to sun light and exercise may play an important role in the presence or absence of hypertension in obesity.

Topics: Animals; Appetite; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Exercise; Gene-Environment Interaction; Humans; Hypertension; Leptin; Obesity; Potassium, Dietary; Protective Factors; Receptor, Melanocortin, Type 4; Sodium, Dietary; Sympathetic Nervous System

Obesity and its medical complications represent a significant problem throughout the world. In recent decades, mechanisms underlying the progression of obesity have been intensively examined. The involvement of both the behavioral aspects, such as calorie-rich diet, low physical activity and sleep deprivation, and the intrinsic factors, including adipose tissue deregulation, chronic inflammation, oxidative stress, and chronodisruption, has been identified. The circadian disturbances of the adipose tissue endocrine function have been correlated with obesity. Leptin and adiponectin are adipokines strongly associated with glucose and lipid metabolism and with energy balance. Their synthesis and secretion display circadian rhythms that are disturbed in the obese state. Hyperleptinemia resulting in leptin resistance, and hypo-adiponectinemia have been linked to the pathophysiology of the obesity-related disorders. A deficiency of melatonin, one of the consequences of sleep deprivation, has also been demonstrated to correlate with obesity. Melatonin is a pineal secretory product involved in numerous actions, such as regulation of internal biological clocks and energy metabolism, and it functions as an antioxidant and as an anti-inflammatory agent. There exists a substantial amount of evidence supporting the beneficial effects of melatonin supplementation on obesity and its complications. In the current review, the results of studies related to the interactions between melatonin, and both leptin and adiponectin are discussed. Despite the existence of some inconsistencies, melatonin has been found to normalize the expression and secretion patterns of both adipokines. These results support the concept of melatonin as a potential therapeutic agent for obesity and related disorders.

Topics: Adipokines; Adiponectin; Adipose Tissue, White; Animals; Humans; Leptin; Melatonin; Obesity

This article is part of a Special Issue "SBN 2014". Obesity in women of child-bearing age is a growing problem in developed and developing countries. Evidence from human studies indicates that maternal BMI correlates with offspring adiposity from an early age and predisposes to metabolic disease in later life. Thus the early life environment is an attractive target for intervention to improve public health. Animal models have been used to investigate the specific physiological outcomes and mechanisms of developmental programming that result from exposure to maternal obesity in utero. From this research, targeted intervention strategies can be designed. In this review we summarise recent progress in this field, with a focus on cardiometabolic disease and central control of appetite and behaviour. We highlight key factors that may mediate programming by maternal obesity, including leptin, insulin, and ghrelin. Finally, we explore potential lifestyle and pharmacological interventions in humans and the current state of evidence from animal models.

Topics: Animals; Female; Fetus; Ghrelin; Humans; Insulin; Leptin; Obesity; Pregnancy; Pregnancy Complications; Prenatal Exposure Delayed Effects

Metabolic homeostasis requires a tight balance between energy intake and energy expenditure; hence, the physiological circuits implicated in the regulation of energy metabolism must be able to quickly adjust to changes in either side of the equation. Circulating orexigenic and anorexigenic factors, including ghrelin and leptin, are produced in the gastrointestinal tract and adipose tissue, respectively, in relation to an individual's nutritional status. These signals interact with central metabolic circuits to regulate the production and secretion of neuropeptides implicated in the control of appetite and energy expenditure. However, this physiological equilibrium can be perturbed by diverse processes, with weight gain occurring due to a positive energy balance and weight loss taking place if there is a negative energy balance. If a situation of positive energy balance continues for an extended period of time, excess weight is accumulated and this can eventually result in obesity. Obesity has become one of the most important health problems facing the industrialized world, indicating that metabolic equilibrium is frequently disrupted. Understanding how and why this occurs will allow new therapeutical targets to be identified.

Topics: Animals; Appetite Regulation; Drug Discovery; Exercise; Feeding Behavior; Ghrelin; Humans; Hypothalamus; Leptin; Obesity; Signal Transduction

Suboptimal maternal nutrition exerts lasting impacts on obesity risk in offspring, but the direction of the effect is determined by the timing of exposure. While maternal undernutrition in early pregnancy is associated with increased body mass index, in later pregnancy it can be protective. The importance of the timing of maternal undernutrition is also observed in rodents, however, many of the processes that occur in the last trimester of human gestation are delayed to the postnatal period. Neonatal leptin administration exerts lasting impacts on susceptibility to obesity in rodents. Although leptin can influence the formation of hypothalamic circuits involved in homeostatic control of feeding during the postnatal period, these effects are too late to account for its ability to reverse adverse metabolic programming due to early gestational exposure to maternal undernutrition. This review presents an alternative framework for understanding the effects of neonatal leptin through influences on developing thermoregulatory circuits.

Topics: Adult; Female; Humans; Leptin; Malnutrition; Maternal Nutritional Physiological Phenomena; Obesity; Pregnancy; Prenatal Exposure Delayed Effects

Since identification in 1994 of leptin, a hormone produced by adipocytes, adipose tissue has become the subject of intensive research. These studies contributed to the discovery that adipocytes have the ability to synthesize and secrete biologically active substances called "adipokines". Adipokines include a variety of cytokines, peptide hormones and enzymes that play a role in a wide variety of biological functions. For example, they are involved in the regulation of appetite, energy homeostasis, vascular hemostasis, blood pressure, inflammatory and immune processes and play a role in the metabolism of carbohydrates and fats. In obese patients, the secretion of adipokines is frequently abnormal. These changes may predispose to the development of insulin resistance, hypertension and inflammation. Therefore, adipokines are the subject of ongoing clinical trials. The family of adipokines is increasing by the newly discovered peptides. This paper presents the current state of knowledge about retinol binding protein 4 (RBP-4), fasting-induced adipose factor/angiopoietin-like protein 4 (FIAF/ANGPTL4), fibroblast growth factor-21 (FGF21), dipeptidyl peptidase-4 (DPP-4), irisin and their potential role in the pathogenesis of metabolic disorders associated with obesity. The knowledge of the role of newly discovered adipokines may help in the treatment of metabolic syndrome.

Topics: Adipocytes; Adipose Tissue; Humans; Insulin Resistance; Leptin; Metabolic Diseases; Obesity

To summarize previous and current advancements for leptin therapeutics, we described how leptin may be useful in leptin deficient states such as lipodystrophy, for which leptin was recently approved, and how it may be useful in the future for typical obesity.. The discovery of leptin in 1994 built the foundation for understanding the pathophysiology and treatment of obesity. Leptin therapy reverses morbid obesity related to congenital leptin deficiency and appears to possibly treat lipodystrophy, a finding which has led to the approval of leptin for the treatment of lipodystrophy in the USA and Japan. Typical obesity, on the other hand, is characterized by hyperleptinemia and leptin tolerance. Thus, leptin administration has proven ineffective for inducing weight loss on its own but could possibly be useful in combination with other therapies or for weight loss maintenance.. Leptin is not able to treat typical obesity; however, it is effective for reversing leptin deficiency-induced obesity and is possibly useful in lipodystrophy. New mechanisms and pathways involved in leptin resistance are continuously discovered, whereas the development of new techniques and drug combinations which may improve leptin's efficacy and safety regenerate the hope for its use as an effective treatment for typical obesity.

Topics: Animals; Humans; Leptin; Lipodystrophy; Obesity

Achieving maintenance of weight loss is crucial to combat obesity. However, most individuals tend to regain weight. Data from successful maintainers show that they remain vigilant and constantly apply techniques to oppose the course of regaining. On the other hand, current advances in obesity research show that the reduced obese state is a state of altered physiology in terms of energy balance. This review describes the physiological adaptations occurring after weight loss that predispose to regaining. Specifically, changes regarding body composition, hormonal background, energy expenditure and control of food intake are discussed. Moreover, metabolites that can act as regain predictors and dietary techniques to oppose regaining are presented.

Topics: Body Composition; Energy Metabolism; Humans; Leptin; Obesity; Weight Gain; Weight Loss

The prevalence of global obesity is increasing. Obesity is associated with general cancer-related morbidity and mortality and is a known risk factor for development of specific cancers. A recent large systematic review of 24 studies based on meta-analysis of 11,149 patients with prostate cancer showed a significant correlation between obesity and the risk of advanced prostate cancer. Further, a sustained reduction in BMI correlates with a decreased risk of developing aggressive disease. On the other hand, the correlation between consuming different products and prostate cancer occurrence/risk is limited.Here, we review the role of adipose tissue from an endocrine perspective and outline the effect of adipokines on cancer metabolism, with particular focus on leptin. Leptin exerts its physiological and pathological effects through modification of intracellular signalling, most notably activating the Janus kinase (JAK) 2/signal transducer and activator of transcription (STAT) 3 pathway and recently shown sphingolipid pathway. Both high levels of leptin in circulation and leptin receptor mutation are associated with prostate cancer risk in human patients; however, the in vivo mechanistic evidence is less conclusive.Given the complexity of metabolic cancer pathways, it is possible that leptin may have varying effects on prostate cancer at different stages of its development, a point that may be addressed by further epidemiological studies.

Topics: Adipose Tissue; Animals; Carcinogenesis; Genetic Predisposition to Disease; Humans; Janus Kinases; Leptin; Male; Obesity; Polymorphism, Genetic; Prostatic Neoplasms; Receptors, Leptin; Signal Transduction; STAT3 Transcription Factor

Leptin resistance is one of the main challenges of obesity. To date, two levels of resistance have been identified, first a decreased rate of leptin uptake into the brain and secondly a diminished central response to leptin. New findings have identified the mechanisms of leptin transport and demonstrated that it can be rescued in obesity, but it did not overcome the problem of central resistance. Alteration in the actions of leptin following diet-induced obesity (DIO) appears to be a multifactorial condition. Several phosphatases are inhibiting leptin signaling pathways in a pathological way. Besides, hypothalamic inflammation alters the neuronal circuits that control metabolism. Recent studies describing both mechanisms (inhibition of leptin signaling and inflammation), have provided key insights to potential new targets for treatment. However, recent data showing that DIO mice may conserve a cellular and physiological response to endogenous leptin, highlights the need to redefine the concept of "leptin resistance".

Topics: Animals; Female; Hypothalamus; Inflammation; Leptin; Mice; Obesity; Pregnancy

Infertility now affects one in seven couples, and the prevalence of this condition continues to increase. Ovulatory defects and unknown causes account for more than half of the cases of infertility. It has been postulated that a significant proportion of these cases are directly or indirectly related to obesity, since the presence of excess adipose tissue has a variety of effects on reproductive function. Here, we review on the effects of the two major adipokines (leptin and adiponectin) on fertility, with a focus on the first steps in embryo implantation and the key components of fetal-maternal interface (the placenta and the endometrium). These adipokines are reportedly involved in the regulation of cell proliferation and differentiation, and as such affect local angiogenesis, immune tolerance and inflammatory processes in placental and endometrial tissues. In placental cells, leptin and adiponectin also modulate trophoblast invasiveness and the nutrient supply. These observations strongly suggest by interfering with the placenta and endometrium, adipokines can create a favorable environment for embryo implantation and have a key role in fetal-maternal metabolism, fetal-maternal communication, and gestation. Given that reproductive functions are tightly coupled to the energy balance, metabolic abnormalities may lead to the development of complications of pregnancy and changes in fetal growth. In this context, we suggest that the leptin/adiponectin ratio may be a clinically valuable marker for detecting a number of pathologies in pregnancy.

Topics: Adiponectin; Embryo Implantation; Endometrium; Female; Fetal Development; Humans; Leptin; Maternal-Fetal Exchange; Obesity; Placenta; Pregnancy; Pregnancy Complications

The adipokine leptin realizes signal transduction via four different leptin receptor (OB-R) isoforms. The amount of functionally active OB-R, however, is affected by constitutive shedding of the extracellular domain. The product of the cleavage process, the so-called soluble leptin receptor (sOB-R), is the main binding protein for leptin in human blood and modulates its bioavailability. Concentrations of sOB-R are differentially regulated in metabolic disorders, such as type 1 diabetes mellitus or obesity, and can, therefore, enhance or reduce leptin sensitivity. Lipotoxicity and apoptosis increase OB-R cleavage via ADAM10-dependent mechanisms. In contrast, although increased sOB-R concentrations seem to directly inhibit leptin effects, reduced amounts of sOB-R may reflect decreased membrane expression of OB-R. These findings, in part, explain alterations of leptin sensitivity that are associated with changes in serum sOB-R concentrations seen in metabolic disorders.

Topics: ADAM10 Protein; Animals; Apoptosis; Diabetes Mellitus, Type 1; Humans; Leptin; Obesity; Receptors, Leptin

Energy homeostasis in our body system is maintained by balancing the intake and expenditure of energy. Excessive accumulation of fat by disrupting the balance system causes overweight and obesity, which are increasingly becoming global health concerns. Understanding the pathogenesis of obesity focused on studying the genes related to familial types of obesity. Recently, a rare human genetic disorder, ciliopathy, links the role for genes regulating structure and function of a cellular organelle, the primary cilium, to metabolic disorder, obesity and type II diabetes. Primary cilia are microtubule based hair-like membranous structures, lacking motility and functions such as sensing the environmental cues, and transducing extracellular signals within the cells. Interestingly, the subclass of ciliopathies, such as Bardet-Biedle and Alström syndrome, manifest obesity and type II diabetes in human and mouse model systems. Moreover, studies on genetic mouse model system indicate that more ciliary genes affect energy homeostasis through multiple regulatory steps such as central and peripheral actions of leptin and insulin. In this review, we discuss the latest findings in primary cilia and metabolic disorders, and propose the possible interaction between primary cilia and the leptin and insulin signal pathways which might enhance our understanding of the unambiguous link of a cell's antenna to obesity and type II diabetes.

Topics: Animals; Cilia; Diabetes Mellitus, Type 2; Disease Models, Animal; Energy Metabolism; Homeostasis; Humans; Insulin; Leptin; Metabolic Diseases; Mice; Microtubules; Obesity; Signal Transduction

Links between short sleep duration and obesity, type 2 diabetes, hypertension, and cardiovascular disease may be mediated through changes in dietary intake. This review provides an overview of recent epidemiologic studies on the relations between habitual short sleep duration and dietary intake in adults from 16 cross-sectional studies. The studies have observed consistent associations between short sleep duration and higher total energy intake and higher total fat intake, and limited evidence for lower fruit intake, and lower quality diets. Evidence also suggests that short sleepers may have irregular eating behavior deviating from the traditional 3 meals/d to fewer main meals and more frequent, smaller, energy-dense, and highly palatable snacks at night. Although the impact of short sleep duration on dietary intake tends to be small, if chronic, it may contribute to an increased risk of obesity and related chronic disease. Mechanisms mediating the associations between sleep duration and dietary intake are likely to be multifactorial and include differences in the appetite-related hormones leptin and ghrelin, hedonic pathways, extended hours for intake, and altered time of intake. Taking into account these epidemiologic relations and the evidence for causal relations between sleep loss and metabolism and cardiovascular function, health promotion strategies should emphasize improved sleep as an additional factor in health and weight management. Moreover, future sleep interventions in controlled studies and sleep extension trials in chronic short sleepers are imperative for establishing whether there is a causal relation between short sleep duration and changes in dietary intake.

Topics: Adult; Aged; Cardiovascular Diseases; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Diet; Dietary Fats; Dietary Fiber; Energy Intake; Feeding Behavior; Female; Fruit; Ghrelin; Health Promotion; Health Status; Humans; Hypertension; Leptin; Male; Middle Aged; Nutritive Value; Obesity; Sleep; Sleep Deprivation; Snacks; Time Factors

The increase in obesity rate is a major public health issue associated with increased pathological conditions such as type 2 diabetes or cardiovascular diseases. Obesity also contributes to decreased testosterone levels in men. Indeed, the adipose tissue is an endocrine organ which produces hormones such as leptin, adiponectin and resistin. Obesity results in pathological accumulations of leptin and resistin, whereas adiponectin plasma levels are markedly reduced, all having a negative impact on testosterone synthesis. This review focuses on current knowledge related to transcriptional regulation of Leydig cells' steroidogenesis by leptin, adiponectin and resistin. We show that there are crosstalks between the regulatory mechanisms of these hormones and androgen production which may result in a dramatic negative influence on testosterone plasma levels. Indeed leptin, adiponectin and resistin can impact expression of different steroidogenic genes such as Star, Cyp11a1 or Sf1. Further investigations will be required to better define the implications of adipose derived hormones on regulation of steroidogenic genes expression within Leydig cells under physiological as well as pathological conditions.

Topics: Adiponectin; Adipose Tissue; Body Mass Index; Gene Expression Regulation; Humans; Infertility, Male; Leptin; Leydig Cells; Male; Models, Biological; Obesity; Resistin; Signal Transduction

The role of leptin in regulation of energy homeostasis is well established, yet both the diagnostic as well as the therapeutic relevance of leptin in diet-induced obesity remains unresolved. Nevertheless, in the last few years, the substantial impact of leptin substitution in selected forms of monogenic obesity has advanced our knowledge about the neuroendocrine network of body weight regulation. Moreover, leptin seems to play a crucial role in intestinal nutrient reabsorption, regulation of blood pressure, fertility, inflammation and autoimmune diseases. A better understanding of these processes could possibly provide novel diagnostic and therapeutic options in the future.

Topics: Autoimmune Diseases; Blood Pressure; Body Composition; Body Weight; Energy Metabolism; Fertility; Homeostasis; Humans; Inflammation; Intestinal Absorption; Leptin; Obesity

Over a third of women of childbearing age in the United States are obese, and during pregnancy they are at increased risk for delayed labor onset and slow labor progress that often results in unplanned cesarean delivery. The biology behind this dysfunctional parturition is not well understood. Studies of obesity-induced changes in parturition physiology may facilitate approaches to optimize labor in obese women. In this review, we summarize known and proposed biologic effects of obesity on labor preparation, contraction/synchronization, and endurance, drawing on both clinical observation and experimental data. We present evidence from human and animal studies of interactions between obesity and parturition signaling in all elements of the birth process, including: delayed cervical ripening, prostaglandin insensitivity, amniotic membrane strengthening, decreased myometrial oxytocin receptor expression, decreased myocyte action potential initiation and contractility, decreased myocyte gap junction formation, and impaired myocyte neutralization of reactive oxygen species. We found convincing clinical data on the effect of obesity on labor initiation and successful delivery, but few studies on the underlying pathobiology. We suggest research opportunities and therapeutic interventions based on plausible biologic mechanisms.

Topics: Adipokines; Body Mass Index; Cesarean Section; Cholesterol; Dystocia; Female; Humans; Inflammation; Leptin; Myometrium; Obesity; Obstetric Labor Complications; Parturition; Phenotype; Pregnancy; Pregnancy Complications; Prostaglandins; Receptors, Oxytocin; Signal Transduction; Uterine Contraction; Uterus

According to the World Health Organization, every year about 3.4 million adults die of consequences related to overweight or obesity. People with a Body Mass Index above 30 are more likely to express certain diseases, including some types of cancer. In this narrative review, we assess the role of adipose tissue as a modulator of the endocrine system and facilitator of chronic subclinical inflammation. We discuss how obesity can induce a suitable micro environment for the development of tumors, mainly by enhancing the levels of oxidative stress and the concentrations of hormones such as leptin, insulin and prolactin. We conclude that all together, these factors increase the probability of cancer development.

Topics: Adipose Tissue; Humans; Leptin; Neoplasms; Obesity; Risk Factors

Endometrial cancer is one of the main cancers occurring in industrialized countries. According to the National Cancer Registry in Bulgaria, cancer of the uterine body occupies 8.6% from all cancers in women and ranks second in frequency. It is found that over weight and obesity are a major risk factor for the development of endometrial cancer and the mortality associated with it. Adipose tissue is seen as endocrine organ, synthesizing so called adipocytokine - leptin, adiponectin, vistafin, that play a key role in the carcinogenesis of endometrial cancer and can be used as new markers for establishing the potential risk of this disease. The link between obesity, insulin resistance and endometrial cancer that has been proven, determines it as a socially significant disease. All this makes it necessary to clarify and specify the role of obesity in endometrial carcinogenesis and the development of strategies for the prevention and early diagnosis.

Topics: Adiponectin; Adipose Tissue; Bulgaria; Carcinogenesis; Endometrial Neoplasms; Endometrium; Female; Humans; Insulin Resistance; Leptin; Obesity; Risk Factors

Leptin plays a critical role in the regulation of energy balance and metabolic homeostasis. Impairment of leptin function is closely involved in the pathogenesis of obesity, diabetes mellitus and some other metabolic diseases. Leptin initiates intracellular signal transductions in the leptin-receptor-expressing neurons in the central nervous system to exert its physiological functions. The fact that high circulating levels of leptin partially or completely fail to promote weight loss in obesity has given rise to the notion of "leptin resistance". Recently, the impairment of leptin signalings in the hypothalamus has been regarded as a critical contributor to leptin resistance. In this review, the studies on leptin signaling and leptin resistance are summarized with an emphasis on the progress made during the last five years.

Topics: Central Nervous System; Energy Metabolism; Gene Expression; Homeostasis; Hypothalamus; Leptin; Neurons; Obesity; Signal Transduction

Since identification in 1994 of leptin, a hormone produced by adipocytes, adipose tissue has become the subject of intensive research. These studies contributed to the discovery that adipocytes have the ability to synthesize and secrete biologically active substances called "adipokines". Adipokines include a variety of cytokines, peptide hormones and enzymes that play a role in a wide variety of biological functions. For example, they are involved in the regulation of appetite, energy homeostasis, vascular hemostasis, blood pressure, inflammatory and immune processes and play a role in the metabolism of carbohydrates and fats. In obese patients, the secretion of adipokines is frequently abnormal. These changes may predispose to the development of insulin resistance, hypertension and inflammation. Therefore, adipokines are the subject of ongoing clinical trials. The family of adipokines is increasing by the newly discovered peptides. This paper presents the current state of knowledge about retinol binding protein 4 (RBP-4), fasting-induced adipose factor/angiopoietin-like protein 4 (FIAF/ANGPTL4), fibroblast growth factor-21 (FGF21), dipeptidyl peptidase-4 (DPP-4), irisin and their potential role in the pathogenesis of metabolic disorders associated with obesity. The knowledge of the role of newly discovered adipokines may help in the treatment of metabolic syndrome.

Topics: Adipocytes; Adipokines; Adipose Tissue; Humans; Insulin Resistance; Leptin; Metabolic Diseases; Metabolic Syndrome; Obesity

Leptin is a 16-kDa peptide hormone that is primarily synthesized and secreted by adipose tissue. One of the major actions of this hormone is the control of energy balance by binding to receptors in the hypothalamus, leading to reduction in food intake, elevation in temperature and energy expenditure. In addition, increasing evidence suggests that leptin, through both direct and indirect mechanisms, may play an important role in cardiovascular and renal regulation. Although the relevance of endogenous leptin needs further clarification, it appears to function as a pressure- and volume-regulating factor under conditions of health. However, in abnormal situations characterized by chronic hyperleptinemia such as obesity, it may function pathophysiologically for the development of hypertension and possibly also for direct renal, vascular and cardiac damage.

Topics: Animals; Humans; Hypertension; Leptin; Neurosecretory Systems; Obesity

Leptin is a small peptide hormone (16 kDa), a product of the obesity gene (Ob), and is mainly synthesized and secreted by adipocytes. It is removed from the blood by the kidneys. The kidney is not only a site of leptin clearance, but also a target organ for its action in different pathophysiological states. Several studies have documented a strong relationship between chronic kidney disease (CKD) and accelerated cardiovascular disease (CVD) defined as a cardiorenal syndrome. Patients with stage 3 and 4 CKD develop cardiovascular complications and are at increased risk of death from CVD. Renal dysfunction promotes several mechanisms responsible for exacerbation of cardiovascular disease. These include activation of the renin-angiotensin system, oxidative stress, elevated asymmetric dimethylarginine (ADMA), low-grade inflammation with increased circulating cytokines, and dyslipidemia. Recently, it has been observed that plasma leptin level is elevated in patients with cardiorenal syndrome. In obesity, hyperleptinemia combined with selective leptin resistance appear to have a critical role in the development and progression of kidney disease, CVD and metabolic syndrome. This has clinical implications for the treatment of obesity-related hypertension and kidney disease. In this paper the role of leptin in chronic kidney disease and accelerated cardiovascular disease is out lined. The link between hyperleptinemia and development and progression of morphologic changes that effect kidney in obese patients is also discussed.

Topics: Animals; Cardio-Renal Syndrome; Cardiovascular System; Disease Progression; Humans; Kidney; Leptin; Models, Cardiovascular; Obesity; Protein Isoforms; Receptors, Leptin; Risk Factors; Signal Transduction

A world-wide obesity epidemic is threatening to have a major impact on the prevalence of chronic and acute vascular diseases. In addition to weight loss interventions, which have met with modest success to date, it will be important to understand mechanisms by which obesity promotes vascular disease processes. Studies of leptin, a hormone produced by the adipocyte, have supported the concept that adipocyte-specific products may be mediating some of the vascular risk associated with obesity. This mini-review provides an overview of some of the preclinical studies demonstrating causal relationships between leptin and vascular endpoints. Therapeutic strategies designed to block leptin-mediated signaling events in cells contributing to vascular disease may prove beneficial in obese subjects at risk for vascular complications.

Topics: Animals; Arteries; Atherosclerosis; Endothelium, Vascular; Humans; Leptin; Models, Cardiovascular; Muscle, Smooth, Vascular; Obesity; Receptors, Leptin; Signal Transduction; Thrombosis; Tunica Intima

Numerous laboratory studies involving both animal and human models indicate that weight loss induces changes in leptin, ghrelin and insulin sensitivity, which work to promote weight regain. It is unclear, however, whether these biological changes serve as a biomarker for predicting weight regain in free-living humans in which biological, behavioral and environmental factors are likely at play. We identified 12 studies published between January 1995 and December 2011 that reported changes in leptin, ghrelin or insulin during intentional weight loss with a follow-up period to assess regain. Two of the nine studies examining leptin suggested that larger decreases were associated with greater regain, three studies found the opposite (smaller decreases were associated with greater regain), whereas four studies found no significant relationship; none of the studies supported the hypothesis that increases in ghrelin during weight loss were associated with regain. One study suggested that improvements in insulin resistance were associated with weight gain, but five subsequent studies reported no association. Changes in leptin, ghrelin or insulin sensitivity, taken alone, are not sufficient to predict weight regain following weight loss in free-living humans. In future studies, it is important to include a combination of physiological, behavioral and environmental variables in order to identify subgroups at greatest risk of weight regain.

Topics: Biomarkers; Body Mass Index; Body Weight; Diet, Reducing; Exercise; Female; Ghrelin; Humans; Insulin; Insulin Resistance; Leptin; Male; Obesity; Predictive Value of Tests; Weight Gain; Weight Loss

This meta-analysis aimed to assess the gender-specific differences in the relationship between circulating leptin levels and risk of type 2 diabetes. Published prospective studies that reported the association of leptin levels with risk of type 2 diabetes for a certain gender or those that reported gender-specific associations were considered. Dose-response relationships were assessed by the generalized least squares trend estimation and summary relative risks (RRs) with 95% confidence interval (CI) were computed with the random-effects model. Stratified and sensitivity analyses were also performed to investigate potential sources of heterogeneity. Overall, 11 prospective studies were identified. The summary RR for an increment in leptin levels of 1-log ng mL(-1) was 1.37 (95% CI, 1.13-1.66) for men and 0.96 (95% CI, 0.90-1.03) for women. The differences between genders were statistically significant (P for interaction = 0.006). Subgroup and sensitivity analyses generally confirmed the robustness of these findings. Furthermore, the increased risk in men appeared non-linear, with a tendency to plateau at high levels (P for non-linearity = 0.03). Little evidence of publication bias was found. Collectively, higher leptin levels were found to be associated with elevated risk of type 2 diabetes in men but not in women.

Topics: Biomarkers; Diabetes Mellitus, Type 2; Female; Humans; Leptin; Male; Obesity; Prospective Studies; Risk Factors; Sex Factors

Osteoarthritis (OA) is the most common cause of musculoskeletal disability and pain in the world. The current drug treatment for OA is symptom relieving, and there is an urgent need for treatments that could retard, prevent or repair cartilage destruction in OA. Obesity is a major risk factor for OA. Traditionally, it has been thought to contribute to the development of OA by increasing the load on weight-bearing joints. However, this appears to be an over-simplification, because obesity is also linked to OA in the hand and finger joints. Recent studies have shown that adipocytokine leptin is a possible link between obesity and OA: Leptin levels in synovial fluid are increased in obese patients, leptin receptor (Ob-R) is expressed in cartilage, and leptin induces the production of matrix metalloproteinases (MMPs), pro-inflammatory mediators and nitric oxide (NO) in chondrocytes. Furthermore, according to the very recent findings, not only leptin levels in the joint but also leptin sensitivity in the cartilage are enhanced in obese OA patients. The findings supporting leptin as a causative link between obesity and OA offer leptin as a potential target to the development of disease-modifying drugs for osteoarthritis (DMOAD), especially for obese patients.

Topics: Animals; Disease Models, Animal; Gene Expression Regulation; Humans; Leptin; Obesity; Osteoarthritis; Receptors, Leptin; Synovial Fluid

Leptin, a hormone secreted by adipocytes, plays a crucial role in regulating energy balance. Estrogen, like leptin, reduces food intake and adiposity while increasing energy expenditure in animals and humans of both sexes through its actions on the central nervous system. We reviewed the literature for studies of the effects of exogenously administered estrogen on serum leptin concentrations and adiposity in women.. Using PubMed/Medline, we searched for studies of hormone therapy that enrolled healthy postmenopausal women. Studies were further evaluated to determine if leptin and adiposity were monitored both at baseline and throughout a treatment period of at least 2 months.. Twenty articles met inclusion criteria. We found no consistent effects of exogenous estrogen on serum leptin concentrations, adiposity, or weight gain.. Despite suggestive data from animal studies, the current literature does not provide compelling evidence that estrogen therapy attenuates weight gain, alters circulating leptin levels, or improves leptin action in postmenopausal women.

Topics: Adiposity; Animals; Body Mass Index; Estrogen Replacement Therapy; Estrogens; Female; Humans; Leptin; MEDLINE; Obesity; Randomized Controlled Trials as Topic; Weight Gain

The OB-receptor or leptin receptor (LR) is crucial for energy homeostasis and regulation of food uptake. Leptin is a 16 kDa hormone that is mainly secreted by fat cells into the bloodstream. Under normal circumstances, circulating leptin levels are proportionate to the fat body mass. Sensing of elevated leptin levels by the hypothalamic neuro-circuitry activates a negative feedback loop resulting in reduced food intake and increased energy expenditure. Decreased leptin concentrations lead to opposite effects. Therefore, rational design of leptin agonists/antagonists could be an appealing challenge in the battle against obesity. The Leptin/LR interactions have been studied in several works by means of different molecular modelling approaches, spreading from homology modelling to manual docking. No small molecules have ever been proposed as agonists of the Ob receptor but researchers' efforts focused only on leptin-related synthetic peptides as receptor antagonists and on peptidomimetics. In this review we try to track a timeline of obtained in silico information to clarify the mechanism of interaction between leptin and its receptor, together to summarize the more recent efforts to propose new drugs usable in anti-obesity therapy. Final considerations could be useful starting points for the rational drug design of new lead compounds.

Topics: Anti-Obesity Agents; Body Weight; Drug Design; Humans; Infant, Newborn; Leptin; Models, Molecular; Obesity; Protein Binding; Receptors, Leptin; Risk Factors; Signal Transduction

Regulatory T cells (Treg cells) are crucial in mediating immune homeostasis and promoting the establishment and maintenance of peripheral tolerance. Excess body weight and obesity are typified by 'low-degree' chronic inflammation and are associated with an increased risk of atherosclerosis, diabetes, fatty liver disease, autoimmune diseases and cancer. All these pathological conditions are characterized by chronic inflammation, abnormal cytokine production, elevated acute-phase reactants, and the activation of several inflammatory signaling pathways. In this context, the discovery of the adipose tissue-derived hormone leptin has shed fundamental insights on how these processes might occur. Leptin represents a link among metabolic disorders and immune tolerance; indeed, leptin can negatively affect the generation and proliferation of Treg cells, key players in this context. Treg cells play also a central role in tumor progression; different reports have proposed that tumor microenvironment can induce the recruitment of Treg cells which can promote tumor tolerance and angiogenesis through expression of suppressive molecules, cytokines and angiogenic factors (i.e. vascular endothelial growth factor, leptin). This work aims to discuss some of the most recent advances on the relationship between angiogenesis, leptin and immune tolerance, focusing on the role of Treg cell function in this context.

Topics: Acute-Phase Proteins; Adipose Tissue; Autoimmune Diseases; Cytokines; Gene Expression Regulation; Humans; Immune Tolerance; Inflammation; Leptin; Neovascularization, Pathologic; Neovascularization, Physiologic; Obesity; Signal Transduction; T-Lymphocytes, Regulatory

Evolution has molded metabolic thrift within humans, a genetic heritage that, when thrust into our modern "obesogenic" environment, creates the current obesity crisis. Modern genetic analysis has identified genetic and epigenetic contributors to obesity, an understanding of which will guide the development of environmental, pharmacologic, and genetic therapeutic interventions.

Topics: Adipose Tissue; Appetite Regulation; Biological Evolution; Biomarkers; Climate; Energy Metabolism; Environment; Epigenesis, Genetic; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Leptin; Obesity; Phenotype; Polymorphism, Single Nucleotide

Mother-child cohort studies have established that both pre-pregnancy body mass index (BMI) and gestational weight gain are independently associated with cardio-metabolic risk factors in young adult offspring, including systolic and diastolic blood pressure. Animal models in sheep and non-human primates provide further evidence for the influence of maternal obesity on offspring cardiovascular function, whilst recent studies in rodents suggest that perinatal exposure to the metabolic milieu of maternal obesity may permanently change the central regulatory pathways involved in blood pressure regulation. Leptin plays an important role in the central control of appetite, is also involved in activation of efferent sympathetic pathways to both thermogenic and non-thermogenic tissues, such as the kidney, and is therefore implicated in obesity-related hypertension. Leptin is also thought to have a neurotrophic role in the development of the hypothalamus, and altered neonatal leptin profiles secondary to maternal obesity are associated with permanently altered hypothalamic structure and function. In rodent studies, maternal obesity confers persistent sympathoexcitatory hyper-responsiveness and hypertension acquired in the early stages of development. Experimental neonatal hyperleptinaemia in naive rat pups provides further evidence of heightened sympathetic tone and proof of principle that hyperleptinaemia during a critical window of hypothalamic development may directly lead to adulthood hypertension. Insight from these animal models raises the possibility that early-life exposure to leptin in humans may lead to early onset essential hypertension. Ongoing mother-child cohort and intervention studies in obese pregnant women provide a unique opportunity to address associations between maternal obesity and offspring cardiovascular function. The goal of the review is to highlight the potential importance of leptin in the developmental programming of hypertension in obese pregnancy.

Topics: Animals; Female; Humans; Hypertension; Leptin; Mothers; Obesity; Pregnancy; Prenatal Exposure Delayed Effects

The adipocyte-derived hormone/cytokine leptin acts as a metabolic switch, connecting the body's nutritional status to high energy consuming processes such as reproduction and immune responses. Inappropriate leptin responses can promote autoimmune diseases and tumorigenesis. In this review we discuss the current strategies to modulate leptin signaling and the possibilities for their use in research and therapy.

Topics: Adipocytes; Humans; Leptin; Obesity; Signal Transduction

Obesity has been considered as an important risk factor for the development of colorectal cancer (CRC), but the association has not been fully elucidated. Obesity is linked significantly to adipose tissue dysfunction and to alteration of adipokines in blood; in particular, obesity-induced inflammation is thought to be an important link between obesity and colorectal cancer. Based on epidemiological studies, we undertook a systematic review to understand the association of circulating levels of selected adipokines, including adiponectin, leptin, resistin, IL-6 and TNF-α, with the level of CRC risk. Most prospective studies suggested protective effects of adiponectin, but these were attenuated by body mass index (BMI) and waist circumference (WC) data in our meta-analysis. On the other hand, meta-analyses for leptin and CRC did not demonstrate any association, similar to the results of systematic review. Although it proved difficult to determine whether other selected adipokines (resistin, IL-6 and TNF-α) were related to CRC risk due to small number of reports, the present systematic review suggested a positive association with elevated resistin levels but null associations with IL-6 and TNF-α.

Topics: Adiponectin; Body Mass Index; Colorectal Neoplasms; Humans; Inflammation; Interleukin-6; Leptin; Obesity; Resistin; Risk Factors; Tumor Necrosis Factor-alpha; Waist Circumference

Leptin, an adipose tissue-derived hormone, plays a central role in regulating human energy homeostasis. The role of leptin in regulating blood pressure, activating the sympathetic nervous system, insulin resistance, platelet aggregation, arterial thrombosis, angiogenesis, and inflammatory vascular responses suggests that leptin may have a close relationship with the development of coronary heart disease (CHD). However, no conclusive data are available to determine the association between leptin and CHD.. The PubMed, EMBASE and Cochrane databases were surveyed for original studies describing the association between leptin and CHD outcome from the date of publication of each database through March 2013. The data were extracted by two investigators independently.. The meta-analysis reported here was comprised of eight original articles with a total of 21,064 participants (10,842 men, 10,222 women) and 2053 CHD events. The odds ratio for the sociodemographic-adjusted study reported here was 1.57 (95% confidence interval, 1.14-2.16) and 1.72 (95% confidence internal, 1.03-2.87) in males and females, respectively. Further adjustment for additional cardiovascular risk factors resulted in an odds ratio of 1.36 (95% confidence interval, 0.98-1.88) in males and 1.50 (95% confidence interval, 0.93-2.42) in females. Sensitivity analysis restricted to sociodemographics-adjusted studies with high methodological quality indicated an estimate of 1.47 (95% confidence internal, 1.06-2.04) in males and 1.85 (95% confidence internal, 0.61-5.63) in females. Sensitivity analysis restricted to cardiovascular risk factor-adjusted studies showed no significant differences in both males and females.. The results of the meta-analysis represents the most precise and accurate estimate of the relationship between leptin and CHD. Although the associations of leptin and CHD were not statistically significant both in male and female overall, males with high levels of leptin should be paid more attention to. Our findings highlight the need for additional well-designed and gender-specific prospective studies to evaluate the role of leptin on the development of CHD.

Topics: Adult; Aged; Case-Control Studies; Cohort Studies; Coronary Disease; Female; Humans; Leptin; Male; Middle Aged; Obesity; Risk Factors; Sensitivity and Specificity

To examine the association between a common single nucleotide polymorphism identified in the 5' untranslated region of leptin gene (LEP-2548 G/A SNP) and obesity.. Meta-analysis of published studies, included if subjects were genotyped at polymorphism LEP-2548 G/A and both obese and nonobese subjects were selected, based on a reported cutoff BMI limit. Meta-analysis of the total and subgroup populations was conducted using dominant and recessive models, and OR and 95% CI were calculated in the fixed-effect model. I2 statistic was calculated to examine heterogeneity, and publication bias was evaluated by Egger test.. After testing each control group for Hardy-Woinberg equilibrium, the final selection enrolled 11 studies, including 5210 subjects (2541 obesity subjects and 2669 healthy). In the combined analysis of all eligible studies, none significant association was identified between LEP-2548 G/A SNP and obesity either in dominant model or the recessive one with pooled odds ratios 1.14 (95% CI 0.98-1.31, P = 0.08) and 1.03 (95% CI 0.85-1.25, P = 0.76). However, subgroup analysis found a significant association of GG homozygote in American population [OR = 1.53 (95% CI 1.17-2.00), P = 0.002]. No significant evidence was found in other populations.. This first metaanalysis of data from published studies did not detect any association between the polymorphism of LEP-2548 G/A and risk of obesity in overall population. Nevertheless, the presence of the GG genotype in the gene appears to be a significant risk factor for obesity in American.

Topics: Genotype; Humans; Leptin; Obesity; Polymorphism, Genetic; Randomized Controlled Trials as Topic

Follicle wall rupture and ovum release, i.e., ovulation, has been described as a controlled inflammatory event. The process involves tissue remodeling achieved through leukocyte-mediated proteolysis. In birds, ovulation is the first step in the energy-intensive process of egg formation, yet hens that consume energy in excess of productive requirements experience impaired egg-laying ability. Broiler chickens, selected for rapid lean muscle gain, and coincidentally hyperphagia, develop adult obesity when given free access to feed. Obese broiler hens experience elevated circulating concentrations of insulin and leptin, changes in lipid and lipoprotein metabolism similar to those of human metabolic syndrome, as well as increased systemic inflammation. Overall, the manifestations in poultry are similar to those of women with polycystic ovary syndrome. It was shown recently that, in hens, as in mammals, changes in lipid synthesis and metabolism cause granulosa cell apoptosis and altered immune function and hormone production, further compromising ovarian function. To date, there is insufficient information on the means used by the ovary to direct leukocyte function toward successful ovulation. More information is needed regarding the control of proteolytic actions by leukocytes with regards to the roles of specific enzymes in both ovulation and atresia. The broiler hen has provided unique insight into the interrelations of energy intake, obesity, leukocyte function, and reproduction. Additional work with this model can serve the dual purposes of improving avian reproduction and providing novel insights into polycystic ovary syndrome in women.

Topics: Animals; Body Weight; Chickens; Disease Models, Animal; Energy Intake; Female; Humans; Insulin; Leptin; Mammals; Obesity; Ovary; Oviposition; Polycystic Ovary Syndrome; Reproduction

Being overweight and obese has become an increasingly serious clinical and socioeconomic problem worldwide. The rapidly rising prevalence of obesity has prompted studies on modifiable, causative factors and novel treatment options for this disorder. Recent evidence indicates that excessive weight gain that leads to being overweight and obese may result from alterations in gut microflora. Studies in humans and animals demonstrated that the composition of gut microbiota may differ in lean and obese subjects, suggesting that these differences result in the increased efficiency of caloric extraction from food, enhanced lipogenesis, and impaired central and peripheral regulation of energy balance. Other studies revealed an excessive increase in body weight in a significant percentage of people infected with human adenoviruses SMAM-1 and Ad-36. Dysregulation of adipocyte function by viruses appears to be the most likely cause of excessive fat accumulation in these individuals. Studies on the pathomechanisms related to the pathogenesis of obesity indicated that a high-fat diet triggers the inflammatory response in the hypothalamus, an event that promotes weight gain and further defends elevated body weight through the initiation of central leptin and insulin resistance and impairment of regenerative capacity of hypothalamic neurons. Exposure to a high-calorie diet appears to predispose individuals to obesity not only because of excessive caloric intake but also because of the induction of microbiota- and central inflammatory response-dependent changes that lead to a dysregulation of energy balance.

Topics: Animals; Bacterial Infections; Body Weight; Energy Intake; Energy Metabolism; Gastrointestinal Tract; Humans; Hypothalamus; Inflammation; Insulin Resistance; Leptin; Obesity; Virus Diseases

Numerous studies address the physiology of adipose tissue (AT). The interest surrounding the physiology of AT is primarily the result of the epidemic outburst of obesity in various contemporary societies. Briefly, the two primary metabolic activities of white AT include lipogenesis and lipolysis. Throughout the last two decades, a new model of AT physiology has emerged. Although AT was considered to be primarily an abundant energy source, it is currently considered to be a prolific producer of biologically active substances, and, consequently, is now recognized as an endocrine organ. In addition to leptin, other biologically active substances secreted by AT, generally classified as cytokines, include adiponectin, interleukin-6, tumor necrosis factor-alpha, resistin, vaspin, visfatin, and many others now collectively referred to as adipokines. The secretion of such biologically active substances by AT indicates its importance as a metabolic regulator. Cell turnover of AT has also recently been investigated in terms of its biological role in adipogenesis. Consequently, the objective of this review is to provide a comprehensive critical review of the current literature concerning the metabolic (lipolysis, lipogenesis) and endocrine actions of AT.

Topics: Adipocytes; Adipogenesis; Adipokines; Adipose Tissue, White; Animals; Cytokines; Humans; Leptin; Lipolysis; Mice; Nicotinamide Phosphoribosyltransferase; Obesity; Rats; Resistin; Signal Transduction

Ghrelin and leptin show opposite effects on energy balance. Ghrelin constitutes a gut hormone that is secreted to the bloodstream in two major forms, acylated and desacyl ghrelin. The isoforms of ghrelin not only promote adiposity by the activation of hypothalamic orexigenic neurons but also directly stimulate the expression of several fat storage-related proteins in adipocytes, including ACC, FAS, LPL and perilipin, thereby stimulating intracytoplasmic lipid accumulation. Moreover, both acylated and desacyl ghrelin reduce TNF-α-induced apoptosis and autophagy in adipocytes, suggesting an anti-inflammatory role of ghrelin in human adipose tissue. On the other hand, leptin is an adipokine with lipolytic effects. In this sense, leptin modulates via PI3K/Akt/mTOR the expression of aquaglyceroporins such as AQP3 and AQP7 that facilitate glycerol efflux from adipocytes in response to the lipolytic stimuli via its translocation from the cytosolic fraction (AQP3) or lipid droplets (AQP7) to the plasma membrane. Ghrelin and leptin also participate in the homeostasis of the cardiovascular system. Ghrelin operates as a cardioprotective factor with increased circulating acylated ghrelin concentrations in patients with left ventricular hypertrophy (LVH) causally related to LV remodeling during the progression to LVH. Additionally, leptin induces vasodilation by inducible NO synthase expression (iNOS) in the vascular wall. In this sense, leptin inhibits the angiotensin II-induced Ca(2+) increase, contraction and proliferation of VSMC through NO-dependent mechanisms. Together, dysregulation of circulating ghrelin isoforms and leptin resistance associated to obesity, type 2 diabetes, or the metabolic syndrome contribute to cardiometabolic derangements observed in these pathologies.

Topics: Adipose Tissue; Adiposity; Cardiovascular Diseases; Cardiovascular System; Ghrelin; Humans; Inflammation; Leptin; Lipid Metabolism; Obesity

Obesity is a pandemic and a serious global health concern. Obesity is a risk factor for multiple conditions and contributes to multi-morbidities, resulting in increased health costs and millions of deaths each year. Obesity has been associated with changes in brain structure, cognitive deficits, dementia and Alzheimer׳s disease. Adipokines, defined as hormones, cytokines and peptides secreted by adipose tissue, may have more widespread influence and functionality in the brain than previously thought. In this review, six adipokines, and their actions in the obese and non-obese conditions will be discussed. Included are: plasminogen activator inhibitor-1 (PAI-1), interleukin-6 (IL-6), tumor necrosis factors alpha (TNF-α), angiotensinogen (AGT), adiponectin and leptin. Their functionality in the periphery, their ability to cross the blood brain barrier (BBB) and their influence on dementia processes within the brain will be discussed.

Topics: Adipokines; Adiponectin; Angiotensinogen; Animals; Brain; Dementia; Humans; Interleukin-6; Leptin; Models, Biological; Obesity; Plasminogen Activator Inhibitor 1; Tumor Necrosis Factor-alpha

Obesity, which has developed into a global epidemic, is a risk factor in most chronic diseases and some forms of malignancy. The discovery of leptin in 1994 has opened a new field in obesity research. Currently, we know that leptin is the primary signal from energy stores and exerts negative feedback effects on energy intake. However, most individuals with diet-induced obesity (DIO) develop leptin resistance, which is characterized by elevated circulating leptin levels and decreased leptin sensitivity. To date, though various mechanisms have been proposed to explain leptin resistance, the exact mechanisms of leptin resistance in obesity are poorly understood. Consequently, it's an important issue worth discussing regarding what the exact interrelations between leptin resistance and obesity are. Here, we review the latest advancements in the molecular mechanisms of leptin resistance and the exact interrelations between leptin resistance, obesity, and obesity-related diseases, in order to supply new ideas for the study of obesity.

Topics: Animals; Humans; Leptin; Obesity; Receptors, Leptin

Both reduction in total sleep duration with slow-wave sleep (SWS) largely preserved and alterations of sleep quality (especially marked reduction of SWS) with preservation of total sleep duration are associated with insulin resistance without compensatory increase in insulin secretion, resulting in impaired glucose tolerance and increased risk of type 2 diabetes. When performed under rigorously controlled conditions of energy intake and physical activity, sleep restriction is also associated with a decrease in circulating levels of leptin (an anorexigenic hormone) and an increase in circulating levels of ghrelin (an orexigenic hormone), hunger and appetite. Furthermore, sleep restriction is also associated with a stimulation of brain regions sensitive to food stimuli, indicating that sleep loss may lead to obesity through the selection of high-calorie food. There is also evidence that sleep restriction could provide a permissive environment for the activation of genes that promote obesity. Indeed, the heritability of body mass index is increased in short sleepers. Thus, chronic sleep curtailment, which is on the rise in modern society, including in children, is likely to contribute to the current epidemics of type 2 diabetes and obesity.

Topics: Animals; Diabetes Mellitus, Type 2; Eating; Energy Metabolism; Ghrelin; Humans; Insulin; Insulin Resistance; Leptin; Obesity; Sleep

As the population of the world ages, the prevalence of neurodegenerative disease continues to rise, accompanied by increases in disease burden related to obesity and metabolic disorders. Thus, it will be essential to develop tools for preventing and slowing the progression of these major disease entities. Epidemiologic studies have shown strong associations between obesity, metabolic dysfunction, and neurodegeneration, while animal models have provided insights into the complex relationships between these conditions. Experimentally, the fat-derived hormone leptin has been shown to act as a neuroprotective agent in various animal models of dementia, toxic insults, ischemia/reperfusion, and other neurodegenerative processes. Specifically, leptin minimizes neuronal damage induced by neurotoxins and pro-apoptotic conditions. Leptin has also demonstrated considerable promise in animal models of obesity and metabolic disorders via modulation of glucose homeostasis and energy intake. However, since obesity is known to induce leptin resistance, we hypothesize that resistance to the neuroprotective effects of leptin contributes to the pathogenesis of obesity-associated neurodegenerative diseases. This review aims to explore the literature pertinent to the role of leptin in the protection of neurons from the toxic effects of aging, obesity and metabolic disorders, to investigate the physiological state of leptin resistance and its causes, and to consider how leptin might be employed therapeutically in the prevention and treatment of neurodegenerative disease.

Topics: Alzheimer Disease; Animals; Brain; Disease Models, Animal; Humans; Hypothalamus; Leptin; Mice; Neurons; Neuroprotective Agents; Obesity; Parkinson Disease; Rats

Among the most widely used animal models in obesity-induced type 2 diabetes mellitus (T2DM) research are the congenital leptin- and leptin receptor-deficient rodent models. These include the leptin-deficient ob/ob mice and the leptin receptor-deficient db/db mice, Zucker fatty rats, Zucker diabetic fatty rats, SHR/N-cp rats, and JCR:LA-cp rats. After decades of mechanistic and therapeutic research schemes with these animal models, many species differences have been uncovered, but researchers continue to overlook these differences, leading to untranslatable research. The purpose of this review is to analyze and comprehensively recapitulate the most common leptin/leptin receptor-based animal models with respect to their relevance and translatability to human T2DM. Our analysis revealed that, although these rodents develop obesity due to hyperphagia caused by abnormal leptin/leptin receptor signaling with the subsequent appearance of T2DM-like manifestations, these are in fact secondary to genetic mutations that do not reflect disease etiology in humans, for whom leptin or leptin receptor deficiency is not an important contributor to T2DM. A detailed comparison of the roles of genetic susceptibility, obesity, hyperglycemia, hyperinsulinemia, insulin resistance, and diabetic complications as well as leptin expression, signaling, and other factors that confound translation are presented here. There are substantial differences between these animal models and human T2DM that limit reliable, reproducible, and translatable insight into human T2DM. Therefore, it is imperative that researchers recognize and acknowledge the limitations of the leptin/leptin receptor- based rodent models and invest in research methods that would be directly and reliably applicable to humans in order to advance T2DM management.

Topics: Animals; Blood Glucose; Diabetes Complications; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Humans; Hyperglycemia; Hyperinsulinism; Insulin Resistance; Leptin; Mice; Mice, Inbred Strains; Mice, Obese; Obesity; Rats; Rats, Inbred Strains; Rats, Zucker; Receptors, Leptin

Leptin has long been associated with metabolism as it is a critical regulator of both food intake and energy expenditure, but recently, leptin dysregulation has been proposed as a mechanism of psychopathology. This review discusses the evidence supporting a role for leptin in mental health disorders and describes potential mechanisms that may underlie this association. Leptin plays a critical role in pregnancy and in fetal growth and development. Leptin's role and profile during development is examined in available human studies, and the validity of applying studies conducted in animal models to the human population are discussed. Rodents experience a postnatal leptin surge, which does not occur in humans or larger animal models. This suggests that further research using large mammal models, which have a leptin profile across pregnancy and development similar to humans, are of high importance. Maternal obesity and hyperleptinemia correlate with increased leptin levels in the umbilical cord, placenta, and fetus. Leptin levels are thought to impact fetal brain development; likely by activating proinflammatory cytokines that are known to impact many of the neurotransmitter systems that regulate behavior. Leptin is likely involved in behavioral regulation as leptin receptors are widely distributed in the brain, and leptin influences cortisol release, the mesoaccumbens dopamine pathway, serotonin synthesis, and hippocampal synaptic plasticity. In humans, both high and low levels of leptin are reported to be associated with psychopathology. This inconsistency is likely due to differences in the metabolic state of the study populations. Leptin resistance, which occurs in the obese state, may explain how both high and low levels of leptin are associated with psychopathology, as well as the comorbidity of obesity with numerous mental illnesses. Leptin resistance is likely to influence disorders such as depression and anxiety where high leptin levels have been correlated with symptomatology. Schizophrenia is also associated with both low and high leptin levels. However, as anti-psychotics pharmacotherapy induces weight gain, which elevates leptin levels, drug-naïve populations are needed for further studies. Elevated circulating leptin is consistently found in childhood neurodevelopmental disorders including autism spectrum disorders and Rhett disorder. Further, studies on the impact of leptin and leptin resistance on psychopathology and neurodevelopmental disorder

Topics: Animals; Brain; Female; Humans; Leptin; Mental Disorders; Obesity; Pregnancy; Prenatal Exposure Delayed Effects

Breast cancer is the most common in women worldwide, with some 5-10% of all cases due to inherited mutations of BRCA1 and BRCA2 genes. Obesity, hormone therapy and use of alcohol are possible causes and over-expression of leptin in adipose tissue may also play a role. Normally surgery, radiation therapy and chemotherapy allow a good prognosis where screening measures are in place. New hope in treatment measures include adjuvant therapy, neoadjuvant therapy, and introduction of mono-clonal antibodies and enzyme inhibitors.

Topics: Adipose Tissue; Alcohol Drinking; Breast Neoplasms; Carcinoma, Ductal, Breast; Carcinoma, Lobular; Chemotherapy, Adjuvant; Estrogen Replacement Therapy; Female; Genes, BRCA1; Genes, BRCA2; Humans; Leptin; Mastectomy; Neoadjuvant Therapy; Obesity; Radiotherapy, Adjuvant; Risk Factors; Sedentary Behavior; Selective Estrogen Receptor Modulators

Topics: Adipokines; Adiponectin; Humans; Inflammation; Leptin; Obesity; Respiratory Tract Diseases; Stress, Physiological

Obesity is characterized by high secretion of several cytokines from adipose tissue and is a recognized risk factor for many cancers. Among these cytokines, leptin mainly produced by adipose tissue and cancer cells is the most studied adipokine. Leptin is an activator of cell proliferation, an antiapoptotic molecule and inducer of cancer stem cells in many cell types, and its critical roles in obesity-related tumorigenesis are based on its oncogenic, mitogenic, pro-inflammatory and pro-angiogenic actions.. These leptin-induced signals and action are critical for their biological effects on energy balance, adiposity, endocrine systems, immunity, angiogenesis as well as oncogenesis. This review focuses on the up-to-date knowledge on the oncogenic role of leptin signaling, clinical significance and specific drug target development in colorectal cancer (CRC). Additionally, leptin-induced angiogenic ability and molecular mechanisms in CRC cells are discussed.. Stringent binding affinity of leptin/Ob-R and overexpression of leptin/Ob-R and their targets in cancer cells make it a unique drug target for prevention and treatment of CRC, particularly in obesity colorectal patients.

Topics: Animals; Antineoplastic Agents; Colorectal Neoplasms; Drug Design; Humans; Leptin; Molecular Targeted Therapy; Obesity; Risk Factors; Signal Transduction

The control of energy homeostasis relies on robust neuronal circuits that regulate food intake and energy expenditure. Although the physiology of these circuits is well understood, the molecular and cellular response of this program to chronic diseases is still largely unclear. Hypothalamic inflammation has emerged as a major driver of energy homeostasis dysfunction in both obesity and anorexia. Importantly, this inflammation disrupts the action of metabolic signals promoting anabolism or supporting catabolism. In this review, we address the evidence that favors hypothalamic inflammation as a factor that resets energy homeostasis in pathological states.

Topics: Animals; Anorexia; Central Nervous System; Energy Metabolism; Homeostasis; Humans; Hypothalamus; Inflammation; Insulin; Leptin; Models, Biological; Obesity; Signal Transduction

With rising rates of obesity, research continues to explore the contributions of homeostatic and hedonic mechanisms related to eating behaviour. In this Review, we synthesize the existing information on select biological mechanisms associated with reward-related food intake, dealing primarily with consumption of highly palatable foods. In addition to their established functions in normal feeding, three primary peripheral hormones (leptin, ghrelin and insulin) play important parts in food reward. Studies in laboratory animals and humans also show relationships between hyperphagia or obesity and neural pathways involved in reward. These findings have prompted questions regarding the possibility of addictive-like aspects in food consumption. Further exploration of this topic may help to explain aberrant eating patterns, such as binge eating, and provide insight into the current rates of overweight and obesity.

Topics: Adult; Animals; Behavior, Addictive; Brain; Bulimia; Dopamine; Eating; Feeding Behavior; Female; Ghrelin; Homeostasis; Humans; Insulin; Leptin; Male; Obesity; Receptors, Dopamine; Reward; Weight Gain

The growing epidemic of childhood obesity has forced scientists to search for methods to prevent feeding disorders. Increasing interest in appetite regulating hormones has revealed their influence on energy homeostasis after birth or even in utero.. The presence of ghrelin in the stomach of human foetuses and the distinctive production in the pancreas of neonates suggests the role of ghrelin in pre- and post-natal development. The neonatal period appears to be a critical time for the formation of adipose tissue-hypothalamus circuits, thus the amount of adipocytes in foetal life may be a major regulator of food intake. Insulin's orexigenic effect in the arcuate nucleus of the hypothalamus can be a major modulator of foetal development.. This review, based on available literature, aims to analyses the role of appetite regulating hormones in foetal development.. Different concentrations of hormones, such as ghrelin, leptin and insulin during foetal life raises the question whether or not they can be modulated, thereby avoiding obesity before birth. Children with pancreas agenesis showed smaller body size at birth, which emphasises the probable role of insulin in foetal growth. Study of sheep foetuses with IUGR confirmed these finding. Appetite-regulating hormones show different roles in foetal development and seem to be essential in the perinatal period.

Topics: Animals; Fetal Development; Ghrelin; Humans; Insulin; Leptin; Obesity; Sheep

Resistant hypertension in diabetes is associated with poor cardiovascular and renal outcomes. This brief review will examine the definitions and epidemiology of resistant hypertension and consider the differences between apparent resistant hypertension and truly resistant or refractory hypertension. It will review the role of the sympathetic nervous system in resistant hypertension. It will consider the relationship between obesity and leptin resistance and sympathetic signaling; the role of obstructive sleep apnea in resistant hypertension; and the role of aldosterone in resistant hypertension. It will conclude by mentioning briefly renal nerve ablation.

Topics: Aldosterone; Diabetes Mellitus; Humans; Hypertension; Leptin; Obesity; Sympathetic Nervous System

The molecular mechanisms of body weight and body composition regulation have long been a research focus in the hopes of identifying tractable pathways for therapeutic interventions for obesity and diabetes, as well as related disorders such as nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH) and polycystic ovary syndrome. The metabolic consequences of obesity and type 2 diabetes (T2D) were already a focus of the world's attention in 1994 when the discovery of leptin generated enormous enthusiasm for the potential to treat common (non-monogenic) obesity and its associated metabolic disorders with an adipokine hormone that regulated body weight as well as lipid and carbohydrate metabolism. Recombinant human leptin and many leptin analogs were developed and studied in animals and a few in human clinical trials. Overall, the opportunity for leptin as a therapeutic in unselected patients with obesity and T2D has not been substantiated in clinical trials. The potential for combination therapy suggested by clinical studies with leptin and pramlintide supports a path toward obesity treatment through the leptin pathway. The profound metabolic benefits seen with leptin in numerous forms of leptin deficiency, including lipodystrophy, provide hope for the opportunity to identify selected subsets of patients who could benefit from leptin treatment. This review provides a comprehensive overview of the clinical data on a subset of the potential utilities of leptin, specifically as a therapeutic for general or common obesity and its metabolic consequences including T2D and NAFLD/NASH.

Topics: Animals; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Islet Amyloid Polypeptide; Leptin; Lipodystrophy; Non-alcoholic Fatty Liver Disease; Obesity; Treatment Outcome

Short sleep duration has been shown to be associated with elevated body mass index (BMI) in many epidemiological studies. Several pathways could link sleep deprivation to weight gain and obesity, including increased food intake, decreased energy expenditure, and changes in levels of appetite-regulating hormones, such as leptin and ghrelin. A relatively new factor that is contributing to sleep deprivation is the use of multimedia (e.g. television viewing, computer, and internet), which may aggravate sedentary behavior and increase caloric intake. In addition, shift-work, long working hours, and increased time commuting to and from work have also been hypothesized to favor weight gain and obesity-related metabolic disorders, because of their strong link to shorter sleep times. This article reviews the epidemiological, biological, and behavioral evidence linking sleep debt and obesity.

Topics: Appetite; Body Mass Index; Energy Intake; Energy Metabolism; Ghrelin; Humans; Leptin; Obesity; Sedentary Behavior; Sleep; Sleep Deprivation; Weight Gain

A common single-nucleotide polymorphism identified in the 5'-untranslated region of the leptin gene (LEP -2548 G/A polymorphism) may be associated with obesity, but the existing research findings are inconsistent, so we conducted this meta-analysis.. Medline, Embase and ISI Web of Science databases were searched to identify relevant studies. Meta-analysis of the total and subgroup populations was conducted using allelic, additive, dominant and recessive models, and odds ratios and their 95% confidence intervals were calculated in a fixed-effect model if no heterogeneity (evaluated as I(2) statistic) existed. Otherwise, a random-effects model was adopted. Subgroup analysis was performed by ethnicity. Meta-regression and the HETRED analysis were used to explore the potential sources of between-study heterogeneity. Egger's test and influence analysis were conducted to evaluate the publication bias and study power, respectively.. The final selection enrolled 9 studies, including 2,988 subjects (1,372 obese subjects and 1,616 controls). No significant association was identified between the LEP -2548 G/A polymorphism and obesity for all genetic models in the overall population and Caucasians. We found a significant association with allelic, additive and dominant models for subjects of mixed race from South America. Notwithstanding, this significance should be treated cautiously for it is based on a rather small sample (788 involved subjects).. In total, the combined analysis of data from current and published studies suggested that the LEP -2548 G/A polymorphism does not contribute to the development of obesity, despite the fact that a significant association exists in a small subgroup from South America. Further studies are needed to elucidate the relationship. .

Topics: Alleles; Databases, Factual; Ethnicity; Genetic Predisposition to Disease; Humans; Leptin; Obesity; Polymorphism, Single Nucleotide; Risk Factors

Periodontitis is a chronic inflammatory disease of the periodontium, which is caused by pathogenic bacteria in combination with other risk factors. The bacteria induce an immunoinflammatory host response, which can lead to irreversible matrix degradation and bone resorption. Periodontitis can be successfully treated. To achieve regenerative periodontal healing, bioactive molecules, such as enamel matrix derivative (EMD), are applied during periodontal surgery. Recently, it has been shown that obesity is associated with periodontitis and compromised healing after periodontal therapy. The mechanisms underlying these associations are not well understood so far, but adipokines may be a pathomechanistic link. Adipokines are bioactive molecules that are secreted by the adipose tissue, and that regulate insulin sensitivity and energy expenditure, but also inflammatory and healing processes. It has also been demonstrated that visfatin and leptin increase the synthesis of proinflammatory and proteolytic molecules, whereas adiponectin downregulates the production of such mediators in periodontal cells. In addition, visfatin and leptin counteract the beneficial effects of EMD, whereas adiponectin enhances the actions of EMD on periodontal cells. Since visfatin and leptin levels are increased and adiponectin levels are reduced in obesity, these adipokines could be a pathomechanistic link whereby obesity and obesity-related diseases enhance the risk for periodontitis and compromised periodontal healing. Recent studies have also revealed that adipokines, such as visfatin, leptin and adiponectin, are produced in periodontal cells and regulated by periodontopathogenic bacteria. Therefore, adipokines may also represent a mechanism whereby periodontal infections can impact on systemic diseases.

Topics: Adipokines; Adiponectin; Humans; Leptin; Nicotinamide Phosphoribosyltransferase; Obesity; Periodontitis

Leptin, as a key hormone in energy homeostasis, regulates neuroendocrine function, including reproduction. It has a permissive role in the initiation of puberty and maintenance of the hypothalamic-pituitary-gonadal axis. This is notable in patients with either congenital or acquired leptin deficiency from a state of chronic energy insufficiency. Hypothalamic amenorrhea is the best-studied, with clinical trials confirming a causative role of leptin in hypogonadotropic hypogonadism. Implications of leptin deficiency have also emerged in the pathophysiology of hypogonadism in type 1 diabetes. At the other end of the spectrum, hyperleptinemia may play a role in hypogonadism associated with obesity, polycystic ovarian syndrome, and type 2 diabetes. In these conditions of energy excess, mechanisms of reproductive dysfunction include central leptin resistance as well as direct effects at the gonadal level. Thus, reproductive dysfunction due to energy imbalance at both ends can be linked to leptin.

Topics: Amenorrhea; Energy Metabolism; Female; Humans; Hypogonadism; Hypothalamic Diseases; Leptin; Obesity; Reproduction

The hyperphagia, low sympathetic nervous system tone, and decreased circulating concentrations of bioactive thyroid hormones that are common to states of congenital leptin deficiency and hypoleptinemia following and during weight loss suggest that the major physiological function of leptin is to signal states of negative energy balance and decreased energy stores. In weight-reduced humans, these phenotypes together with pronounced hypometabolism and increased parasympathetic nervous system tone create the optimal circumstance for weight regain. Based on the weight loss induced by leptin administration in states of leptin deficiency (obese) and observed similarity of phenotypes in states of congenital and dietary-induced states of hypoleptinemia (reduced obese), it has been suggested that exogenous leptin could potentially be useful in initiating, promoting, and sustaining weight reduction. However, the responses of human beings to exogenous leptin administration are dependent not only on extant energy stores but also on energy balance. Leptin administration to humans at usual weight has little, if any, effect on body weight while leptin administration during weight loss mitigates hunger, especially if given in supraphysiological doses during severe caloric restriction. Leptin repletion is most effective following weight loss by dietary restriction. In this state of weight stability but reduced energy stores, leptin at least partially reverses many of the metabolic, autonomic, neuroendocrine, and behavioral adaptations that favor weight regain. The major physiological function of leptin is to signal states of negative energy balance and decreased energy stores. Leptin, and pharmacotherapies affecting leptin signaling pathways, is likely to be most useful in sustaining weight loss.

Topics: Body Weight; Energy Metabolism; Homeostasis; Humans; Leptin; Models, Biological; Obesity; Signal Transduction

Until the discovery of leptin 20 years ago, adipose tissue was considered only as a fat storage organ, involved in the regulation of energy homeostasis. At present, it is well known that adipokines, being leptin the forerunner of this superfamily, may act in different biological processes, including inflammation and immunity. In this review, we have explored the recent evidence about the relationship between leptin and immune system, summarizing the most important findings related to the involvement of leptin in both innate and adaptive immune response.

Topics: Adaptive Immunity; Adipose Tissue; Animals; Energy Metabolism; Humans; Immunity, Innate; Immunomodulation; Inflammation; Leptin; Obesity

Despite the known glucose-lowering effects of metformin, more recent clinical interest lies in its potential as a weight loss drug. Herein, we discuss the potential mechanisms by which metformin decreases appetite and opposes unfavorable fat storage in peripheral tissues.. Many individuals struggle to maintain clinically relevant weight loss from lifestyle and bariatric surgery interventions. Long-term follow-up from the Diabetes Prevention Program demonstrates that metformin produces durable weight loss, and decreased food intake by metformin is the primary weight loss mechanism. Although the effect of metformin on appetite is likely to be multifactorial, changes in hypothalamic physiology, including leptin and insulin sensitivity, have been documented. In addition, novel work in obesity highlights the gastrointestinal physiology and circadian rhythm changes by metformin as not only affecting food intake, but also the regulation of fat oxidation and storage in liver, skeletal muscle, and adipose tissue.. Metformin induces modest weight loss in overweight and obese individuals at risk for diabetes. A more detailed understanding of how metformin induces weight loss will likely lead to optimal co-prescription of lifestyle modification with pharmacology for the treatment of obesity independent of diabetes.

Topics: Appetite Depressants; Diabetes Mellitus, Type 2; Eating; Humans; Hypoglycemic Agents; Hypothalamus; Insulin Resistance; Leptin; Metformin; Obesity; Risk Reduction Behavior; Signal Transduction; Treatment Outcome; Weight Loss

Historically, adipose tissue was considered to be a passive storage vessel discharging nutrients in times of famine and accumulating fat in times of surfeit. This view changed with the identification of leptin as an adipocyte hormone. Leptin functions as an afferent signal in a negative feedback loop that regulates food intake and metabolism to maintain homeostatic control of adipose tissue mass. Before this, the existence of a system maintaining homeostatic control of energy balance was unclear. The identification of leptin has thus uncovered a new endocrine system that also links changes in nutrition to adaptive responses in most if not all other physiologic systems. Further studies have revealed a set of clinical syndromes caused by leptin deficiency, including lipodystrophy and hypothalamic amenorrhea. This work has led to new therapeutic approaches for a number of human conditions and has also established a conceptual framework for studying the pathogenesis of obesity.

Topics: Adipose Tissue; Animals; Eating; Energy Metabolism; Homeostasis; Humans; Leptin; Obesity

Body weight is a highly heritable trait across species. In humans, genetic variation plays a major role in determining the inter-individual differences in susceptibility or resistance to environmental factors which influence energy intake and expenditure. In this review, I discuss how genetic studies have contributed to our understanding of the central pathways that govern energy homeostasis. The study of individuals harboring highly penetrant genetic variants that disrupt the leptin-melanocortin pathway has informed our understanding of the physiological pathways involved in mammalian energy homeostasis.

Topics: Animals; Body Weight; Energy Metabolism; Genetic Variation; Genome-Wide Association Study; Humans; Leptin; Metabolic Networks and Pathways; Obesity; Receptor, Melanocortin, Type 4; Signal Transduction

Osteocalcin is a bone matrix protein that has been associated with several hormonal actions on energy and glucose metabolism. Animal and experimental models have shown that osteocalcin is released into the bloodstream and exerts biological effects on pancreatic beta cells and adipose tissue. Undercarboxylated osteocalcin is the hormonally active isoform and stimulates insulin secretion and enhances insulin sensitivity in adipose tissue and muscle. Insulin and leptin, in turn, act on bone tissue, modulating the osteocalcin secretion, in a traditional feedback mechanism that places the skeleton as a true endocrine organ. Further studies are required to elucidate the role of osteocalcin in the regulation of glucose and energy metabolism in humans and its potential therapeutic implications in diabetes, obesity and metabolic syndrome.

Topics: Adipose Tissue; Animals; Bone and Bones; Diabetes Mellitus, Type 2; Energy Metabolism; Glucose; Humans; Insulin; Insulin Resistance; Insulin-Secreting Cells; Leptin; Metabolic Syndrome; Muscles; Obesity; Osteocalcin

Obesity is currently considered a major public health problem in the world, already reaching epidemic characteristics, according to the World Health Organization. Excess weight is the major risk factor associated with various diseases, such as type 2 diabetes mellitus, hypertension, dyslipidemia and osteometabolic diseases, including osteoporosis and osteoarthritis. Osteoarthritis is the most prevalent rheumatic disease and the leading cause of physical disability and reduced quality of life of the population over 65 years. It mainly involves the joints that bear weight - knees and hips. However, along with the cases of obesity, its prevalence is increasing, and even in other joints, such as hands. Thus, it is assumed that the influence of obesity on the development of OA is beyond mechanical overload. The purpose of this review was to correlate the possible mechanisms underlying the genesis and development of these two diseases. Increased fat mass is directly proportional to excessive consumption of saturated fatty acids, responsible for systemic low-grade inflammation condition and insulin and leptin resistance. At high levels, leptin assumes inflammatory characteristics and acts in the articular cartilage, triggering the inflammatory process and changing homeostasis this tissue with consequent degeneration. We conclude that obesity is a risk factor for osteoarthritis and that physical activity and changes in diet composition can reverse the inflammatory and leptin resistance, reducing progression or preventing the onset of osteoarthritis.

Topics: Cytokines; Humans; Leptin; Obesity; Osteoarthritis; Risk Factors

Resistant hypertension (RH) is a multifactorial disease, frequently associated with obesity and characterized by blood pressure above goal (140/90 mm Hg) despite the concurrent use of ≥3 antihypertensive drugs of different classes. The mechanisms of obesity-related hypertension include, among others, aldosterone excess and inflammatory adipokines, which have demonstrated a significant role in the pathogenesis of metabolic syndrome and RH. This review aims to summarize recent studies on the role of the adipokines leptin, resistin, and adiponectin in the pathophysiology of RH and target-organ damage associated with this condition. The deregulation of adipokine levels has been associated with clinical characteristics frequently recognized in RH such as diabetes, hyperactivity of sympathetic and renin-angiotensin-aldosterone systems, and vascular and renal damage. Strategies to regulate adipokines may be promising for the management of RH and some clinical implications must be considered when managing controlled and uncontrolled patients with RH.

Topics: Adipokines; Adiponectin; Antihypertensive Agents; Drug Resistance; Drug Therapy, Combination; Humans; Hypertension; Leptin; Obesity; Resistin

Obesity and thyroid diseases are common disorders in the general population and they frequently occur in single individuals. Alongside a chance association, a direct relationship between 'thyroid and obesity' has been hypothesized. Thyroid hormone is an important determinant of energy expenditure and contributes to appetite regulation, while hormones and cytokines from the adipose tissue act on the CNS to inform on the quantity of energy stores. A continuous interaction between the thyroid hormone and regulatory mechanisms localized in adipose tissue and brain is important for human body weight control and maintenance of optimal energy balance. Whether obesity has a pathogenic role in thyroid disease remains largely a matter of investigation. This review highlights the complexity in the identification of thyroid hormone deficiency in obese patients. Regardless of the importance of treating subclinical and overt hypothyroidism, at present there is no evidence to recommend pharmacological correction of the isolated hyperthyrotropinemia often encountered in obese patients. While thyroid hormones are not indicated as anti-obesity drugs, preclinical studies suggest that thyromimetic drugs, by targeting selected receptors, might be useful in the treatment of obesity and dyslipidemia.

Topics: Adipose Tissue; Animals; Anti-Obesity Agents; Autoimmunity; Body Weight; Energy Intake; Energy Metabolism; Feedback, Physiological; Feeding Behavior; Humans; Hypothyroidism; Leptin; North America; Obesity; Randomized Controlled Trials as Topic; Thyroid Gland; Thyroid Hormones; Thyroid Neoplasms; Thyroiditis, Autoimmune; Thyrotropin

The discovery of leptin has provided a robust framework upon which our current understanding of the mechanisms involved in energy homeostasis has been built. In this review, we describe how the identification of humans with mutations in the genes encoding leptin and the leptin receptor and the characterisation of the associated clinical phenotypes have provided insights into the role of leptin-responsive pathways in the regulation of eating behaviour, intermediary metabolism and the onset of puberty. Importantly, administration of recombinant human leptin in leptin deficiency represents the first mechanistically based targeted therapy for obesity and has provided immense clinical benefits for the patients concerned. In subsequent years, we and others have shown that human obesity can result from a multiplicity of defects in the pathways downstream of leptin signalling within the brain.

Topics: Animals; Brain; Energy Metabolism; Humans; Leptin; Models, Genetic; Mutation; Obesity; Receptors, Leptin; Signal Transduction

Globally, the prevalence of obesity is increasing which subsequently increases the risk of the development of obesity-related chronic diseases. Low-grade chronic inflammation and dysregulated adipose tissue inflammatory mediator/adipokine secretion are well-established in obesity, and these factors increase the risk of developing inflammation-associated cancer. Breast cancer is of particular interest given that increased inflammation within the subcutaneous mammary adipose tissue depot can alter the local tissue inflammatory microenvironment such that it resembles that of obese visceral adipose tissue. Therefore, in obese women with breast cancer, increased inflammatory mediators both locally and systemically can perpetuate inflammation-associated pro-carcinogenic signaling pathways, thereby increasing disease severity. Herein, we discuss some of these inflammation-associated pro-carcinogenic mechanisms of the combined obese breast cancer phenotype and offer evidence that dietary long chain n-3 polyunsaturated fatty acids (PUFA) may have utility in mitigating the severity of obesity-associated inflammation and breast cancer.

Topics: Adiponectin; Aromatase; Breast Neoplasms; Cytokines; Estrogens; Fatty Acids, Omega-3; Fatty Acids, Omega-6; Female; Humans; Inflammation; Intra-Abdominal Fat; Leptin; Obesity; Paracrine Communication; Prevalence

Matrix metalloproteinases (MMPs) play an important role during physiological tissue remodeling in embryonic development and angiogenesis, as well as in pathophysiological conditions such as obesity and development and vulnerability of atherosclerotic plaque. Moreover, MMP circulating levels have emerged as potential biomarkers of cardiovascular disease. MMP expression and activity are regulated by different factors such as insulin resistance and obesity. Expanded fat tissue has been demonstrated to be an active organ, where MMPs also exert a role in adipogenesis, angiogenesis, and proliferation of extracellular matrix (ECM). However, the lack of association between adipose tissue and plasma levels of some MMPs, specifically MMP-2 and MMP-9, suggests that this tissue is not a major contributor to circulating gelatinases. MMPs are also co-expressed or co-repressed in response to inflammatory adipocytokines, like adiponectin and leptin. Adiponectin may also play a protective role in plaque rupture through selectively increasing the tissue inhibitor of metalloproteinase (TIMP) expression. Leptin induces the expression of MMP-2 activators as well as the expression of MMP-2, MMP-9, and TIMP-1 in different human cells. Furthermore, sex hormones also participate in MMP regulation. In postmenopausal women, hormone replacement therapy produces an increase in MMP activity, leading to a breakdown in ECM homeostasis and accelerated progression of vascular pathologies. Besides, in men, an inverse relationship between testosterone levels and MMP-2 activity has been described. It is still necessary to go forward in the study of MMPs in different metabolic situations to corroborate their role as vulnerable plaque biomarkers.

Topics: Adiponectin; Adipose Tissue; Animals; Gonadal Steroid Hormones; Humans; Leptin; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Matrix Metalloproteinases; Metabolic Syndrome; Myocardium; Obesity; Risk Factors

Obesity and excess of adipose tissue are associated with the development of cardiovascular risk factors such as diabetes, hypertension, and hyperlipidemia. At the cardiac level, various morphological adaptations in cardiac structure and function occur in obese individuals. Different mechanisms linking obesity to these modifications have been postulated. Adipose tissue and epicardial fat releases a large number of cytokines and bioactive mediators such as leptin. Leptin circulates in proportion to body fat mass, thus serving as a satiety signal and informing central metabolic control centers as to the status of peripheral energy stores. It participates in numerous other functions both peripherally and centrally, as indicated by the wide distribution of leptin and the different isoforms of its receptor in different tissues including the heart. This hormone has distinct effects on the reproductive, cardiovascular, and immune systems; however, its role in the heart could mediate wide physiological effects observed in obese individuals. Oxidative stress is associated with obesity and may be considered to be a unifying mechanism in the development of obesity-related comorbidities. It has been reported that obesity may induce systemic oxidative stress; in turn, oxidative stress is associated with an irregular production of adipokines. We herein review the current knowledge of cardiac effects of leptin and the possible mechanisms that are involved, including oxidative stress that plays a major role in the development of cardiovascular damage.

Topics: Cardiovascular Diseases; Humans; Leptin; Obesity; Oxidative Stress; Receptors, Leptin

It is well known that hypercholesterolemia can lead to atherosclerosis and coronary heart disease. Adipose tissue represents an active endocrine and metabolic site, which might be involved in the development of chronic disease. Because adipose tissue is a key site for cholesterol metabolism and the presence of hypercholesterolemia has been shown to induce adipocyte cholesterol overload, it is critical to investigate the role of hypercholesterolemia on normal adipose function. Studies in preadipocytes revealed that cholesterol accumulation can impair adipocyte differentiation and maturation by affecting multiple transcription factors. Hypercholesterolemia has been observed to cause adipocyte hypertrophy, adipose tissue inflammation, and disruption of endocrine function in animal studies. Moreover, these effects can also be observed in obesity-independent conditions as confirmed by clinical trials. In humans, hypercholesterolemia disrupts adipose hormone secretion of visfatin, leptin, and adiponectin, adipokines that play a central role in numerous metabolic pathways and regulate basic physiologic responses such as appetite and satiety. Remarkably, treatment with cholesterol-lowering drugs has been shown to restore adipose tissue endocrine function. In this review the role of hypercholesterolemia on adipose tissue differentiation and maturation, as well as on hormone secretion and physiologic outcomes, in obesity and non–obesity conditions is presented.

Topics: Adipocytes; Adiponectin; Adipose Tissue; Adiposity; Animals; Anticholesteremic Agents; Cell Differentiation; Clinical Trials as Topic; Disease Models, Animal; Humans; Hypercholesterolemia; Inflammation; Leptin; Nicotinamide Phosphoribosyltransferase; Obesity

Previous reports indicate that over 13 different tumors, including hepatocellular carcinoma (HCC), are related to obesity. Obesity-associated inflammatory, metabolic, and endocrine mediators, as well as the functioning of the gut microbiota, are suspected to contribute to tumorigenesis. In obese people, proinflammatory cytokines/chemokines including tumor necrosis factor-alpha, interleukin (IL)-1 and IL-6, insulin and insulin-like growth factors, adipokines, plasminogen activator inhibitor-1, adiponectin, and leptin are found to play crucial roles in the initiation and development of cancer. The cytokines induced by leptin in adipose tissue or tumor cells have been intensely studied. Leptin-induced signaling pathways are critical for biological functions such as adiposity, energy balance, endocrine function, immune reaction, and angiogenesis as well as oncogenesis. Leptin is an activator of cell proliferation and anti-apoptosis in several cell types, and an inducer of cancer stem cells; its critical roles in tumorigenesis are based on its oncogenic, mitogenic, proinflammatory, and pro-angiogenic actions. This review provides an update of the pathological effects of leptin signaling with special emphasis on potential molecular mechanisms and therapeutic targeting, which could potentially be used in future clinical settings. In addition, leptin-induced angiogenic ability and molecular mechanisms in HCC are discussed. The stringent binding affinity of leptin and its receptor Ob-R, as well as the highly upregulated expression of both leptin and Ob-R in cancer cells compared to normal cells, makes leptin an ideal drug target for the prevention and treatment of HCC, especially in obese patients.

Topics: Animals; Carcinoma, Hepatocellular; Humans; Leptin; Liver Neoplasms; Molecular Targeted Therapy; Obesity; Signal Transduction

Insulin resistance (IR) is a general phenomenon of many physiological states, disease states, and diseases. IR has been described in diabetes mellitus, obesity, infection, sepsis, trauma, painful states such as postoperative pain and migraine, schizophrenia, major depression, chronic mental stress, and others. In arthritis, abnormalities of glucose homeostasis were described in 1920; and in 1950 combined glucose and insulin tests unmistakably demonstrated IR. The phenomenon is now described in rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis, polymyalgia rheumatica, and others. In chronic inflammatory diseases, cytokine-neutralizing strategies normalize insulin sensitivity. This paper delineates that IR is either based on inflammatory factors (activation of the immune/ repair system) or on the brain (mental activation via stress axes). Due to the selfishness of the immune system and the selfishness of the brain, both can induce IR independent of each other. Consequently, the immune system can block the brain (for example, by sickness behavior) and the brain can block the immune system (for example, stress-induced immune system alterations). Based on considerations of evolutionary medicine, it is discussed that obesity per se is not a disease. Obesity-related IR depends on provoking factors from either the immune system or the brain. Chronic inflammation and/or stress axis activation are thus needed for obesity-related IR. Due to redundant pathways in stimulating IR, a simple one factor-neutralizing strategy might help in chronic inflammatory diseases (inflammation is the key), but not in obesity-related IR. The new considerations towards IR are interrelated to the published theories of IR (thrifty genotype, thrifty phenotype, and others).

Topics: Brain; Chronic Disease; Cytokines; Endocrinology; Energy Metabolism; Fasting; Humans; Inflammation; Insulin Resistance; Leptin; Models, Biological; Neuroimmunomodulation; Obesity; Selection, Genetic; Starvation; Stress, Psychological

THE PURPOSE OF THE REVIEW: Analyze the basic data on the role of obesity in the pathogenesis of pancreatic cancer (PC) and the modern mechanisms of this association.. In the European Union and in Russia incidence of pancreatic diseases increases, such pancreatic cancer (PC) ranks 10th among cancer diseases. Obesity is a risk factor for not only of severe acute pancreatitis, but also PC at that independently of diabetes. In a meta-analysis the PC risk in obese increased by 47%, while the person with a central obesity have a higher PC risk compared to those with a peripheral type of obesity (odds ratio = 1,45, 95% CI: 1,02-2,07), but association between BMI and PC risk in this Japanese population may be different from that in Western populations, sometimes inversely. The link between obesity and PC is explained by insulin resistance and hyperinsulinemia: was proved a direct correlation between the level of circulating C-peptide and PC, low levels of serum adiponektin and leptin increase the PC risk. There are also genetic risk factors for PC: a statistically significant interaction between IVS1-27777C> and IVS1-23525A>T genotypes of the FTO gene with obesity and the PC risk: AA genotype in patients with BMI < 25 kg/m2 reduced PC risk by 22%-28% (p < 0,0001), and with BMI ≥ 25 kg/m2 was associated with 54%-60% increased PC risk (p < 0,0015). Lifestyle factors (smoking, consumption of saturated fats, etc.) increase the PC risk.

Topics: Humans; Leptin; Obesity; Pancreatic Neoplasms; Pancreatitis; Risk Factors

The purposeful use of plant minor biologically active food substances (with demonstrated evident hypoglycemic, hypocholesterolemic and antioxidant action) in the composition of specialized dietary products can become the inno- vative approach for the dietary treatment of type 2 diabetes mellitus. Clinical testing of minor biologically active food substances of plant origin and their further use in the composition of specialized dietary products should be preceded by the stage of complex physiological and biochemical studies in vivo. It all turns on the question: to which extent the results obtained with the biomodel can be extrapolated on the human body. Hence, this review comparatively evaluates the rat models of type 2 diabetes. In this paper, we overview the most frequently used monogenic models of obesity with the damage of the leptin signaling path- way, when the animal loses control over saturation, hyperphagia and subsequent obesity appear. We describe polygenic models of obesity-related diabetes with fatty rats, which are more approximated to type 2 diabetes mellitus in humans. The characteristic of the type 2 diabetes model without obesity is given in the article: the SDT (Spontaneously Diabetic Torii) rats are genetically predisposed to glucose intolerance. Spontaneously Diabetic Torii-fa/fa (SDT fatty) rat is a new model of obese type 2 diabetes. Both male and female SDT fatty rats show overt obesity, and hyperglycemia and hyperlipidemia are observed at a younger age as compared with SDTrats. In conclusion, the SDT fatty rats are useful as a model for the development of new drugs and/or specialized dietary products to reduce body fat mass.

Topics: Animal Feed; Animals; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Dietary Supplements; Genetic Testing; Glucose Intolerance; Insulin Resistance; Leptin; Micronutrients; Nutritional Status; Obesity; Rats; Signal Transduction

Obesity is rapidly becoming pandemic and is associated with increased carcinogenesis, especially hepatocellular carcinoma (HCC). Adipose tissue is considered as an endocrine organ because of its capacity to secrete a variety of adipokines, such as leptin, adiponectin and resistin. Recently, adipokines have been demonstrated to be associated with kinds of chronic liver diseases including fibrosis, cirrhosis and carcinogenesis. Direct evidence is accumulating rapidly supporting the inhibitory and/or activating role of adipokines in the process of carcinogenesis and progression of human HCC. This review aims to provide important insight into the potential mechanisms of adipokines in the development of HCC.

Topics: Adiponectin; Adipose Tissue; Carcinoma, Hepatocellular; Cell Transformation, Neoplastic; Disease Progression; Humans; Leptin; Liver Cirrhosis; Liver Neoplasms; Obesity; Resistin

Mutations in genes involved in energy balance regulation within the central nervous system lead to monogenic forms of obesities. Individuals with these mutations are characterized by early-onset obesity and in some cases by endocrine abnormalities. Carriers of leptin gene mutations are able to normalize their body weight after daily subcutaneous leptin administration. Pharmacotherapy targeting the specific-gene deficiencies has not clinically been tested in other monogenic obesities. Mutations in the melanocortin 4 receptor gene (MC4R) represent the most common monogenic cause of human obesity. Several treatment options have been investigated in subjects with MC4R mutations. Few studies showed that an intensive life-style intervention induces similar weight reduction in MC4R mutation carriers in comparison to MC4R mutation noncarriers. However, long-term body weight maintenance is hardly ever achieved in MC4R mutation carriers. Sibutramine, serotonin and noradrenalin reuptake inhibitor, in MC4R mutation carriers induced weight reduction and improved cardiometabolic health risks. This result was also found in our homozygous MC4R mutation carrier. In vitro studies of melanocortin agonists efficiently activate mutated MC4R with impaired endogenous agonist functional response and thus, further research in the development of drugs for MC4R mutations is needed. An administration of intranasal adrenocorticotropic hormone was not shown to be effective in subjects with pro-opiomelanocortin gene mutations. Bariatric surgery has also been performed in few of MC4R mutation carriers. After gastric banding, lower body weight reduction and worse improvement of metabolic complications was found in MC4R mutation carriers versus noncarriers. However, preliminary results suggest that diversionary operations as gastric bypass represent a suitable method also for MC4R mutation carriers. In conclusion, the management of monogenic obesities still remains a challenge.

Topics: Bariatric Surgery; Body Mass Index; Body Weight; Child; Cyclobutanes; Energy Metabolism; Heterozygote; Homozygote; Humans; Leptin; Mutation; Obesity; Pro-Opiomelanocortin; Receptor, Melanocortin, Type 4; Weight Loss

Parabiosis is a chronic preparation that allows exchange of whole blood between two animals. It has been used extensively to test for involvement of circulating factors in feedback regulation of physiological systems. The total blood volume of each animal exchanges approximately ten times each day, therefore, factors that are rapidly cleared from the circulation do not reach equilibrium across the parabiotic union whereas those with a long half-life achieve a uniform concentration and bioactivity in both members of a pair. Involvement of a circulating factor in the regulation of energy balance was first demonstrated when one member of a pair of parabiosed rats became hyperphagic and obese following bilateral lesioning of the ventromedial hypothalamus. The non-lesioned partner stopped eating, lost a large amount of weight and appeared to be responding to a circulating "satiety" factor released by the obese rat. These results were confirmed using different techniques to induce obesity in one member of a pair. Studies with phenotypically similar ob/ob obese and db/db diabetic mice indicated that the obese mouse lacked a circulating signal that regulated energy balance, whereas the diabetic mouse appeared insensitive to such a signal. Positional cloning studies identified leptin as the circulating factor and subsequent parabiosis studies confirmed leptin's ability to exchange effectively between parabionts. These studies also suggest the presence of additional unidentified factors that influence body composition. This article is part of a Special Issue entitled: Animal Models of Disease.

Topics: Animals; Diabetes Mellitus, Experimental; Disease Models, Animal; Energy Metabolism; Humans; Leptin; Mice; Obesity; Parabiosis; Rats

Peptide hormones and proteins control body weight and glucose homeostasis by engaging peripheral and central metabolic signalling pathways responsible for the maintenance of body weight and euglycaemia. The development of obesity, often in association with type 2 diabetes mellitus (T2DM), reflects a dysregulation of metabolic, anorectic and orexigenic pathways in multiple organs. Notably, therapeutic attempts to normalize body weight and glycaemia with single agents alone have generally been disappointing. The success of bariatric surgery, together with emerging data from preclinical studies, illustrates the rationale and feasibility of using two or more agonists, or single co-agonists, for the treatment of obesity and T2DM. Here, we review advances in the science of co-agonist therapy, and highlight promising areas and challenges in co-agonist development. We describe mechanisms of action for combinations of glucagon-like peptide 1, glucagon, gastric inhibitory polypeptide, gastrin, islet amyloid polypeptide and leptin, which enhance weight loss whilst preserving glucoregulatory efficacy in experimental models of obesity and T2DM. Although substantial progress has been achieved in preclinical studies, the putative success and safety of co-agonist therapy for the treatment of patients with obesity and T2DM remains uncertain and requires extensive additional clinical validation.

Topics: Animals; Blood Glucose; Body Weight; Central Nervous System; Diabetes Mellitus, Type 2; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Humans; Leptin; Obesity

Classically, leptin resistance has been associated with increased body fat and circulating leptin levels, and the condition is believed to contribute to the onset and/or maintenance of obesity. Although a great deal is known about the central nervous system mechanisms mediating leptin resistance, considerably less is known about the role of diet in establishing and maintaining this altered hormonal state. An exciting new finding has recently been published demonstrating the existence of leptin resistance in normal-weight rats with lean leptin levels by feeding them a high-concentration-fructose diet. This finding has opened the possibility that specific macronutrients may be capable of inducing leptin resistance, independently of the amount of body fat or circulating leptin present in the treated animals. This review describes several lines of research that have recently emerged indicating that specific types of dietary sugars and fats are capable of inducing leptin resistance in experimental rodent models. The results further show that diet-induced leptin resistance is capable of increasing energy intake and elevating body weight gain under appropriate dietary challenges. It appears that biological mechanisms on multiple levels may underlie the dietary induction of leptin resistance, including alterations in the leptin blood-to-brain transport system, in peripheral glucose metabolism, and in central leptin receptor signaling pathways. What is clear from the findings reviewed here is that diet-induced leptin resistance can occur in the absence of elevated circulating leptin levels and body weight, rendering it a potential cause and/or predisposing factor to excess body weight gain and obesity.

Topics: Adipose Tissue; Animals; Brain; Diet; Dietary Fats; Dietary Sucrose; Energy Intake; Glucose; Humans; Leptin; Metabolic Diseases; Obesity; Weight Gain

Obesity is a major health problem contributing to increased subfertility in males, as well as increased morbidity for diseases related to a decline in testosterone production with aging. Leptin is a hormone produced by adipose tissue whose production increases with the amount of body fat. Several studies have supported a relationship between increased leptin production and regulation of reproductive function. Indeed, leptin acts at all levels of the hypothalamus-pituitary-gonadal (HPG) axis in males. However, most of the obese individuals become insensitive to increased endogenous leptin production and develop a functional leptin resistance. This deregulation of leptin signaling might result in abnormal endocrine and reproductive functions. Altered leptin dynamics may contribute to male infertility in different ways, leading to hypogonadism. These include leptin resistance or leptin insufficiency at the hypothalamus and leptin modulation of testicular physiology. In this review, we address the mechanisms of action of leptin at different levels of the HPG axis. Moreover, the influences of leptin on steroidogenesis and spermatogenesis, as well as seasonal variations of leptin's action on male reproduction are discussed.

Topics: Animals; Humans; Hypothalamo-Hypophyseal System; Infertility, Male; Leptin; Leydig Cells; Male; Obesity; Receptors, Leptin; Seasons; Spermatogenesis; Testosterone

The obesity prevalence is growing worldwide and largely responsible for the increased incidence of cardiovascular disease, the most common cause of death in the western world. Excessive food intake along with insufficient physical exercise is the basic impetus for this development. The obese state is commonly associated with an increase in leptin levels and chronic immune-mediated inflammation. Despite high leptin levels, the leptin response, normally associated with satiety and satiation, seems to be impaired and individuals continue to consume calorie-rich food. Antioxidant food additives such as sodium sulphite, sodium benzoate and curcumin were shown to suppress the leptin release in lipopolysaccharide- treated murine adipocytes. Based on this, we hypothesize that the insufficient leptin release, caused by excessive consumption of food additives, may lead to a reduced exposure of the central nervous system to leptin and ultimately propagate obesity. On the other hand, leptin has been shown to favor Th1-type activity, which ultimately decreases tryptophan levels. Tryptophan derivatives, serotonin and melatonin, induce satiety/satiation through several mechanisms. In this context, the antioxidant suppression of leptin release and Th1-type activity is beneficial to increase serotonin and melatonin levels. The molecules in the mechanism described in this review are highly integrated in the reward system, and have been implicated in the addiction behavior of obesity. Based on these facts, the involvement of antioxidant food supplements in the mechanisms of the reward-deficiency syndrome which perpetuates obesity will be discussed.

Topics: Adaptive Immunity; Animals; Antioxidants; Food Additives; Humans; Inflammation; Leptin; Obesity

Although obesity is a well-known risk factor for hypertension, the mechanisms by which hypertension develops in obese patients are not entirely clear. Animal models of obesity and their different susceptibilities to develop hypertension have revealed some of the mechanisms linking obesity and hypertension. Adipose tissue is an endocrine organ secreting hormones that impact blood pressure, such as elements of the renin-angiotensin system whose role in hypertension have been established. In addition, the appetite-suppressing adipokine leptin activates the sympathetic nervous system via the melanocortin system, and this activation, especially in the kidney, increases blood pressure. Leptin secretion from adipocytes is increased in most models of obesity due to leptin resistance, although the resistance is often selective to the anorexigenic effect, while the susceptibility to the hypertensive effect remains intact. Understanding the pathways by which obesity contributes to increased blood pressure will hopefully pave the way to and better define the appropriate treatment for obesity-induced hypertension.

Topics: Animals; Blood Pressure; Disease Models, Animal; Humans; Hypertension; Leptin; Obesity; Renin-Angiotensin System

More than one million new cases of breast cancer are diagnosed each year worldwide and more than 400,000 deaths occur due to this pathology. Obesity is a risk factor for postmenopausal breast cancer and the place held by the adipose tissue and secretions (i.e. adipokines) begins to be recognized. Indeed, firstly, plasma adipokine levels, modulated in obesity situation, could have effects "remotely" on mammary carcinogenesis and, secondly, breast cancer cells are surrounded by adipocyte microenvironment, which is probably more important in the case of obesity, and may be locally influenced by it. In this context, leptin appears to be strongly involved in mammary carcinogenesis and may contribute to the angiogenesis process and local pro-inflammatory mechanisms, especially in obese patients for whom increased metastatic potential and risk of mortality are described.

Topics: Adipocytes; Animals; Breast Neoplasms; Cell Transformation, Neoplastic; Female; Humans; Leptin; Obesity

Leptin is secreted into the bloodstream by adipocytes and is required for the maintenance of energy homeostasis and body weight. Leptin deficiency or genetic defects in the components of the leptin signaling pathways cause obesity. Leptin controls energy balance and body weight mainly through leptin receptor b (LEPRb)-expressing neurons in the brain, particularly in the hypothalamus. These LEPRb-expressing neurons function as the first-order neurons that project to the second-order neurons located within and outside the hypothalamus, forming a neural network that controls the energy homeostasis and body weight. Multiple factors, including inflammation and endoplasmic reticulum (ER) stress, contribute to leptin resistance. Leptin resistance is the key risk factor for obesity. This review is focused on recent advance about leptin action, leptin signaling, and leptin resistance.

Topics: Animals; Body Weight; Energy Metabolism; Homeostasis; Humans; Leptin; Mice; Neurons; Obesity; Risk Factors; Signal Transduction

The adiposity hormone leptin has been implicated in the regulation of behavioral and metabolic controls of body weight. Leptin receptors are found in multiple peripheral and central tissues, particularly within hypothalamic and brainstem neuronal populations. Central leptinergic signaling acts as an indirect control to modulate the feeding inhibitory potency of the direct controls of meal size. Mouse models of neuronal leptin loss and gain of function have helped to identify and characterize how central leptin contributes to the central control of food intake.

Topics: Adiposity; Animals; Body Weight; Eating; Feeding Behavior; Humans; Hypothalamus; Leptin; Meals; Models, Animal; Obesity; Portion Size; Receptors, Leptin; Signal Transduction

The basic mechanisms that lead obesity are not fully understood; however, several peptides undoubtedly play a role in regulating body weight. Obesity, a highly complex metabolic disorder, involves central mechanisms that control food intake and energy expenditure. Previous studies have shown that central or peripheral oxytocin administration induces anorexia. Recently, in an apparent discrepancy, rodents that were deficient in oxytocin or the oxytocin receptor were shown to develop late-onset obesity without changing their total food intake, which indicates the physiological importance of oxytocin to body metabolism. Oxytocin is synthesized not only within magnocellular and parvocellular neurons but also in several organs, including the ovary, uterus, placenta, testis, thymus, kidney, heart, blood vessels, and skin. The presence of oxytocin receptors in neurons, the myometrium and myoepithelial cells is well recognized; however, this receptor has also been identified in other tissues, including the pancreas and adipose tissue. The oxytocin receptor is a typical class I G protein-coupled receptor that is primarily linked to phospholipase C-β via Gq proteins but can also be coupled to other G proteins, leading to different functional effects. In this review, we summarize the present knowledge of the effects of oxytocin on controlling energy metabolism, focusing primarily on the role of oxytocin on appetite regulation, thermoregulation, and metabolic homeostasis.

Topics: Adipose Tissue; Appetite Regulation; Body Temperature Regulation; Body Weight; Eating; Energy Metabolism; Homeostasis; Humans; Leptin; Neurons; Obesity; Oxytocin; Phospholipase C beta; Receptors, Oxytocin

Obesity is a heterogeneous pathologic condition that is driven by interactions between multiple genetic and environmental factors. The discovery of leptin has provided the useful clue to the molecular dissection of central pathways involved in the regulation of food intake and body weight. Monogenic obesity in human has been documented. Several obesity causing genes within the leptin-POMC-melanocortin axis have been identified: Leptin, leptin receptor, proopiomelanocortin (POMC), prohormone convertase 1 (PC1), and melanocortin receptor-4 (MC4-R) genes. The patients who have a mutation of such genes developed early onset of obesity and distinct metabolic abnormalities. Also, several gene mutations have been identified in some syndromes presenting hereditary symptomatic obesity.

Topics: Body Weight; Humans; Leptin; Mutation; Obesity; Receptor, Melanocortin, Type 4; Receptors, Leptin

This review will examine the recent scientific literature on the mechanisms that are thought to link obesity to colorectal cancer (CRC) risk.. Obesity has emerged as a leading environmental risk factor for the development of CRC. However, the mechanisms underlying this relationship have not yet been fully elucidated. Recent literature has focused on inflammatory processes, adipokines, and estrogen. Obesity-enhanced inflammation is largely orchestrated by increases in adipose tissue macrophages leading to the secretion of inflammatory cytokines including tumor necrosis factor-α, monocyte chemoattractant protein-1, and interleukin-6, all of which are linked to CRC. Adiponectin is decreased with obesity and has been reported to be negatively associated with CRC, whereas leptin, which is increased, is positively associated with the disease. Estrogen has been shown to influence CRC, although its role remains controversial; some studies have implicated estrogen as being protective, whereas others have suggested it to be a risk factor. We highlight the most important recent advances that have been made on the aforementioned mechanisms that are thought to link obesity to CRC.. A better understanding of the mechanisms linking obesity to CRC risk is necessary for the design of effective treatment approaches in future clinical trials.

Topics: Adiponectin; Adipose Tissue; Chemokine CCL2; Colorectal Neoplasms; Estrogens; Humans; Inflammation; Interleukin-6; Leptin; Macrophages; Obesity; Tumor Necrosis Factor-alpha

Leptin is an adipokine with pleiotropic actions that regulates food intake, energy metabolism, inflammation and immunity, and also participates in the complex mechanism that regulates skeleton biology, both at bone and cartilage level. Leptin is increased in obesity and contributes to the "low-grade inflammatory state" of obese subjects causing a cluster of metabolic aberrations that affects joints and bone. In this review, we report the most recent research advances about the role of leptin in bone and cartilage function and its implication in inflammatory and degenerative joint diseases, such as osteoarthritis, rheumatoid arthritis and osteoporosis.

Topics: Adipose Tissue; Animals; Bone Diseases; Energy Metabolism; Humans; Joint Diseases; Leptin; Obesity; Signal Transduction

To highlight recent developments relating control of food intake after surgery and the gut-brain axis by reviewing clinically relevant English language articles mainly from January 2011 to March 2013.. The gut-brain axis involves a number of complex interactions between hypothalamic nuclei and the gastrointestinal tract. In the postoperative period, release of cytokines and neuromodulators are involved in the control of food intake. Analogues of neuromodulators have been developed and tested in animal studies. The emerging field of metabolic surgery has allowed study of these mechanisms in greater detail.. The current epidemic of worldwide obesity demands further research into the mechanisms underlying control of food intake.

Topics: Animals; Appetite; Bariatric Surgery; Cytokines; Eating; Gastrointestinal Tract; Ghrelin; Humans; Hypothalamus; Insulin; Leptin; Neurotransmitter Agents; Obesity; Postoperative Period

A tight relationship between iron deficiency and obesity is known to exist. The chronic low-grade inflammation that characterizes obesity enhances hepcidin production, the principal regulator of iron availability. Adipose tissue is known to secret interleukin-6 and leptin that triggers hepcidin production. It was found that adipose tissue also expresses hepcidin and hemojuvelin, a regulator of hepcidin production. These recent findings suggest that adipose tissue may have an important role in erythropoiesis particularly on obesity that is still poorly clarified. This paper discusses these findings and how they can modulate erythropoiesis.

Topics: Adipocytes; Adipose Tissue; Erythropoiesis; GPI-Linked Proteins; Hemochromatosis Protein; Hepcidins; Humans; Interleukin-6; Iron; Iron Deficiencies; Leptin; Obesity

Obesity is recognized as a major worldwide health problem. Excess weight gain is the most common cause of elevated blood pressure (BP) and markedly increases the risk of metabolic, cardiovascular and renal diseases. Although the mechanisms linking obesity with hypertension have not been fully elucidated, increased sympathetic nervous system (SNS) activity contributes to elevated BP in obese subjects. Recent evidence indicates that leptin and the central nervous system (CNS) melanocortin system, including melanocortin 4 receptors (MC4R), play a key role in linking obesity with increased SNS activity and hypertension. Leptin, a peptide-hormone produced by adipose tissue, crosses the blood-brain barrier and activates brain centers that control multiple metabolic functions as well as SNS activity and BP via the CNS melanocortin system. The crosstalk between peripheral signals (e.g., leptin) and activation of CNS pathways (e.g., MC4R) that regulate energy balance, SNS activity and BP represents an important target for treating obesity and its metabolic and cardiovascular consequences.

Topics: Animals; Appetite; Blood Pressure; Humans; Hypertension; Leptin; Obesity; Receptor, Melanocortin, Type 4; Receptors, Leptin; Sympathetic Nervous System

The prevalence of obesity is increasing which becomes worrisome due to its association with several diseases and certain types of cancers. While weight control through dietary caloric restriction and/or physical activity protects against cancer in animal models, the underlying mechanisms are not fully defined. Weight loss due to negative energy balance is associated with alterations of multiple growth factors and endocrine hormones. The altered hormones and hormone-related functions appear to be responsible for anti-cancer mechanisms. In this review, we summarize the recent studies related to weight loss and the altered endocrine hormones, focusing on the reduced levels of the mitogenic insulin-like growth factor 1 (IGF-1) and adipokine leptin as well as the raised levels of adiponectin and glucocorticoids. The potential molecular targets of these hormone-dependent signalling pathways are also discussed. Considering the increasing trends of obesity throughout the world, a better understanding of the underlying mechanisms between body weight, endocrine hormones and cancer risk may lead to novel approaches to cancer prevention and treatment.

Topics: Adiponectin; Animals; Caloric Restriction; Glucocorticoids; Humans; Insulin-Like Growth Factor I; Leptin; Neoplasms; Obesity; Prevalence; Weight Loss

Diets involving a reduction in caloric intake are frequently prescribed for the treatment of obesity, but their long-term efficacy is questionable. We considered a calorie restricted diet successful if the weight loss was ≥ 5% after at least 3 years follow up. From published data, calculating a definitive percentage of successful cases is difficult because of the way data are presented and because loss to follow-up is not corrected for in many studies. Judging by the best data available, the success rate is very low. Most individuals will regain weight and sometimes even more than they lost in the first place. The mechanisms driving this weight increase are a decrease in energy expenditure and an increased appetite which is mediated by factors such as leptin. If the first attempt to lose weight fails, the advice to go on a diet should not be endlessly repeated; stabilizing the individual's weight would probably be a more realistic goal.

Topics: Caloric Restriction; Energy Intake; Energy Metabolism; Humans; Leptin; Obesity; Treatment Failure; Treatment Outcome; Weight Gain; Weight Loss

Adipose tissue can be considered as a huge gland producing paracrine and endocrine hormones, the adipo(cyto)kines. There is growing evidence that these adipo(cyto)kines may link obesity to cardiovascular diseases. The excessive adipocyte hypertrophy in obesity induces hypoxia in adipose tissue. This leads to adiposopathy, the process that converts "healthy" adipose tissue to "sick" adipose tissue. This is accompanied by a change in profile of adipo(cyto)kines released, with less production of the "healthy" adipo(cyto)kines such as adiponectin and omentin and more release of the "unhealthy" adipo(cyto)kines, ultimately leading to the development of cardiovascular diseases. The present review provides a concise and general overview of the actual concepts of the role of adipo(cyto)kines in endothelial dysfunction, hypertension, atherosclerosis and heart diseases. The knowledge of these concepts may lead to new tools to improve health in the next generations.

Topics: Adipocytes; Adipokines; Adiponectin; Adipose Tissue; Animals; Atherosclerosis; Body Mass Index; Cardiovascular Diseases; Cell Hypoxia; Endothelium-Dependent Relaxing Factors; Endothelium, Vascular; Heart Diseases; Humans; Hypertension; Leptin; Obesity; Renin-Angiotensin System; Resistin

Obesity is a global epidemic associated with aging-like cellular processes; in both aging and obesity, resistance to hormones such as insulin and leptin can be observed. Leptin is a circulating hormone/cytokine with central and peripheral effects that is released mainly by subcutaneous white adipose tissue. Centrally, leptin controls food intake, energy expenditure, and fat distribution, whereas it controls (among several others) insulin sensitivity, free fatty acids (FFAs) oxidation, and lipolysis in the periphery. Aging is associated with important changes in both the distribution and the composition of adipose tissue. Fat is redistributed from the subcutaneous to the visceral depot and increased inflammation participates in adipocyte dysfunction. This redistribution of adipose tissue in favor of visceral fat influences negatively both longevity and healthy aging as shown in numerous animal models. These modifications observed during aging are also associated with leptin resistance. This resistance blunts normal central and peripheral functions of leptin, which leads to a decrease in neuroendocrine function and insulin sensitivity, an imbalance in energy regulation, and disturbances in lipid metabolism. Here, we review how age-related leptin resistance triggers metabolic disturbances and affects the longevity of obese patients. Furthermore, we discuss the potential impacts of leptin resistance on the decline of brown adipose tissue thermogenesis observed in elderly individuals.

Topics: Adipose Tissue; Aged; Aging; Animals; Humans; Insulin Resistance; Leptin; Longevity; Obesity

In addition to effects on appetite and metabolism, leptin influences many neuroendocrine and physiological systems, including the sympathetic nervous system. Building on my Carl Ludwig Lecture of the American Physiological Society, I review the sympathetic and cardiovascular actions of leptin. The review focuses on a critical analysis of the concept of selective leptin resistance (SLR) and the role of leptin in the pathogenesis of obesity-induced hypertension in both experimental animals and humans. We introduced the concept of SLR in 2002 to explain how leptin might increase blood pressure (BP) in obese states, such as diet-induced obesity (DIO), that are accompanied by partial leptin resistance. This concept, analogous to selective insulin resistance in the metabolic syndrome, holds that in several genetic and acquired models of obesity, there is preservation of the renal sympathetic and pressor actions of leptin despite attenuation of the appetite and weight-reducing actions. Two potential overlapping mechanisms of SLR are reviewed: 1) differential leptin molecular signaling pathways that mediate selective as opposed to universal leptin action and 2) brain site-specific leptin action and resistance. Although the phenomenon of SLR in DIO has so far focused on preservation of sympathetic and BP actions of leptin, consideration should be given to the possibility that this concept may extend to preservation of other actions of leptin. Finally, I review perplexing data on the effects of leptin on sympathetic activity and BP in humans and its role in human obesity-induced hypertension.

Topics: Animals; Brain; Humans; Hypertension; Leptin; Myocardium; Obesity; Sympathetic Nervous System

Nesfatin-1 was discovered in 2006 and introduced as a potential novel anorexigenic modulator of food intake and body weight. The past years have witnessed increasing evidence establishing nesfatin-1 as a potent physiological inhibitor of food intake and body weight and unravelled nesfatin-1's interaction with other brain transmitters to exert its food consumption inhibitory effect. As observed for other anorexigenic brain neuropeptides, nesfatin-1 is also likely to exert additional, if not pleiotropic, actions in the brain and periphery. Recent studies established the prominent expression of the nesfatin-1 precursor, nucleobindin2 (NUCB2), in the stomach and pancreas, where nesfatin-1 influences endocrine secretion. This review will highlight the current experimental state-of-knowledge on the effects of NUCB2/nesfatin-1 on food intake, body weight and glucose homeostasis. Potential implications in human obesity will be discussed in relation to the evidence of changes in circulating levels of NUCB2/nesfatin-1 in disease states, the occurrence of genetic NUCB2 polymorphisms and--in contrast to several other hormones--the independence of leptin signalling known to be blunted under conditions of chronically increased body weight.

Topics: Animals; Appetite Regulation; Body Weight; Calcium-Binding Proteins; DNA-Binding Proteins; Forecasting; Humans; Leptin; Nerve Tissue Proteins; Nucleobindins; Obesity; Signal Transduction

The complex mechanisms linking fat excess to metabolic syndrome are not well understood, but several experimental studies have shown that altered production of adipokines plays a main role in development and progression of this disorder. In particular, reduced secretion of adiponectin has a crucial role in inducing insulin resistance but also in determining the clustering of elevated triglycerides and small, dense LDL particles. Increased leptin secretion may be responsible for sympathetic nervous system overactivity and hypertension, while reduced omentin may have an important permissive role in the development of atherogenic processes. Finally, cytokines and other adipokines (resistin, visfatin) determine and modulate the inflammatory process that is an essential component of this condition of cardiovascular risk. Because obesity is prevalent in polycystic ovary syndrome (PCOS), it is not surprising that patients with PCOS present altered adipokine levels and increased prevalence of metabolic syndrome. However, because of the presence of other CV risk factors (androgen excess), in PCOS adipokine dysfunction is particularly severe. Understanding and treating adipokine dysfunction in young women with PCOS is an essential component of any politics of prevention of CV diseases in the general population.

Topics: Abdominal Fat; Adipokines; Adiponectin; Androgens; Cardiovascular Diseases; Female; Humans; Insulin Resistance; Leptin; Metabolic Syndrome; Obesity; Polycystic Ovary Syndrome; Risk Factors

The purpose of this review is to provide an overview of the effects of adenovirus and influenza virus infections on obesity in various experimental models. We reviewed studies that were conducted within the past 10 years and were related to virus infection and obesity prevalence. Here, we discuss a different causal relationship between adenovirus and influenza infections with obesity. Adenovirus infection can cause obesity, whereas obesity can be a risk factor for increasing influenza virus infection and increases the risk of morbidity and mortality. The prevalence of obesity due to adenovirus infections may be due to an increase in glucose uptake and reduction in lipolysis caused by an increase in corticosterone secretion. Adenovirus infections may lead to increases in appetite by decreasing norepinephrine and leptin levels and also cause immune dysfunction. The relationship between obesity and influenza virus infection could be summarized by the following features: decreases in memory T-cell functionality and interferon (IFN)-α, IFN-β, and IFN-γ mRNA expression, increases in viral titer and infiltration, and impaired dendritic cell function in obese individuals. Moreover, leptin resistance may play an important role in increasing influenza virus infections in obese individuals. In conclusion, prevention of adenovirus infections could be a good approach for reducing obesity prevalence, and prevention of obesity could reduce influenza virus infections from the point of view of viral infections and obesity.

Topics: Adenovirus Infections, Human; Animals; CD8-Positive T-Lymphocytes; Cell Differentiation; Corticosterone; Cytokines; Glucose; Humans; Influenza, Human; Killer Cells, Natural; Leptin; Obesity

Osteoarthritis (OA) is a common disease affecting patients at different ages regardless of gender or ethnicity. As with many chronic diseases, OA is thought to have a multifactorial aetiology, which is not fully understood. Whereas the pathophysiological process of OA can be analysed at a cellular and molecular level, the interaction between genes and lifestyle remains an important factor in the development of this disease. The expanding awareness of different genes that may play a role in OA, together with many chemical mediators thought to be associated with the progression of the disease, will help in better management of this condition. Some of the chemical mediators recently implicated in this condition are the adipokines (leptin, adiponectin and resistin). Few but consistent studies suggest that leptin in association with obesity could be an important factor in OA aetiology. Hence, this could establish a strong and direct molecular link between patient life style (nurture) and the pathological process of OA (nature). However, neither a clear mechanism nor a direct clinical association linking leptin to OA has yet been established. In this article, we explore some of the genetic and environmental factors in OA aetiology. We discuss leptin in obesity and assess its possible association with OA aetiology. This should emphasise the important role of health professionals in treating obesity in order to control OA symptoms and possibly progression.

Topics: Disease Progression; Gene-Environment Interaction; Homeostasis; Humans; Leptin; Life Style; Obesity; Osteoarthritis

The review article summarizes a very complex process of appetite regulation: the part focused on homeostatic regulation of food intake. The aim of homeostatic regulation is to achieve energy balance, stabile weight and optimal nutrient intake, in contrast to hedonic regulation of food intake, in which emotional and motivational factors are involved. Homeostatic regulation could be divided into shortterm and longterm regulation and comprises mainly gastrointestinal peptides, fat tissue hormones and central mechanisms localized in hypothalamus. It is a resultant of the action of orexigenic factors (increasing appetite and food intake) and anorexigenic factors (decreasing appetite and thus food intake), respectively. The anorexigenic factors include gastrointestinal peptides (e.g. cholecystokinin, glucagonlike peptide 1, bombesin, peptide YY and others), hormone of fat tissue leptin and centrally acting melanocortin system. On the contrary, orexigenic factors comprise of gastric ghrelin and centrally acting system of neuropeptide Y/ Agoutirelated peptide. Understanding the principles of the regulation of food intake is essential for comprehension of pathogenesis of eating disorders and obesity, whose prevalence has been recently increasing, and it provides potential targets for pharmacological interventions.

Topics: Adipose Tissue; Appetite Regulation; Body Weight; Eating; Energy Metabolism; Gastrointestinal Hormones; Homeostasis; Humans; Hypothalamus; Leptin; Neuropeptide Y; Obesity

Recent findings in animals suggest that diet-related factors can programme adipose tissue features in early life and remodel white adipose tissue (WAT) towards a brown adipose tissue (BAT)-like phenotype in adulthood, while impacting on body fat content and susceptibility to obesity. The purpose of this review is to address the significance of these results and their applicability in humans.. Nutritional conditions in the perinatal period influence sympathetic innervation to WAT and WAT cellularity in rodents. Leptin intake during the suckling period prevents obesity and other metabolic alterations in later life in rats through mechanisms that include increased sensitivity of adipose tissues to leptin. Recent data support the thermogenic functionality of inducible brown-like cells in rodent WAT and functional thermogenic beige adipogenesis from human progenitor cells. Diet-related factors and exercise can promote BAT activation and/or WAT-to-BAT remodelling (WAT browning) in animals.. Animal studies suggest that adipose tissue health and whole body adiposity might be influenced by early life nutrition and lifestyle factors in adulthood impacting energy metabolism in adipose tissues. For this knowledge to be translated to humans, biomarkers allowing early detection of the programming status of the individual and technologies allowing measuring of the thermogenic activity of adipose tissue depots in vivo are required.

Topics: Adipogenesis; Adipose Tissue, Brown; Adipose Tissue, White; Adiposity; Animals; Diet; Energy Metabolism; Humans; Leptin; Life Style; Nutritional Status; Obesity; Stem Cells

The first adipokine, leptin, discovered almost 20 years ago, is secreted into circulation mainly from adipose tissue and acts both centrally and peripherally. Leptin regulates energy metabolism, reproductive function, bone metabolism, and immune response. However in some physiological or pathological situations such as enhancement of undesired immune responses in autoimmune diseases, tumorigenesis, elevated blood pressure, and certain cardiovascular pathologies, leptin activity may be harmful. In this review we screen different approaches to blocking leptin action, in vitro and in vivo. The recent development of superactive leptin muteins exhibiting antagonistic properties, and other leptin-action-blocking peptides, proteins, monoclonal antibodies, and nanobodies, opens new perspectives for their use in research, and eventually, therapy for cachexia, autoimmune disease, cancer, and other pathologies.

Topics: Adipose Tissue; Animals; Antibodies, Neutralizing; Camelus; Humans; Leptin; Obesity; Peptides; Receptors, Leptin; Species Specificity

Obesity is a chronic disease, and it requires chronic therapy. Hypertension, dyslipidemia, diabetes and cardiovascular diseases are leading causes of mortality in the modern world. All of them are strongly linked to obesity. While treating obesity, those conditions are also managed. Obese patients should always be treated through lifestyle interventions, though the results of such interventions are modest. Pharmacotherapy is a second step in the treatment of obesity, approved only when weight loss targets were not reached through lifestyle intervention. During the history of antiobesity drugs, many of them were withdrawn because of their side effects. Various guidelines recommend prescribing drug therapy for obesity through consideration of the potential benefits and limitations. Orlistat deactivates intestinal lipase and inhibits intestinal fat lipolysis. It is actually the only drug on the European market approved for the treatment of obesity. Orlistat therapy reduces weight to a modest extent, but it reduces the incidence of diabetes beyond the result achieved with lifestyle changes. Recently, some effective antiobesity drugs like sibutramine and rimonabant have been removed from the market due to their side effects. The new combination of topimarate and fentermine is approved in the US but not in Europe. The cost effectiveness of long-term pharmacotherapy of obesity is still an unresolved question.

Topics: Anti-Obesity Agents; Appetite; Combined Modality Therapy; Comorbidity; Cost-Benefit Analysis; Cyclobutanes; Diabetes Mellitus, Type 2; Diet, Diabetic; Drug Combinations; Exercise Therapy; Fructose; Gastrointestinal Hormones; Humans; Incretins; Insulin; Insulin Secretion; Intestines; Lactones; Leptin; Life Style; Models, Biological; Neuropeptides; Obesity; Orlistat; Phentermine; Phytotherapy; Piperidines; Plant Preparations; Pyrazoles; Rimonabant; Topiramate

An increase in adiposity is associated with altered levels of biologically active proteins. These include the hormones adiponectin and leptin. The marked change in circulating concentrations of these hormones in obesity has been associated with the development of insulin resistance and metabolic syndrome. Variations in dietary lipid consumption have also been shown to impact obesity. Specifically, omega-3 fatty acids have been correlated with the prevention of obesity and subsequent development of chronic disease sequalae. This review explores animal and human data relating to the effects of omega-3 fatty acids (marine lipids) on adiponectin and leptin, considering plausible mechanisms and potential implications for obesity management. Current evidence suggests a positive, dose-dependent relationship between omega-3 fatty acid intake and circulating levels of adiponectin. In obese subjects, this may translate into a reduced risk of developing cardiovascular disease, metabolic syndrome and diabetes. In non-obese subjects, omega-3 is observed to decrease circulating levels of leptin; however, omega-3-associated increases in leptin levels have been observed in obese subjects. This may pose benefits in the prevention of weight regain in these subjects following calorie restriction.

Topics: Adiponectin; Animals; Body Mass Index; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dietary Supplements; Dose-Response Relationship, Drug; Fatty Acids, Omega-3; Fatty Acids, Omega-6; Health Promotion; Humans; Inflammation; Leptin; Metabolic Syndrome; Obesity; Randomized Controlled Trials as Topic

Improper body weight control is most critical to the development of morbid obesity, which is often associated with alternation in leptin (Ob) signaling in the central nervous system. Leptin acts to control fat mass through the regulation of both food intake and energy expenditure. In addition to the primary action in metabolic signaling, leptin has also been found to play a role in reproduction and even in breast tumorigenesis in obese patients. Interestingly, estrogen, a sex hormone, has also been recognized as another crucial factor for energy balance and breast tumorigenesis in obese subjects. Obesity in postmenopausal women has been associated with higher risk of breast cancer. There are substantial data in the literature on the connection of estrogen and leptin pathways in development of obesity and breast cancer. In this review, we discuss the cross-talk of leptin and estrogen signaling pathways in body weight control and breast cancer development.

Topics: Animals; Body Weight; Breast Neoplasms; Carcinogenesis; Estrogens; Female; Humans; Leptin; Obesity

High plasma levels of leptin, a major adipocytokine produced by adipocytes, are correlated with increased fat mass in obese state. Leptin is emerging as a key candidate molecule linking obesity with breast cancer. Acting via endocrine, paracrine, and autocrine manner, leptin impacts various stages of breast tumorigenesis from initiation and primary tumor growth to metastatic progression. Leptin also modulates the tumor microenvironment mainly through supporting migration of endothelial cells, neo-angiogenesis and sustaining recruitment of macrophage and monocytes. Various studies have shown that hyperactive leptin-signaling network leads to concurrent activation of multiple oncogenic pathways resulting in enhanced proliferation, decreased apoptosis, acquisition of mesenchymal phenotype, potentiated migration and enhanced invasion potential of tumor cells. Furthermore, the capability of leptin to interact with other molecular effectors of obese state including, estrogen, IGF-1, insulin, VEGF and inflammatory cytokines further increases its impact on breast tumor progression in obese state. This article presents an overview of the studies investigating the involvement of leptin in breast cancer.

Topics: Animals; Breast Neoplasms; Female; Humans; Leptin; Obesity; Receptors, Leptin; Risk Factors; Signal Transduction

Antipsychotic medications are used to effectively treat various symptoms for different psychiatric conditions. Unfortunately, antipsychotic-induced weight gain (AIWG) is a common side effect that frequently results in obesity and secondary medical conditions. Twin and sibling studies have indicated that genetic factors are likely to be highly involved in AIWG. Over recent years, there has been considerable progress in this area, with several consistently replicated findings, as well as the identification of new genes and implicated pathways. Here, we will review the most recent genetic studies related to AIWG using the Medline database (PubMed) and Google Scholar. Among the steadiest findings associated with AIWG are serotonin 2C receptors (HTR2C) and leptin promoter gene variants, with more recent studies implicating MTHFR and, in particular, MC4R genes. Additional support was reported for the HRH1, BDNF, NPY, CNR1, GHRL, FTO and AMPK genes. Notably, some of the reported variants appear to have relatively large effect sizes. These findings have provided insights into the mechanisms involved in AIWG and will help to develop predictive genetic tests in the near future.

Topics: Antipsychotic Agents; Genetic Predisposition to Disease; Genotype; Humans; Leptin; Obesity; Polymorphism, Single Nucleotide; Promoter Regions, Genetic; PubMed; Receptor, Serotonin, 5-HT2C; Weight Gain

Once considered a passive reservoir for lipid storage and an inert provider of thermal/mechanical insulation, white adipose tissue (WAT) is presently seen as a highly dynamic endocrine organ that actively modulates a variety of physiologic processes, including energy balance, food intake, inflammation, immunity, metabolism, as well as cardio-vascular (CV) and neuroendocrine homeostasis. Actually, other than fatty acids and lipid moieties, WAT secretes a wide range of bioactive factors, considerably different in therms of structure and functions, including cytokines, chemokines, growth factors, complement system molecules, acute phase reactants, and hormones, among which the products predominantly or exclusively synthesized by and released from adipocytes are categorized as "adipokines". The adipokine expression is intimately linked to various parameters of adiposity (such as total body fat, percentage of body fat, and fat distribution), resulting generally (with very few exceptions, such as adiponectin, omentin, and Zinc-alpha2-glycoprotein) in positive correlation with WAT mass. The adipokine profiles undergo opposite changes in WAT excess or deficiency/dystrophy. In obese subjects, the altered adipokine network strikingly contributes to the development of systemic low-grade inflammation, as well as of obesity-related metabolic/CV comorbidities, that collectively define the so called metabolic syndrome. Adipokine dysregulation has been also observed in patients with chronic inflammatory/autoimmune disorders, such as connective tissue diseases, and adipokine pathway targeting has been thought to represent a potential innovative therapeutic perspective. Comprehensive advances in understanding the WAT biology and signaling may provide crucial insights into the physiopathology of the whole body homeostasis.

Topics: Adipokines; Adiponectin; Adipose Tissue; Animals; Apelin; Cardiovascular System; Chemokines; Cytokines; Gene Expression Regulation; GPI-Linked Proteins; Homeostasis; Humans; Inflammation; Intercellular Signaling Peptides and Proteins; Lectins; Leptin; Lipocalins; Models, Biological; Nicotinamide Phosphoribosyltransferase; Obesity; Retinol-Binding Proteins, Plasma; Seminal Plasma Proteins; Serpins; Signal Transduction; Zn-Alpha-2-Glycoprotein

Decrease in quantity and activity of dopamine receptors at patients with obesity is established. This leads to overeating, and abnormal weight gain. The article presents data on the impact of the dopaminergic system in the levels of leptin, prolactin, insulin, and the development of alimentary-constitutional obesity in these patients.

Topics: Body Mass Index; Dopamine; Humans; Hypothalamus; Insulin; Leptin; Neuropeptide Y; Norepinephrine; Obesity; Pituitary Gland; Prolactin; Receptors, Dopamine; Synaptic Transmission; Waist Circumference

The number of overweight and obese individuals has dramatically increased in the US and other developed nations during the past 30 years. While type II diabetes and cardiovascular disease are well recognized co-morbid conditions associated with obesity, recent reports have demonstrated a greater severity of illness in obese patients due to influenza during the 2009 H1N1 pandemic. Consistent with these reports, diet-induced obesity has been shown to impair anti-viral host defense in murine models of influenza infection. However, the impact of obesity on the risk of community-acquired and nosocomial pneumonia in human patients is not clear. Relatively few studies have evaluated the influence of diet-induced obesity in murine models of bacterial infections of the respiratory tract. Obese leptin deficient humans and leptin and leptin-receptor deficient mice exhibit greater susceptibility to respiratory infections suggesting a requirement for leptin in the pulmonary innate and adaptive immune response to infection. In contrast to these studies, we have observed that obese leptin receptor signaling mutant mice are resistant to pneumococcal pneumonia highlighting the complex interaction between leptin receptor signaling and immune function. Given the increased prevalence of obesity and poor responsiveness of obese individuals to vaccination against influenza, the development of novel immunization strategies for this population is warranted. Additional clinical and animal studies are needed to clarify the relationship between increased adiposity and susceptibility to community-acquired and nosocomial pneumonia.

Topics: Adiposity; Animals; Bacterial Infections; Disease Models, Animal; Humans; Influenza, Human; Leptin; Mice; Obesity; Pneumonia; Receptors, Leptin; Respiratory Tract Infections; Severity of Illness Index; United States

Our understanding of the regulation of appetite has improved considerably over the last few decades. Recent work, stimulated by efforts aimed at curbing the current obesity epidemic, has unravelled some of the complex pathways regulating energy homeostasis. Key factors to this progress have been the discovery of leptin and the neuronal circuitry involved in mediating its effects, as well as the identification of gut hormones that have important physiological roles relating to energy homeostasis. Despite these advances in research, there are currently no effective treatments for the growing problem of obesity. In this article, we summarise the regulatory pathways controlling appetite with a special focus on gut hormones. We detail how recent findings have contributed to our knowledge regarding the pathogenesis and treatment of common obesity. A number of barriers still need to be overcome to develop safe and effective anti-obesity treatments. We outline problems highlighted by historical failures and discuss the potential of augmenting natural satiety signals, such as gut hormones, to treat obesity.

Topics: Appetite Regulation; Autonomic Pathways; Eating; Female; Gastrointestinal Tract; Homeostasis; Humans; Hypothalamus; Leptin; Male; Obesity; Peptide Hormones; Satiation; Signal Transduction

In 1959 Hervey hypothesized that a circulating feedback signal informed the hypothalamus of the size of fat stores and initiated appropriate corrections to energy balance. The hypothesis resulted from a parabiosis study in which one animal became obese following lesioning of the ventromedial hypothalamus. The partner of the lesioned rat was hypophagic and lost a large amount of body fat. Similar results came from parabiosis studies with obese Zucker rats and rats that overate due to stimulation of the lateral hypothalamus. In studies in which one parabiont was made obese by overfeeding the non-overfed partners lost substantial amounts of fat with a minimal reduction in food intake and no loss of lean tissue. The loss of fat was due to inhibition of adipose lipogenesis and other metabolic adjustments typical of food restriction. Parabiosis with genetically obese mice implied that ob/ob mice did not produce the feedback signal and subsequently the mutant ob protein, leptin, was identified. This paper provides a review and interpretation of parabiosis work that preceded the discovery of leptin, an evaluation of leptin in relation to its function as the circulating feedback signal and evidence for additional circulating factors involved in the control of adipose tissue mass.

Topics: Adipose Tissue; Animals; Body Weight; Eating; Energy Metabolism; History, 20th Century; History, 21st Century; Humans; Hypothalamus; Leptin; Mice; Mice, Obese; Nutritional Sciences; Obesity; Parabiosis; Rats; Rats, Zucker; Satiation

There is increasing evidence that changes in thyroid function are associated with obesity, a condition associated with a chronic low-grade state of inflammation. Meanwhile, recent data have disclosed a relation between obesity and thyroid autoimmunity, with the adipocyte hormone leptin appearing to be the key factor linking these two conditions.. Leptin has variably been implicated in thyroid function, while recent findings suggest that leptin resistance may mitigate leptin deficiency and enhance autoimmunity in obese subjects via mechanisms operating independently of thyroid function. The development of resistance to the weight-lowering effects of leptin in obesity might well be initiated by activation of inflammatory signaling, which substantially contributes to the derangement of immune response and propagation of autoimmunity in susceptible individuals.. Regulation of inflammasome-derived cytokines in obesity is an important step in controlling the trigger of thyroid autoimmunity. The clarification of the pathways may offer innovative therapeutic targets in obesity and thyroid autoimmunity.

Topics: Adipose Tissue; Animals; Appetite Regulation; Autoimmunity; Humans; Inflammasomes; Leptin; Obesity; Thyroid Gland; Thyroiditis, Autoimmune

Polyphenols are natural substances and are enriched in vegetables, fruits, grains, bark, tea, and wine. Some polyphenols have insulin-potentiating and anti-inflammatory effects, both of which are important in obesity. Dietary supplementation with polyphenolic compounds is associated with reduced diet-induced obesity and/or metabolic syndrome in animal and human studies. Insights into mechanisms that regulate food intake and satiety have led to an increased understanding of obesity but the pathogenesis underlying obesity is lacking. Food intake is subject to a complex regulation by the hypothalamus and other brain centers including the brain stem and the hippocampus. An intricate network of interacting feedback mechanisms that involve the aforementioned neural centers along with the stomach, gut, liver, thyroid, and adipose tissue in the periphery, influence the eventual outcome of food intake and satiety. Key peripheral signals, such as leptin, insulin, and ghrelin, have been linked to hypothalamic neuropeptide systems in energy regulation. This review will examine the neural centers important in food intake, the role of various neuropeptides, and the neurohormonal influence on food intake. The potential role of polyphenols in influencing the neuroregulatory factors, the neural signaling pathways and/or the peripheral feedback mechanisms that modulate food intake will also be examined.

Topics: Agouti-Related Protein; Animals; Dietary Supplements; Energy Intake; Gastric Mucosa; Ghrelin; Glucagon-Like Peptide 1; Humans; Hypothalamic Hormones; Hypothalamus; Insulin; Islet Amyloid Polypeptide; Leptin; Liver; Melanins; Melanocortins; Neuropeptide Y; Neurotransmitter Agents; Obesity; Peptide YY; Pituitary Hormones; Polyphenols; Satiation; Signal Transduction; Stomach; Thyroid Gland

Observational studies report lower mortality in obese than in lean critically ill patients, an association referred to as the "obesity paradox." This may suggest a possible protective role for adipose tissue during severe illness.. Relevant publications were identified based on searches in PubMed and on secondary searches of their bibliographies.. The endocrine functions of adipose tissue might play a role in the adaptation to critical illness. In the acute phase of illness, the anti-inflammatory adiponectin is reduced, whereas proinflammatory cytokine expression in adipose tissue is up-regulated. In the prolonged phase of critical illness, both adiponectin and anti-inflammatory cytokine production are increasing. Studies on the proinflammatory adipokine leptin during critical illness are inconsistent, possibly due to confounders such as gender, body mass index, and feeding. Morphologically, adipose tissue of critically ill patients reveals an increased number of newly differentiated, smaller adipocytes. Accentuated macrophage accumulation showing a phenotypic switch to M2-type suggests an adaptive response to the microenvironment of severe illness. Functionally, adipose tissue of critically ill patients develops an increased ability to store glucose and triglycerides.. Endocrine, metabolic, and morphologic properties of adipose tissue change during critical illness. These alterations may suggest a possible adaptive, protective role in optimizing chances of survival. More research is needed to understand the exact role of adipose tissue in lean vs. obese critically ill patients, in order to understand how illness-associated alterations contribute to the obesity paradox.

Topics: Adaptation, Physiological; Adipocytes; Adiponectin; Adipose Tissue; Body Mass Index; Critical Illness; Cytokines; Endocrine System; Energy Metabolism; Humans; Leptin; Macrophage Activation; Obesity

Melanocortin-4 receptor (MC4R) mutations are the most common known cause of monogenic obesity and an important contributor to polygenic obesity. MC4R mutations with partial or total loss of function, as well as the variant rs17782313 mapped near MC4R, are positively associated with obesity. MC4R is involved in the leptin-melanocortin signalling system, located in hypothalamic nuclei, that controls food intake via both anorexigenic or orexigenic signals. Impairment in this receptor might affect eating behaviours. Thus, in the case of MC4R mutation carriers, obesity could be related, at least partly, to inadequate control over eating behaviours. Many published studies address eating behaviours in MC4R mutation carriers. Most studies focus on binge eating disorder, whereas others examine various aspects of intake and motivation. Up to now, no evaluation of this literature has been performed. In this review, we examine the available literature on eating behaviours in carriers of MC4R mutations and variant rs17782313 near MC4R gene. We address binge eating disorder, bulimia nervosa, mealtime hyperphagia, snacking, psychological factors, satiety responsiveness and intake of energy and macro/micronutrient. In a small number of studies, MC4R mutations seem to impair eating behaviours or motivation, but no clear causal effects can be found in the balance of the evidence presented. Improvements in methodologies will be necessary to clarify the behavioural effects of MC4R mutations.

Topics: Body Mass Index; Bulimia; Eating; Feeding Behavior; Female; Humans; Hyperphagia; Leptin; Male; Mutation; Obesity; Phenotype; Postprandial Period; Receptor, Melanocortin, Type 4; Receptors, Cell Surface

The central melanocortin system plays an essential role in the regulation of energy metabolism. Key to this regulation are the responses of neurons expressing proopiomelanocortin (POMC) and agouti-related protein (AgRP) to blood-borne metabolic signals. Recent evidence has demonstrated that POMC and AgRP neurons are not simply mirror opposites of each other in function and responsiveness to metabolic signals, nor are they exclusively first-order neurons. These neurons act as central transceivers, integrating both hormonal and neural signals, and then transmitting this information to peripheral tissues via the autonomic nervous system to coordinate whole-body energy metabolism. This review focuses on most recent developments obtained from rodent studies on the function, metabolic regulation, and circuitry of the central melanocortin system.

Topics: Agouti-Related Protein; Animals; Energy Metabolism; Humans; Leptin; Melanocortins; Models, Biological; Obesity; Receptors, Melanocortin

This review focuses on recent advances in receptor signaling, neurobiology, and pharmacological interactions of amylin with nutritive status, as well as other metabolism-related regulatory signals.. Manipulation of components of the amylin receptor complex revealed important roles for the accessory proteins of amylin receptors in energy balance. In-vitro findings point to potential novel sites of action and postreceptor signaling pathways activated by amylin. Neurobiological studies elucidated how amylin activation of hindbrain neural circuitry modulates hypothalamic signaling and responsiveness to leptin. The notion of 'amylin resistance' was addressed in several models (drug or diet-induced hyper-amylinemia). Finally, progress in the design and delivery of amylinomimetics is briefly discussed.. Collectively, these mechanistic studies deepen our understanding of the role of endogenous amylin in the regulation of appetite and adiposity, and hopefully will help guide research efforts towards the development of more effective amylin-based therapies for metabolic diseases.

Topics: Adiposity; Amyloid; Animals; Appetite Depressants; Appetite Regulation; Energy Metabolism; Humans; Hypothalamus; Islet Amyloid Polypeptide; Leptin; Mice; Mice, Inbred C57BL; Neurobiology; Obesity; Pharmacology; Rats; Rats, Inbred Strains; Receptors, Islet Amyloid Polypeptide; Signal Transduction

There is a pressing need for new effective therapeutic strategies for addressing the epidemic of type 2 diabetes. Leptin has been shown to reduce hyperglycaemia in rodent models of type 1 diabetes and has recently been shown to normalize fasting plasma glucose concentrations in a rodent model of polygenic obesity and type 2 diabetes. Overall, these findings suggest that leptin may be an effective therapeutic option for both type 1 and type 2 diabetes. However, short-term human clinical studies in overweight and obese patients with recently diagnosed type 2 diabetes have reported minimal efficacy of leptin administration to lower blood glucose levels. Herein, the role of leptin in the maintenance of glucose homeostasis and the potential use of leptin in the treatment of type 2 diabetes are discussed.

Topics: Animals; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Leptin; Obesity

The worldwide increase in the prevalence of obesity in children and adolescents during the last decades, as well as the mounting evidence indicating that obesity is associated with an increased incidence of comorbidities and the risk of premature death, resulting in a high economic impact, has stimulated obesity focused research. These studies have highlighted the prominent endocrine activity of adipose tissue, which is exerted through the synthesis and secretion of a wide variety of peptides and cytokines, called adipokines. This review presents a summary of the current knowledge and most relevant studies of adipokine dynamics and actions in children, focusing on the control of energy homeostasis, metabolic regulation (particularly carbohydrate metabolism), and inflammation. The particularities of adipose secretion and actions in healthy children, from birth to adolescence, and the modifications induced by early onset obesity are highlighted.

Topics: Adipokines; Adiponectin; Adipose Tissue; Child; Cytokines; Energy Metabolism; Homeostasis; Humans; Leptin; Nicotinamide Phosphoribosyltransferase; Obesity; Serpins

Leptin (from the Greek word "lepto'' meaning "thin") is a 167-amino acid peptide hormone encoded by the obesity (ob) gene and secreted by white adipocytes. Blood leptin concentrations are increased in obese individuals. Leptin is a satiety hormone that provides negative feedback to the hypothalamus, controlling appetite and energy expenditure. Leptin binds to presynaptic GABAergic neurons to produce its effect, raising the distinct possibility that GABAergic axon terminals are the ultimate subcellular site of action for its effects. Released into the circulation, leptin crosses the blood-brain barrier and binds to leptin receptors, influencing the activity of various hypothalamic neurons, as well as encoding orexigenic and anorexigenic neuropeptides. Moreover, leptin affects a wide range of metabolic functions in the peripheral tissue. In this review, we discuss some physiologic functions of leptin, including effects on obesity and some effects of leptin replacement therapy.

Topics: Animals; Energy Metabolism; Hormone Replacement Therapy; Humans; Leptin; Obesity; Receptors, Leptin

Obesity and diabetes are major causes of CKD and ESRD, and are thus enormous health concerns worldwide. Both obesity and diabetes, along with other elements of the metabolic syndrome including hypertension, are highly interrelated and contribute to the development and progression of renal disease. Studies show that multiple factors act in concert to initially cause renal vasodilation, glomerular hyperfiltration, and albuminuria, leading to the development of glomerulopathy. The coexistence of hypertension contributes to the disease progression, which, if not treated, may lead to ESRD. Although early intervention and management of body weight, hyperglycemia, and hypertension are imperative, novel therapeutic approaches are also necessary to reduce the high morbidity and mortality associated with both obesity-related and diabetes-related renal disease.

Topics: Adiponectin; Animals; Cardiovascular Diseases; Cytokines; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Disease Progression; Early Medical Intervention; Glomerular Filtration Rate; Humans; Kidney; Kidney Failure, Chronic; Leptin; Medication Therapy Management; Mice; Models, Animal; Obesity; Risk Reduction Behavior

Obesity is a major worldwide health problem. Excess weight gain is the most significant preventable cause of increased blood pressure (BP) in patients with essential hypertension and increases the risk for cardiovascular and renal diseases. Our goal is to review the mechanisms that link obesity with hypertension, with special emphasis on the role of leptin and the brain melanocortin system in driving sympathetic activation in obesity.. Despite increased interest in obesity as a major risk for developing hypertension, the precise mechanisms linking excess weight gain with increases in BP are still elusive. Current evidence suggests that increased sympathetic nervous system (SNS) activity contributes to impaired renal-pressure natriuresis and sodium retention in obesity. Recent findings indicate that the adipocyte-derived hormone, leptin, activates brain centers that regulate SNS activity through a melanocortin-system-dependent pathway. The interaction of leptin and the brain melanocortin system represents an important area of research to further our understanding of the mechanisms leading to sympathetic activation in obesity.. Sympathetic overactivity is an important link between excess weight gain and increased BP. Hormones and cytokines secreted by the adipose tissue that interact with neural pathways (e.g. melanocortin system) appear to play a key role in contributing to sympathetic activation in obesity and represent potential new targets for therapies.

Topics: Adipocytes; Animals; Blood Pressure; Central Nervous System; Humans; Hypertension; Leptin; Melanocortins; Obesity; Receptor, Melanocortin, Type 4; Signal Transduction; Sympathetic Nervous System; Weight Gain

Adipokines, that is factors secreted by adipose tissue, act through a network of autocrine, paracrine, and endocrine pathways to regulate several aspects of physiology, including glucose and lipid metabolism, neuroendocrine function, reproduction, and cardiovascular function. In particular, adiponectin, a 30-kDa protein, is associated with the regulation of insulin sensitivity, and its levels in serum are affected by altered metabolic homeostasis. Adiponectin effects are mediated by adiponectin receptors, which occur as two isoforms (AdipoR1 and AdipoR2). Transcriptional regulation of adiponectin is by the peroxisome proliferator-activated receptor-gamma (PPAR-γ). However, acting through AdipoR1 and AdipoR2, adiponectin enhances 5' adenosine monophosphate-activated protein kinase (AMPK) and the PPARα-mediated pathways in the liver and skeletal muscles. Adiponectin receptors mediate a wide spectrum of metabolic reactions, including gluconeogenesis and fatty-acid oxidation. Altogether, adiponectin deficiency and/or decreased adiponectin receptor-mediated activity possibly contribute to insulin resistance in metabolic syndromes, coronary heart disease, and liver disease.

Topics: Energy Metabolism; Homeostasis; Humans; Insulin; Leptin; Obesity; Receptors, Adiponectin

Obesity and its related metabolic diseases have reached a pandemic level worldwide. There are sex differences in the prevalence of obesity and its related metabolic diseases, with men being more vulnerable than women; however, the prevalence of these disorders increases dramatically in women after menopause, suggesting that sex steroid hormone estrogens play key protective roles against development of obesity and metabolic diseases. Estrogens are important regulators of several aspects of metabolism, including body weight and body fat, caloric intake and energy expenditure, and glucose and lipid metabolism in both males and females. Estrogens act in complex ways on their nuclear estrogen receptors (ERs) ERα and ERβ and transmembrane ERs such as G protein-coupled estrogen receptor. Genetic tools, such as different lines of knockout mouse models, and pharmacological agents, such as selective agonists and antagonists, are available to study function and signaling mechanisms of ERs. We provide an overview of the evidence for the physiological and cellular actions of ERs in estrogen-dependent processes in the context of energy homeostasis and body fat regulation and discuss its pathology that leads to obesity and related metabolic states.

Topics: Animals; Energy Metabolism; Homeostasis; Humans; Leptin; Obesity; Receptors, Estrogen; Receptors, G-Protein-Coupled

Short sleep duration and obesity are common occurrence in today's society. An extensive literature from cross-sectional and longitudinal epidemiological studies shows a relationship between short sleep and prevalence of obesity and weight gain. However, causality cannot be inferred from such studies. Clinical intervention studies have examined whether reducing sleep in normal sleepers, typically sleeping 7-9 h/night, can affect energy intake, energy expenditure, and endocrine regulators of energy balance. The aim of this review is to evaluate studies that have assessed food intake, energy expenditure, and leptin and ghrelin levels after periods of restricted and normal sleep. Most studies support the notion that restricting sleep increases food intake, but the effects on energy expenditure are mixed. Differences in methodology and component of energy expenditure analyzed may account for the discrepancies. Studies examining the effects of sleep on leptin and ghrelin have provided conflicting results with increased, reduced, or unchanged leptin and ghrelin levels after restricted sleep compared to normal sleep. Energy balance of study participants and potential sex differences may account for the varied results. Studies should strive for constant energy balance and feeding schedules when assessing the role of sleep on hormonal profile. Although studies suggest that restricting sleep may lead to weight gain via increased food intake, research is needed to examine the impact on energy expenditure and endocrine controls. Also, studies have been of short duration, and there is little knowledge on the reverse question: does increasing sleep duration in short sleepers lead to negative energy balance?

Topics: Eating; Energy Intake; Energy Metabolism; Ghrelin; Humans; Leptin; Obesity; Sleep; Sleep Deprivation; Time Factors

Obesity is now growing at an alarming rate reaching epidemic proportions worldwide thus increasing morbidity and mortality rates for chronic disease. But although we have ample information on the complications associated with obesity, precisely what causes obesity remains poorly understood. Some evidence attributes a major role to a low-grade chronic inflammatory state (neurogenic inflammation) induced in obesity by inflammatory mediators produced and secreted within the expanded activated adipocyte pool. Adipose tissue is an endocrine organ that secretes numerous adipose tissue-specific or enriched hormones, known as adipokines, cytokine-like molecules thought to play a pathogenic role in cardiovascular diseases. The imbalance between increased inflammatory stimuli and decreased anti-inflammatory mechanisms may depend on chronic stress. Hence the positive correlation found between stress, obesity and cardiovascular diseases. The chronic inflammatory state associated with insulin resistance and endothelial dysfunction is highly deleterious for vascular function. This review focuses on the proposed neuroimmunodulatory mechanisms linking chronic (psychological) stress, obesity and cardiovascular diseases.

Topics: Allostasis; Cardiovascular Diseases; Comorbidity; Extracellular Matrix; Humans; Inflammation; Leptin; Macrophages; Neuroimmunomodulation; Obesity; Risk Factors; Stress, Psychological

Maternal obesity is associated with increased risks of pregnancy complications. Excessive fat mass, common to obese women, has the potential to influence production and secretion of adipose tissue derived proteins called adipokines. The adipokine leptin is involved in the regulation of multiple aspects of maternal metabolic homeostasis. In addition, leptin has been shown to be important for placentation and maternal-fetal exchanges processes regulating growth and development. In later stages of a healthy pregnancy, central leptin resistance occurs to allow increased nutrient availability for the fetus. Disruption of the signaling capacity of leptin associated with obesity is emerging as a potential risk factor leading to pregnancy complications as a result of aberrant fuel partitioning in utero. In this review we discuss the influence of obesity on the roles of leptin and leptin resistance at the central and placental level.

Topics: Adipose Tissue; Adult; Drug Resistance; Female; Humans; Leptin; Maternal-Fetal Exchange; Obesity; Placenta; Pregnancy; Pregnancy Complications; Signal Transduction

The number of obese or overweight humans continues to increase worldwide. Hypertension is a serious disease that often develops in obesity, but it is not clear how obesity increases the risk of hypertension. However, both obesity and hypertension increase the risk of cardiovascular diseases (CVD). In this review, we examine how obesity may increase the risk of developing hypertension. Specifically, we discuss how the adipose-derived hormone leptin influences the sympathetic nervous system (SNS), through actions in the brain to elevate energy expenditure (EE) while also contributing to hypertension in obesity.

Topics: Brain; Energy Metabolism; Humans; Hypertension; Leptin; Obesity

Polycystic ovary syndrome (PCOS) is the most common endocrinopathy associated with infertility and metabolic disorder in women of reproductive age. Dysfunction of adipose tissue has been implicated in the pathophysiology of PCOS. Increasing evidence shows that the dysregulated expression of adipokines, the secreted products of adipose tissue, plays an important role in the pathology of PCOS. Here, we review the role of several identified adipokines that may act as a link between obesity and PCOS. PCOS also reciprocally influences the profile of adipokines. Insight into the underlying mechanisms will help better understand the pathology of PCOS and identify new therapeutic targets of this syndrome.

Topics: Acute-Phase Proteins; Adipokines; Chemokines; Cytokines; Female; GPI-Linked Proteins; Humans; Intercellular Signaling Peptides and Proteins; Lectins; Leptin; Lipocalin-2; Lipocalins; Nicotinamide Phosphoribosyltransferase; Obesity; Polycystic Ovary Syndrome; Proto-Oncogene Proteins; Resistin; Retinol-Binding Proteins, Plasma

The rapidly increasing prevalence of obesity confers a huge health burden globally. The hypothalamus plays a central role in the regulation of energy homeostasis by integrating multiple metabolic signals from peripheral organs and modulating feeding behavior and energy metabolism. Leptin, a key appetite-regulating hormone derived from the white adipose tissue, primarily acts on hypothalamic neurons to activate catabolic pathway and inhibit anabolic pathway, which can result in anorexia and weight reduction. Despite striking obesity resulting from leptin deficiency, treatment with this hormone in human obesity has been unsuccessful due to leptin resistance. In this review, we describe recent researches extending our understanding of obesity-associated hypothalamic leptin resistance.

Topics: Animals; Body Weight; Energy Metabolism; Homeostasis; Humans; Hypothalamus; Leptin; Obesity

Besides the well-characterized effects of brain insulin and leptin in regulating food intake, insulin and leptin signaling to the central nervous system modulates a variety of metabolic processes, such as glucose and lipid homeostasis, as well as energy expenditure. This review summarizes the current literature on the contribution of central nervous insulin and leptin action to metabolic control in animals and humans. Potential therapeutic options based on the direct delivery of these peptides to the brain by, for example, intranasal administration, are discussed.

Topics: Animals; Brain; Energy Metabolism; Humans; Insulin; Leptin; Obesity; Signal Transduction

The use of translational noninvasive neuroimaging has revealed that drug addiction and obesity share striking similarities in functional impairment in discrete brain regions and neurotransmitter circuits. Imaging experiments in both humans and rodents (using complementary experimental designs) show similar abnormalities in brain glucose metabolism in the prefrontal cortex (involved in inhibitory control) and hippocampus (memory) as well as impairments in dopamine signaling in the striatum (involved in food and drug reward, goal orientation, motivation, and habit formation). In both species, many of these observations have been obtained through concurrent and parallel monitoring of both brain activity and behavioral manifestations during drug administration, food sensory (visual, olfactory) stimulation, and craving. This review aims to show that noninvasive brain imaging strategies such as small animal positron emission tomography offer significant potential and promise for modeling motivational disorders such as drug addiction and obesity in humans. Rodent addiction models will prove valuable for understanding brain responses to drug cues and will help guide treatment, especially in relapse situations triggered by exposure to conditioned drug cues.

Topics: Animals; Dopamine; Humans; Leptin; Magnetic Resonance Imaging; Neuroimaging; Obesity; Positron-Emission Tomography; Substance-Related Disorders

One of the major contributing factors to the continuous rise in obesity rates is the increase in caloric intake, which is driven to a large extent by the ease of access and availability of palatable high-fat, high-sugar 'junk foods'. It is also clear that some individuals are more likely to overindulge in these foods than others; however, the factors that determine an individual's susceptibility towards the overconsumption of palatable foods are not well understood. There is growing evidence that an increased preference for these foods may have its origins early in life. Recent work from our group and others has reported that in utero and early life exposure to these palatable foods in rodents increased the offspring's preference towards foods high in fat and sugar. One of the potential mechanisms underlying the programming of food preferences is the altered development of the mesolimbic reward system, a system that plays an important role in driving palatable food intake in adults. The aim of this review is to explore the current knowledge of the programming of food preferences, a relatively new and emerging area in the DOHAD field, with a particular focus on maternal overnutrition, the development of the mesolimbic reward system and the biological mechanisms which may account for the early origins of an increased preference for palatable foods.

Topics: Adult; Animals; Feeding Behavior; Female; Fetal Development; Humans; Insulin; Leptin; Limbic System; Maternal Nutritional Physiological Phenomena; Obesity; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Receptors, Dopamine; Receptors, Opioid

Leptin and adiponectin are adipokines produced by the white adipose tissue. The adipokines have been shown to be valuable quantitative markers of adiposity in dogs. Leptin positively correlates with body condition score (BCS) in dogs, regardless of age, sex and breed, and is influenced by feeding state, pharmacological treatment and thyroid gland activity. Conversely, adiponectin negatively correlates with body fat mass and is therefore more abundant in lean animals. The implication of leptin and adiponectin in the pathogenesis of metabolic syndrome is well established in humans, but currently lacking in dogs. Additional studies are necessary to demonstrate their potential usefulness for monitoring the progression of obesity-related diseases and response to treatment. To date, measurement of canine leptin and adiponectin has been used in experimental studies only, whereas bodyweight and BCS are considered the first-approach parameters for the routine assessment of body fat content in obese dogs.

Topics: Adiponectin; Animals; Dog Diseases; Dogs; Leptin; Obesity

Polymorphisms in adipokine genes, such as leptin (LEP), leptin receptor (LEPR), resistin (RETN), adiponectin (ADIPOQ), interleukin-1β (IL-1β), IL-6 (IL-6), and tumor necrosis factor-α (TNF-α) may be involved in the development of obesity. We conducted a systematic review of published evidence on the association between different adipokine genes and the risk of obesity. Librarian-designed searches of PubMed and HuGeNet, review of reference lists from published reviews and content expert advice identified potentially eligible studies. The genotyping information and polymorphisms of different adipokine genes, numbers of genotyped cases and controls and frequencies of genotypes were extracted from 48 eligible studies included in this review. Twenty-one polymorphisms each associated with obesity in at least one study were identified. Polymorphisms in the adipokine genes, LEP, LEPR, and RETN were not associated with obesity susceptibility, whereas ADIPOQ G276T (T vs. G: odds ratio (OR), 1.59; 95% confidence interval (CI), 1.39-1.81), IL-1β C3953T (CC vs. CT+TT: OR, 1.61; 95% CI, 1.18-2.20), and TNF-α G308A (GG vs. GA+AA: OR, 1.19; 95% CI, 1.02-1.39) polymorphisms were associated with an increased risk of obesity. The IL-6 G174C polymorphism was also associated obesity when using allelic comparisons, the recessive genetic model and the dominant genetic model with OR (95% CI) of 1.95 (1.37-2.77), 1.44 (1.15-1.80), and 1.36 (1.16-1.59), respectively. No significant evidence of publication bias was present. However, these "null" results were underpowered due to a small pooled sample size, and analysis of additional case-control studies with larger sample sizes should provide further clarifications.

Topics: Adipokines; Adiponectin; Case-Control Studies; China; Female; Genetic Predisposition to Disease; Genotype; Humans; Interleukin-1beta; Interleukin-6; Leptin; Male; Obesity; Polymorphism, Single Nucleotide; Receptors, Leptin; Resistin; Tumor Necrosis Factor-alpha

The discovery of the adipocyte hormone leptin completely changed our view of energy metabolism. In addition, the discovery of leptin rapidly progressed to clinical development. After a decade of clinical studies, leptin appears not to be the magic bullet therapy for obesity; however, it has a robust role in rare human conditions characterized by its deficiency. Recent exciting work from the Unger laboratory suggests that leptin therapy may also have a potential role for the treatment of Type 1 diabetes. In this review we discuss the positive evidence why such an approach is worthwhile. In order to achieve this broad goal, we reviewed available literature and provided our interpretation of the evidence presented in the original research papers. The potential cautionary aspects of this novel approach will be discussed in an accompanying article.

Topics: Adipocytes; Animals; Diabetes Mellitus, Type 1; Energy Metabolism; Humans; Leptin; Lipid Metabolism; Lipodystrophy; Mutation; Obesity; Receptor, Insulin

Obesity and the accompanying metabolic syndrome are among the most important causes of cardiovascular pathologies associated with endothelial dysfunction, such as arterial hypertension and atherosclerosis. This detrimental effect of obesity is mediated, in part, by excessive production of the adipose tissue hormone leptin. Under physiological conditions leptin induces endothelium-dependent vasorelaxation by stimulating nitric oxide (NO) and endothelium-derived hyperpolarizing factor (EDHF). Leptin activates endothelial NO synthase (eNOS) through a mechanism involving AMP-activated protein kinase (AMPK) and protein kinase B/Akt, which phosphorylates eNOS at Ser(1177) , increasing its activity. Under pathological conditions, such as obesity and metabolic syndrome, the NO-mediated vasodilatory effect of leptin is impaired. Resistance to the acute NO-mimetic effect of leptin is accounted for by chronic hyperleptinaemia and may result from different mechanisms, such as downregulation of leptin receptors, increased levels of circulating C-reactive protein, oxidative stress and overexpression of suppressor of cytokine signalling-3. In short-lasting obesity, impaired leptin-induced NO production is compensated by EDHF; however, in advanced metabolic syndrome, the contribution of EDHF to the haemodynamic effect of leptin becomes inefficient. Resistance to the vasodilatory effects of leptin may contribute to the development of arterial hypertension owing to unopposed stimulation of the sympathetic nervous system by this hormone.

Topics: Animals; Blood Pressure; Endothelium, Vascular; Humans; Hypertension; Leptin; Metabolic Syndrome; Obesity; Vasodilation

Obesity is linked to increased risk of colon cancer, currently the third most common cancer. Consequently rising levels of obesity worldwide are likely to significantly impact on obesity-related colon cancers in the decades to come. Understanding the molecular mechanisms whereby obesity increases colon cancer risk is thus a focus for research to inform strategies to prevent the increasing trend in obesity-related cancers. This review will consider research on deregulation of adipokine signalling, a consequence of altered adipokine hormone secretion from excess adipose tissue, with a focus on leptin, which has been studied extensively as a potential mediator of obesity-related colon cancer. Numerous investigations using colon cell lines in vitro, in vivo studies in rodents and investigations of colon cancer patients illuminate the complexity of the interactions of leptin with colon tissues via leptin receptors expressed by the colon epithelium. Although evidence indicates a role for leptin in proliferation of colon epithelial cells in vitro, this has been contradicted by studies in rodent models. However, recent studies have indicated that leptin may influence inflammatory mediators linked with colon cancer and also promote cell growth dependent on genotype and is implicated in growth promotion of colon cancer cells. Studies in human cancer patients indicate that there may be different tumour sub-types with varying levels of leptin receptor expression, indicating the potential for leptin to induce variable responses in the different tumour types. These studies have provided insights into the complex interplay of adipokines with responsive tissues prone to obesity-related colon cancer. Deregulation of adipokine signalling via adipokine receptors located in the colon appears to be a significant factor in obesity-related colon cancer. Molecular profiling of colon tumours will be a useful tool in future strategies to characterise the influence that adipokines may have on tumour development and subsequent therapeutic intervention. Study of the molecular mechanisms linking obesity with cancer also supports recommendations to maintain a normal body weight to reduce the risk of colon cancer.

Topics: Adipose Tissue; Animals; Colon; Colonic Neoplasms; Humans; Inflammation Mediators; Intestinal Mucosa; Leptin; Obesity; Receptors, Leptin

Obesity markedly increases the risk of hypertension and cardiovascular disease, which may be related to activation of the sympathetic nervous system (SNS). Sympathetic overactivity directly and indirectly contributes to blood pressure (BP) elevation in obesity, including stimulation of the renin-angiotensin-aldosterone system (RAAS). The adipocyte-derived peptide leptin suppresses appetite, increases thermogenesis, but also raises SNS activity and BP. Obese individuals exhibit hyperleptinemia but are resistant to its appetite-suppressing actions. Interestingly, animal models of obesity exhibit preserved sympathoexcitatory and pressor actions of leptin, despite resistance to its anorexic and metabolic actions, suggesting selective leptin resistance. Disturbance of intracellular signaling at specific hypothalamic neural networks appears to underlie selective leptin resistance. Delineation of these pathways should lead to novel approaches to treatment. In the meantime, treatment of obesity-hypertension has relied on antihypertensive drugs. Although sympathetic blockade is mechanistically attractive in obesity-hypertension, in practice its effects are disappointing because of adverse metabolic effects and inferior outcomes. On the basis of subgroup analyses of obese patients in large randomized clinical trials, drugs such as diuretics and RAAS blockers appear superior in preventing cardiovascular events in obesity--hypertension. An underused alternative approach to obesity-hypertension is induction of weight loss, which reduces circulating leptin and insulin, partially reverses resistance to these hormones, decreases sympathetic activation and improves BP and other risk factors. Though weight loss induced by lifestyle is often modest and transient, carefully selected pharmacological weight loss therapies can produce substantial and sustained antihypertensive effects additive to lifestyle interventions.

Topics: Humans; Hypertension; Leptin; Obesity; Renin-Angiotensin System; Sympathetic Nervous System; Weight Loss

Circadian rhythms (approximately 24h) are widely characterized at molecular level and their generation is acknowledged to originate from oscillations in expression of several clock genes and from regulation of their protein products. While general entrainment of organisms to environmental light-dark cycles is mainly achieved through the master clock of the suprachiasmatic nucleus in mammals, this molecular clockwork is functional in several organs and tissues. Some studies have suggested that disruption of the circadian system (chronodisruption (CD)) may be causal for manifestations of the metabolic syndrome. This review summarizes (1) how molecular clocks coordinate metabolism and their specific role in the adipocyte; (2) the genetic aspects of and scientific evidence for obesity as a chronobiological illness; and (3) CD and its causes and pathological consequences. Finally, ideas about use of chronobiology for the treatment of obesity are discussed.

Topics: Adiponectin; Adipose Tissue; Animals; ARNTL Transcription Factors; Cardiovascular Diseases; Chronotherapy; Circadian Rhythm; Cryptochromes; Female; Gene Expression Regulation; Humans; Jet Lag Syndrome; Leptin; Male; Mammals; Metabolic Syndrome; Neoplasms; Obesity; Period Circadian Proteins; PPAR gamma; Receptors, Adiponectin; Receptors, Leptin

To evaluate the laboratory diagnosis aspects of obesity-related health problems with special reference to postmenopausal breast cancer.. We conducted a systemic search of the literature primarily from the PubMed to obtain the relevant data.. Obesity is associated with the dysregulations of a number of body components such as blood constituents, extracellular matrix, and hormones/growth factors axes, which could be utilized for early diagnosis.. Obesity-related disorders including breast cancer have emerged as major health problems in almost all the nations. There is a need to elucidate different biochemical markers that are being used in the clinics or have the potential for such use. A precise understanding of the complex pathologies related with obesity is useful in prevention, early diagnosis and overall clinical management.

Topics: Biomedical Research; Breast Neoplasms; Female; Humans; Insulin Resistance; Intercellular Signaling Peptides and Proteins; Leptin; Obesity; Postmenopause

Amylin is an important control of nutrient fluxes because it reduces energy intake, modulates nutrient utilization by inhibiting postprandial glucagon secretion, and increases energy disposal by preventing compensatory decreases of energy expenditure in weight-reduced individuals. The best investigated function of amylin which is cosecreted with insulin is to reduce eating by promoting meal-ending satiation. This effect is thought to be mediated by a stimulation of specific amylin receptors in the area postrema. Secondary brain sites to mediate amylin action include the nucleus of the solitary tract and the lateral parabrachial nucleus, which convey the neural signal to the lateral hypothalamic area and other hypothalamic nuclei. Amylin may also signal adiposity because plasma levels of amylin are increased in adiposity and because higher amylin concentrations in the brain result in reduced body weight gain and adiposity, while amylin receptor antagonists increase body adiposity. The central mechanisms involved in amylin's effect on energy expenditure are much less known. A series of recent experiments in animals and humans indicate that amylin is a promising option for anti-obesity therapy especially in combination with other hormones. The most extensive dataset is available for the combination therapy of amylin and leptin. Ongoing research focuses on the mechanisms of these interactions.

Topics: Adiposity; Animals; Anti-Obesity Agents; Brain Stem; Energy Metabolism; Female; Gastric Emptying; Homeostasis; Humans; Insulin; Islet Amyloid Polypeptide; Leptin; Male; Mice; Obesity; Rats; Receptors, Islet Amyloid Polypeptide; Satiation

The adipose tissue has pleiotropic functions far beyond the mere storage of energy, and it secretes a number of hormones and cytokines, called adipokines, which have biological effects that impact heath and disease. Adipokines are markedly elevated in the plasma of uremic patients, mainly due to decreased renal excretion. They have pluripotent signaling effects on inflammation/oxidative stress (leptin, adiponectin, resistin), protein-energy wasting (leptin, adiponectin), insulin signaling (adiponectin, leptin, visfatin), endothelial dysfunction (visfatin), and vascular damage (adiponectin, leptin, resistin), which are prevalent in uremic patients. Obesity superimposed to uremia may further aggravate hyperadipokinemia, with the exception of adiponectinemia, which is mitigated by adiposity. Among adipokines and until more data become available, only leptin may be considered as a full uremic toxin owing to adverse effects on protein-energy wasting, cardiovascular damage, inflammation, and the immune system, which have been documented both clinically and experimentally. Resistin and visfatin display some features of uremic toxins, but more data are needed to consider these adipokines as true uremic toxins. In contrast, high levels of adiponectin and chemerin seen in uremia appear to be beneficial. Further research is needed to investigate whether selective removal of leptin, resistin, and visfatin and increments of adiponectin and chemerin levels may have clinical relevance in uremic patients.

Topics: Adipokines; Adiponectin; Adipose Tissue; Drug-Related Side Effects and Adverse Reactions; Humans; Inflammation; Leptin; Nicotinamide Phosphoribosyltransferase; Obesity; Oxidative Stress; Resistin; Signal Transduction; Uremia

The central nervous system (CNS) plays key role in the homeostatic regulation of body weight. Satiation and adiposity signals, providing acute and chronic information about available fuel, are produced in the periphery and act in the brain to influence energy intake and expenditure, resulting in the maintenance of stable adiposity. Diet-induced obesity (DIO) does not result from a failure of these central homeostatic circuits. Rather, the threshold for defended adiposity is increased in environments providing ubiquitous access to palatable, high-fat foods, making it difficult to achieve and maintain weight loss. Consequently, mechanisms by which nutritional environments interact with central homeostatic circuits to influence the threshold for defended adiposity represent critical targets for therapeutic intervention.

Topics: Adiposity; Animals; Central Nervous System; Dietary Fats; Endoplasmic Reticulum Stress; Food Supply; Homeostasis; Humans; Insulin Resistance; Leptin; Models, Biological; Obesity; Protein Kinase C

The hormone leptin, secreted predominantly from adipose tissue, plays a crucial role in the regulation of numerous neuroendocrine functions, from energy homeostasis to reproduction. Genetic deficiency as a consequence of leptin or leptin receptor mutations, although rare in humans, leads to early onset of chronic hyperphagia and massive obesity. In most human obesity, however, leptin levels are chronically elevated. Under these conditions of persistent hyperleptinaemia, and particularly when obesity is associated with a high-fat diet, leptin resistance develops, and signalling through the leptin receptor is curtailed, fuelling further weight gain. Here, we review the role of leptin receptors in the regulation of feeding and obesity development. Leptin receptors are found in each of the major components of the CNS "feeding" circuitry-the brainstem, hypothalamus and distributed reward centres. Through these receptors, leptin exerts influences on signalling and integration within these circuits to alter feeding behaviours. Although some progress is now being made with peptide analogues, the leptin receptor has not proved to be amenable to small molecule pharmacological intervention to date. Where clinical benefit from recombinant leptin administration has been achieved, this has been under circumstances of complete endogenous leptin deficiency or relative hypoleptinaemia such as in lipodystrophy.

Topics: Adipose Tissue; Animals; Appetite Regulation; Brain; Eating; Feeding Behavior; Humans; Leptin; Obesity; Receptors, Leptin; Signal Transduction

Amylin's best investigated function is to reduce eating via a meal size effect by promoting meal-ending satiation. This effect seems to depend on an activation of specific area postrema neurons. Brain areas that convey the neural signal to the forebrain include the nucleus of the solitary tract and the lateral parabrachial nucleus. Acute application of amylin modulates the activity of hypothalamic areas involved in the control of eating, namely, the lateral hypothalamic area and possibly the ventromedial hypothalamic nucleus. Amylin also interacts with other satiating signals, such as cholecystokinin, presumably in the brainstem. Interestingly, amylin also exhibits characteristics of adiposity signals; plasma levels of amylin are higher in obese individuals, chronic infusion of amylin into the brain reduces body weight gain and adiposity, and infusion of amylin antagonists increases adiposity. Furthermore, amylin maintains energy expenditure at higher levels than would be expected considering its body weight-lowering effect. However, much less is known (e.g., site of action, signaling pathways, differential activation of brain sites, and, most importantly, physiological relevance) with respect to its role as adiposity signal and regulator of energy expenditure than about its satiating action. Notwithstanding, and perhaps because amylin resistance does not seem to be a general and prohibitive concomitant of obesity, animal data and recent clinical data in humans indicate that amylin is a very promising candidate for the treatment of obesity. Amylin seems to be particularly effective when combined with other hormones such as leptin.

Topics: Adiposity; Animals; Anti-Obesity Agents; Appetite Regulation; Brain; Eating; Energy Metabolism; Humans; Islet Amyloid Polypeptide; Leptin; Obesity; Satiety Response; Signal Transduction

Acute lymphoblastic leukemia is the most common malignancy in childhood. Continuous progress in risk-adapted treatment for childhood acute lymphoblastic leukemia has secured 5-year event-free survival rates of approximately 80% and 8-year survival rates approaching 90%. Almost 75% of survivors, however, have a chronic health condition negatively impacting on cardiovascular morbidity and mortality. Obesity can be considered one of the most important health chronic conditions in the general population, with an increasing incidence in patients treated for childhood cancers and especially in acute lymphoblastic leukemia survivors who are, at the same time, more at risk of experiencing precocious cardiovascular and metabolic co-morbidities. The hypothalamic-pituitary axis damage secondary to cancer therapies (cranial irradiation and chemotherapy) or to primary tumor together with lifestyle modifications and genetic factors could affect long-term outcomes. Nevertheless, the etiology of obesity in acute lymphoblastic leukemia is not yet fully understood. The present review has the aim of summarizing the published data and examining the most accepted mechanisms and main predisposing factors related to weight gain in this particular population.

Topics: Body Mass Index; Child; Comorbidity; Energy Metabolism; Growth Hormone; Humans; Hypothalamus; Leptin; Life Style; Metabolic Syndrome; Obesity; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Radiotherapy; Risk Factors; Survivors; Weight Gain

Despite a higher incidence and less favorable outcome of malignant tumors in obese patients, much less recognized is the link between obesity and cancer. The mechanism of the association of obesity with carcinogenesis remains incompletely understood. Postulated mechanisms include insulin resistance, insulin-like growth factor signaling, chronic inflammation, immunomodulation, hyperglycemia-induced oxidative stress, and changes of intestinal microbiome. Insulin resistance leads to direct mitogenic and antiapoptotic signaling by insulin and the insulin-like growth factor axis. Obesity can be considered to be a state of chronic low-grade inflammation. In obesity, numerous proinflammatory cytokines are released from adipose tissue which may involve in carcinogenesis. Hyperglycemia in susceptible cells results in the overproduction of superoxide and this process is the key to initiating all damaging pathways related to diabetes. This hyperglycemia-induced oxidative stress could be one possible link among obesity, diabetes, and cancer development. The role of obesity-related changes in the intestinal microbiome in gastrointestinal carcinogenesis deserves further attention.

Topics: Adipokines; Gastrointestinal Neoplasms; Humans; Inflammation; Insulin; Leptin; Obesity; Oxidative Stress; Somatomedins

A number of studies to better understand the complex physiological mechanism involved in regulating body weight have been conducted. More specifically, the hormones related to appetite, leptin and ghrelin, and their association to obesity have been a focus of investigation. Circadian patterns of these hormones are a new target of research. The behaviour of these hormones in individuals subject to atypical working times such as shiftwork remains unclear. Shiftwork is characterized by changes in biological rhythms and cumulative circadian phase changes, being associated with high rates of obesity and metabolic syndrome. Truck drivers, who work irregular shifts, frequently present a high prevalence of obesity, which might be associated with work-related factors and/or lifestyle. In this context, the aim of this paper was to discuss the relationship of body mass index, appetite-related hormones and sleep characteristics in truck drivers who work irregular shifts compared with day workers.

Topics: Circadian Rhythm; Energy Metabolism; Ghrelin; Humans; Leptin; Metabolic Diseases; Motor Vehicles; Obesity; Occupational Diseases; Transportation; Work Schedule Tolerance

Obesity and the metabolic syndrome (MS) are growing epidemics associated with an increased risk for many types of cancer. In the liver, inflammatory and angiogenic changes due to insulin resistance and fatty liver disease are associated with an increased incidence of liver cancer. Regardless of underlying liver disease, cirrhosis remains the most important risk factor for hepatocellular carcinoma (HCC) although rare cases of HCC arising without cirrhosis raise the possibility of a direct carcinogenesis secondary to nonalcoholic fatty liver disease (NAFLD). Moreover, MS and its different features may also increase the risk of HCC in the setting of chronic liver diseases of other causes such as viral hepatitis or alcohol abuse. Taking into account all these data, it is necessary to better determine the risk of developing HCC in patients with MS to improve the screening guidelines and develop prophylactic treatments in this setting.

Topics: Adiponectin; Carcinoma, Hepatocellular; Diabetes Complications; Disease Progression; Fatty Liver; Hepatitis C, Chronic; Humans; Leptin; Liver Neoplasms; Metabolic Syndrome; Non-alcoholic Fatty Liver Disease; Obesity; Risk Factors

Polycystic ovary syndrome (PCOS) is the most frequent female endocrine disorder, affecting 5%-10% of women, causing infertility due to dysfunctional follicular maturation and ovulation, distinctive multicystic ovaries and hyperandrogenism, together with metabolic abnormalities including obesity, hyperinsulinism, an increased risk of type 2 diabetes, and cardiovascular disease. The etiology of PCOS is unclear, and decisive clinical studies are limited by ethical and logistic constraints. Consequently treatment is palliative rather than curative and focuses on symptomatic approaches. Hence, a suitable animal model could provide a valuable means with which to study the pathogenesis of the characteristic reproductive and metabolic abnormalities and thereby identify novel and more effective treatments. So far there is no consensus on the best experimental animal model, which should ideally reproduce the key features associated with human PCOS. The prenatally androgenized rhesus monkey displays many characteristics of the human condition, including hyperandrogenism, anovulation, polycystic ovaries, increased adiposity, and insulin insensitivity. However, the high cost of nonhuman primate studies limits the practical utility of these large-animal models. Rodent models, on the other hand, are inexpensive, provide well-characterized and stable genetic backgrounds readily accessible for targeted genetic manipulation, and shorter reproductive life spans and generation times. Recent rodent models display both reproductive and metabolic disturbances associated with human PCOS. This review aimed to evaluate the rodent models reported to identify the advantages and disadvantages of the distinct rodent models used to investigate this complex endocrine disorder.

Topics: Androgens; Animals; Aromatase Inhibitors; Disease Models, Animal; Estrogens; Female; Humans; Leptin; Luteinizing Hormone; Mice; Mutation; Obesity; Plasminogen Activator Inhibitor 1; Polycystic Ovary Syndrome; Progestins; Rats; Receptors, Leptin

It is now well accepted that early life events can contribute substantially to the likelihood of an individual becoming obese, although many of the mechanisms for this are not well understood. Maternal over- and under-nutrition as well as the postnatal nutritional environment can contribute significantly to obesity throughout life. This review will provide an overview of early life events associated with neuroendocrine programming of obesity and metabolic dysfunction. In particular this review will focus on the long-term impact of perinatal nutrition, as well as the perinatal role of leptin, insulin, and glucocorticoids in programming the hypothalamic circuitry responsible for appropriate regulation of feeding and metabolism throughout life.

Topics: Female; Glucocorticoids; Humans; Hypothalamus; Infant, Newborn; Insulin; Leptin; Maternal Nutritional Physiological Phenomena; Obesity; Pregnancy; Prenatal Exposure Delayed Effects

Currently, obesity presents one of the biggest health problems. Management strategies for weight reduction in obese individuals include changes in life style such as exercise and diet, behavioral therapy, and pharmacological treatment, and in certain cases surgical intervention. Diet and exercise are best for both prevention and treatment, but both require much discipline and are difficult to maintain. Drug treatment of obesity offer a possible adjunct, but it may only have modest results, limited by side effects; furthermore, the weight lowering effects last only as long as the drug is being taken and, unfortunately, as soon as the administration is stopped, the weight is regained. These strategies should be used in a combination for higher efficacy. Drugs used to induce weight loss have various effects: they increase satiety, reduce the absorption of nutrients or make metabolism faster; but their effect is usually moderate. In the past, several drugs were used in the pharmacological therapy of weight reduction including thyroid hormone, dinitrophenol, amphetamines and their analogues, e.g. fenfluramine, At present, only orlistat is available in the long term treatment (≥ 24 weeks) of obesity as sibutramine and rimonabant were withdrawn form the market. Several new anti-obesity drugs are being tested at present, and liraglutide, a GLP-1 analogue (incretin mimetic), is the most promising one.

Topics: Amides; Anti-Obesity Agents; Anticonvulsants; Antidepressive Agents; Basal Metabolism; Benzazepines; Benzoxazines; Body Mass Index; Bridged Bicyclo Compounds, Heterocyclic; Ciliary Neurotrophic Factor; Clinical Trials as Topic; Combined Modality Therapy; Cyclobutanes; Dexfenfluramine; Fatty Acids; Female; Fenfluramine; Glucagon-Like Peptide 1; Human Growth Hormone; Humans; Intestinal Absorption; Lactones; Leptin; Life Style; Liraglutide; Male; Norepinephrine; Obesity; Obesity, Morbid; Orlistat; Piperidines; Pyrazoles; Pyridines; Receptor, Melanocortin, Type 4; Rimonabant; Satiation; Serotonin; Sodium-Glucose Transport Proteins; Sucrose; Thyroid Hormones

Leptin levels during the perinatal period are important for the development of metabolic systems involved in energy homeostasis. In rodents, there is a postnatal leptin surge, with circulating leptin levels increasing around postnatal day (PND) 5 and peaking between PND 9 and PND 10. At this time circulating leptin acts as an important trophic factor for the development of hypothalamic circuits that control energy homeostasis and food seeking and reward behaviors. Blunting the postnatal leptin surge results in long-term leptin insensitivity and increased susceptibility to diet-induced obesity during adulthood. Pharmacologically increased leptin levels in the postnatal period also have long-term effects on metabolism. Nevertheless, this effect is controversial as postnatal hyperleptinemia is reported to both increase and decrease the predisposition to obesity in adulthood. The different effects reported in the literature could be explained by the different moments at which this hormone was administered, suggesting that modifications of the neonatal leptin surge at specific time points could selectively affect the development of central and peripheral systems that are undergoing modifications at this moment resulting in different metabolic and behavioral outcomes. In addition, maternal nutrition and the hormonal environment during pregnancy and lactation may also modulate the offspring's response to postnatal modifications in leptin levels. This review highlights the importance of leptin levels during the perinatal period in the development of metabolic systems that control energy homeostasis and how modifications of these levels may induce long-lasting and potentially irreversible effects on metabolism.

Topics: Animals; Energy Metabolism; Female; Humans; Hypothalamus; Infant, Newborn; Leptin; Maternal Nutritional Physiological Phenomena; Metabolome; Obesity; Pregnancy

A focus of much cancer research is at the molecular and cellular levels. In contrast, the effects of social interactions and psychological state are less investigated, and considered by many a "soft" science. Yet several highly rigorous studies have begun to tease out biochemical pathways by which the brain can influence the development and growth of cancer. Previous reviews have discussed the concept of stress and cancer. Here, we discuss recent work showing environments that are more complex and challenging, but not stressful per se, and that have robust effects on peripheral cancer by activating a specific neuroendocrine brain-adipocyte axis. These enriched environments lead to activation of the sympathetic innervation of fat tissue, suppression of leptin, and a reduction in cancer proliferation by inducing hypothalamic BDNF expression. We summarize this work and discuss how these data integrate into the body of literature regarding stress, the environment, and cancer.

Topics: Adipocytes; Animals; Brain; Brain-Derived Neurotrophic Factor; Environment; Humans; Hypothalamus; Leptin; Loneliness; Models, Biological; Neoplasms; Obesity; Signal Transduction; Social Support; Stress, Psychological; Sympathetic Nervous System

This paper reviews the literature on the variations in energy intake (EI), energy expenditure (EE) and the factors which may affect the fluctuations in EI across the menstrual cycle. While no significant changes in body weight and body fat percentage have been noted across the cycle, increases in EI and EE have been well documented during the luteal phase in lean women. The occurrence and severity of the premenstrual syndrome (PMS) and food reinforcement are suggested to affect EI. It is not known, however, whether food reinforcement may affect EI across the menstrual cycle. These factors may also affect overweight/obese women differently than normal-weight women at times during which women may be more prone to episodes of overeating during the menstrual cycle. Certain studies have also noted fluctuations in leptin levels across the menstrual cycle, while others have not. It has also been suggested that variations in leptin levels may affect the rewarding value of food in order to maintain proper body weight and adiposity level. We emphasize that future studies should evaluate the variations in energy balance across the cycle in overweight/obese women, as well as the strength of the relationships between food reinforcement and the severity of PMS with energy and macronutrient intakes.

Topics: Adult; Dietary Carbohydrates; Energy Intake; Energy Metabolism; Female; Humans; Leptin; Luteal Phase; Menstrual Cycle; Obesity; Premenstrual Syndrome; Reward

Recombinant methionyl human leptin (r-metHuLeptin) was first used as a replacement therapy in patients bearing inactivating mutations in the leptin gene. In this indication, it was shown since 1999 to be very efficient in inducing a dramatic weight loss in rare children and adults with severe obesity due to the lack of leptin. These first clinical trials clearly showed that r-metHuLeptin acted centrally to reduce food intake, inducing loss of fat mass, and to correct metabolic alterations, immune and neuroendocrine defects. A few years later, r-metHuLeptin was also shown to reverse the metabolic complications associated with lipodystrophic syndromes, due to primary defects in fat storage, which induce leptin deficiency. The beneficial effects, which could be mediated by central and/or peripheral mechanisms, are thought to mainly involve the lowering effects of leptin on ectopic lipid storage, in particular in liver and muscles, reducing insulin resistance. Interestingly, r-metHuLeptin therapy also reversed the hypothalamic-pituitary-gonadal axis dysfunctions associated with hypothalamic amenorrhea. However, if r-metHuLeptin treatment has been shown to be dramatically efficient in leptin-deficient states, its very limited effect in inducing weight loss in common obese patients revealed that, in patients with adequate leptin secretion, mechanisms of leptin resistance and leptin tolerance prevent r-metHuLeptin from inducing any additional effects. This review will present the current data about the effects of r-metHuLeptin therapy in humans, and discuss the recent perspectives of this therapy in new indications.

Topics: Animals; Diabetes Mellitus; Humans; Leptin; Mutation; Obesity

The obesity epidemic is associated with the recent availability of highly palatable and inexpensive caloric food as well as important changes in lifestyle. Genetic factors, however, play a key role in regulating energy balance and numerous twin studies have estimated the BMI heritability between 40 and 70%. While common variants, identified through genome-wide association studies (GWAS) point toward new pathways, their effect size are too low to be of any use in the clinic. This review therefore concentrates on genes and genomic regions associated with very high risks of human obesity. Although there are no consensus guidelines, we review how the knowledge on these "causal factors" can be translated into the clinic for diagnostic purposes. We propose genetic workups guided by clinical manifestations in patients with severe early-onset obesity. While etiological diagnoses are unequivocal in a minority of patients, new genomic tools such as Comparative Genomic Hybridization (CGH) array, have allowed the identification of novel "causal" loci and next-generation sequencing brings the promise of accelerated pace for discoveries relevant to clinical practice.

Topics: Cilia; Comparative Genomic Hybridization; Genetic Testing; Genome-Wide Association Study; Humans; Hypothalamic Diseases; Learning Disabilities; Leptin; Melanocortins; Obesity; Prader-Willi Syndrome; Twins, Dizygotic; Twins, Monozygotic

Food intake and nutritional status modify the physiological responses of the immune system to illness and infection and regulate the development of chronic inflammatory processes, such as kidney disease. Adipose tissue secretes immune-related proteins called adipokines that have pleiotropic effects on both the immune and neuroendocrine systems, linking metabolism and immune physiology. Leptin, an adipose tissue-derived adipokine, displays a variety of immune and physiological functions, and participates in several immune responses. Here, we review the current literature on the role of leptin in kidney diseases, linking adipose tissue and the immune system with kidney-related disorders. The modulation of this adipose hormone may have a major impact on the treatment of several immune- and metabolic-related kidney diseases.

Topics: Adiponectin; Adipose Tissue; Autoimmunity; Energy Metabolism; Humans; Kidney Diseases; Leptin; Nutritional Physiological Phenomena; Obesity

Leptin, an adipocyte-derived cytokine, crosses the blood-brain barrier to act on many regions of the central nervous system (CNS). It participates in the regulation of energy balance, inflammatory processes, immune regulation, synaptic formation, memory condensation, and neurotrophic activities. This review focuses on the newly identified actions of leptin on astrocytes. We first summarize the distribution of leptin receptors in the brain, with a focus on the hypothalamus, where the leptin receptor is known to mediate essential feeding suppression activities, and on the hippocampus, where leptin facilitates memory, reduces neurodegeneration, and plays a dual role in seizures. We will then discuss regulation of the nonneuronal leptin system in obesity. Its relationship with neuronal leptin signaling is illustrated by in vitro assays in primary astrocyte culture and by in vivo studies on mice after pretreatment with a glial metabolic inhibitor or after cell-specific deletion of intracellular signaling leptin receptors. Overall, the glial leptin system shows robust regulation and plays an essential role in obesity. Strategies to manipulate this nonneuronal leptin signaling may have major clinical impact.

Topics: Animals; Astrocytes; Biological Transport; Blood-Brain Barrier; Brain; Energy Metabolism; Hippocampus; Humans; Hypothalamus; Leptin; Mice; Mice, Inbred C57BL; Obesity; Receptors, Leptin

Obese children have a theoretically increased risk of sustaining an extremity fracture because of potential variations in their bone mineral density, serum leptin levels, and altered balance and gait. Trauma databases suggest an increased rate of extremity fractures in obese children and adolescents involved in polytrauma compared with nonobese children and adolescents. Anesthetic and other perioperative concerns for obese pediatric trauma patients undergoing surgery include higher baseline blood pressures, increased rates of asthma, and obstructive sleep apnea. A child's weight must be considered when choosing the type of implant for fixation of pediatric femoral fractures. Fracture prevention strategies in obese pediatric patients consist of ensuring properly sized safety gear for both motor vehicles and sporting activities and implementing structured weight-loss programs.

Topics: Adolescent; Age Factors; Bone Density; Child; Female; Fractures, Bone; Humans; Leptin; Male; Obesity; Postural Balance; Risk Factors

Topics: Animals; Breast Neoplasms; Female; Humans; Leptin; MCF-7 Cells; Mice; Obesity

Growing evidence links the stress at the endoplasmic reticulum (ER) to pathologies such as diabetes mellitus, obesity, liver, heart, renal and neurodegenerative diseases, endothelial dysfunction, atherosclerosis, and cancer. Therefore, identification of molecular pathways beyond ER stress and their appropriate modulation might alleviate the stress, and direct toward novel tools to fight this disturbance. An interesting resident of the ER membrane is protein tyrosine phosphatase 1B (PTP1B), an enzyme that negatively regulates insulin and leptin signaling, contributing to insulin and leptin resistance. Recently, new functions of PTP1B have been established linked to ER stress response. This review evaluates the novel data on ER stressors, discusses the mechanisms beyond PTP1B function in the ER stress response, and emphasizes the potential therapeutic exploitation of PTP1B to relieve ER stress.

Topics: Diabetes Mellitus; Dyslipidemias; Endoplasmic Reticulum Stress; Fatty Liver; Heart Diseases; Humans; Insulin; Kidney Diseases; Leptin; Obesity; Protein Tyrosine Phosphatase, Non-Receptor Type 1

It has been pointed out that obesity is a risk factor for, and is involved in the exacerbation of asthma. Mounting evidence about adipose tissue-derived proteins (adipokines) gave rise to the current understanding of obesity as a systemic inflammatory disorder. In this review, we summarized the involvement of leptin, focusing on eosinophil functions. Several studies have indicated that leptin can restrain eosinophil apoptosis, enhance migration, increase adhesion molecules and induce cytokine production. Since leptin also acts on a variety of immune cells related to allergic response, increased leptin in obese individuals potentially explains the mechanism by which obesity leads to an exacerbation of asthma. Further studies targeting adipokines will delineate the association between obesity and eosinophil-associated diseases.

Topics: Adipose Tissue; Eosinophilia; Humans; Inflammation; Leptin; Obesity

The studies based on candidate genes and encoded proteins known to cause severe obesity in rodents, have shown that these genes also contribute to human early-onset obesity especially for those involved in the leptin pathway: the leptin (LEP) and leptin receptor (LEPR) genes. Since 1997, less than 20 individuals carrying a LEP gene mutation have been identified. Patients are mostly characterized by severe early-onset obesity with severe hyperphagia and associated phenotype such hypogonadotrophic hypogonadism, high rate of infection associated with a deficiency in T cell and abnormalities of sympathetic nerve function. Therapeutic option (subcutaneous daily injection of leptin) is available for patients with LEP deficiency. It results in weight loss, mainly of fat mass, with a major effect on reducing food intake and on other dysfunctions including immunity and induction of puberty even in adults. In LEPR deficient subjects, phenotypic similarities with the LEP-deficient subjects were noticed, especially the exhibited rapid weight gain in the first few months of life, with severe hyperphagia and the endocrine abnormalities (hypogonadotrophic hypogonadism, insufficient somatotrophic or thyreotropic secretion). Leptin treatment is useless in the LEPR deficient subjects. Factors that could possibly bypass normal leptin delivery systems are being developed but are not yet currently available for the treatment of these patients. Measurement of circulating leptin may help for the diagnosis of such obesity: it is undetectable in LEP mutation carriers or extremely elevated in LEPR mutation carriers. Thus, LEPR gene screening might be also considered in subjects with the association of severe obesity with endocrine dysfunctions such as hypogonadism and with leptin related to corpulence level.

Topics: Animals; Humans; Leptin; Obesity; Receptors, Leptin

Recent studies have demonstrated the role of insulin resistance in renal injury related to obesity, with hyperfiltration leading to glomerulomegaly in a pattern similar to that found in diabetic nephropathy. Similarities in the histologic patterns of damage from obesity and diabetes point to overlapping mechanisms of injury. In this review, we will examine the hormonal mechanisms, signaling pathways and injury patterns in renal injury resulting from obesity and attempt to draw conclusions on the reasons for these similarities.

Topics: Adiponectin; Diabetic Nephropathies; Female; Glomerular Filtration Rate; Hemodynamics; Humans; Insulin Resistance; Insulin-Secreting Cells; Kidney; Leptin; Male; Membrane Proteins; Obesity; Podocytes; Resistin; Signal Transduction; Sleep Apnea, Obstructive

A disproportionate expansion of white adipose tissue and abnormal recruitment of adipogenic precursor cells can not only lead to obesity but also impair glucose metabolism, which are both common causes of insulin resistance and diabetes mellitus. The development of novel and effective therapeutic strategies to slow the progression of obesity, diabetes mellitus and their associated complications will require improved understanding of adipogenesis and glucose metabolism. Klotho might have a role in adipocyte maturation and systemic glucose metabolism. Klotho increases adipocyte differentiation in vitro, and mice that lack Klotho activity are lean owing to reduced white adipose tissue accumulation; moreover, mice that lack the Kl gene (which encodes Klotho) are resistant to obesity induced by a high-fat diet. Knockout of Kl in leptin-deficient Lep(ob/ob) mice reduces obesity and increases insulin sensitivity, which lowers blood glucose levels. Energy metabolism might also be influenced by Klotho. However, further studies are needed to explore the possibility that Klotho could be a novel therapeutic target to reduce obesity and related complications, and to determine whether and how Klotho might influence the regulation and function of a related protein, β-Klotho, which is also involved in energy metabolism.

Topics: Animals; Energy Metabolism; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Glucuronidase; Humans; Insulin Resistance; Klotho Proteins; Leptin; Obesity

Epidemiological data have demonstrated that the prevalence of either obesity or hepatocellular carcinoma (HCC) is increasing worldwide during past decades, and obesity has been unequivocally shown to be a risk factor for HCC. It has been reported that a significant proportion of HCC in obesity develops in cryptogenic cirrhosis, which is largely associated with the progression of nonalcoholic fatty liver disease, especially nonalcoholic steatohepatitis. Since the HCC is a highly malignant tumor with a poor prognosis, a better understanding of the molecular mechanisms may help researchers to explore new approaches for preventing and treating the obesity-related HCC, and thereby facilitating a substantial reduction of morbidity and mortality. In this article, we reviewed the mechanisms underlying the relationship between obesity and HCC, with an emphasis on the roles of insulin/insulin-like growth factor axis, adipose tissue derived hormones, oxidative stress, and liver stem cells. In addition, we will discuss the impact of life-style modification on obesity-related HCC.

Topics: Adipokines; Adiponectin; Animals; Carcinoma, Hepatocellular; Growth Substances; Humans; Insulin; Insulin Resistance; Leptin; Life Style; Liver Neoplasms; Models, Biological; Obesity; Oxidative Stress; Risk Factors; Signal Transduction; Somatomedins; Stem Cells

Obesity is an important public health problem worldwide. It increases the risk of many chronic diseases such as diabetes and cardiovascular diseases. Meanwhile, obesity is a major risk factor for several types of cancer including gastric cancer. Possible mechanisms linking obesity with gastric cancer may include obesity associated gastro-oesophageal reflux, insulin resistance, altered levels of adiponectin, leptin, ghrelin, and an abnormally increased blood level of insulin-like growth factor (IGF). Helicobacter pylori (H. pylori) infection is a well-recognized risk factor for peptic ulcer and gastric cancer. Recent studies have revealed an increased prevalence of H. pylori infection in obese patients, providing another clue for the increased incidence of gastric cancer in obese population. If this connection can be confirmed in animal models and a large cohort of patients, then eradicating H. pylori together with life style modification in obese individuals may help prevent the development of gastric cancer in the increasingly obese population.

Topics: Adiponectin; Animals; Gastroenteritis; Gastroesophageal Reflux; Ghrelin; Helicobacter Infections; Helicobacter pylori; Humans; Inflammation; Insulin Resistance; Insulin-Like Growth Factor I; Leptin; Obesity; Risk Factors; Signal Transduction; Stomach Neoplasms

Topics: Allostasis; Anti-Inflammatory Agents; Biomarkers; Body Mass Index; Child; Cholesterol, HDL; Cholesterol, LDL; Dehydroepiandrosterone Sulfate; Humans; Hydrocortisone; Leptin; Obesity; Obesity, Abdominal; Risk Assessment; Risk Factors; Skinfold Thickness; Waist Circumference; Waist-Hip Ratio

Obesity is now recognised as one of the most important risk factors for heart disease. Obese individuals have high circulating levels of leptin, a hormone secreted by adipose tissue and involved in energy homeostasis. Growing evidence suggests that leptin may contribute to the development of cardiac dysfunction. In a large prospective study leptin has been shown to be an independent risk factor for coronary heart disease. An independent positive association has also been found between plasma leptin levels and heart rate in hypertensive patients and heart transplant recipients. In animal studies chronic leptin infusion increased heart rate and blood pressure. It has also been demonstrated that circulating leptin levels are elevated in patients with heart failure. The level of plasma leptin was associated with increased myocardial wall thickness and correlated with left ventricular mass, suggesting a role for this hormone in mediating left ventricular hypertrophy in humans. Moreover, leptin directly induced hypertrophy and hyperplasia in human and rodent cardiomyocytes, accompanied by cardiac extracellular matrix remodelling. Leptin may also influence energy substrate utilisation in cardiac tissue. These findings suggest that leptin acting directly or through the sympathetic nervous system may have adverse effects on cardiac structure and function, and that chronic hyperleptinaemia may greatly increase the risk of cardiac disorders. Additional studies are needed to define the role of leptin in cardiac physiology and pathophysiology, nevertheless the reduction in plasma leptin levels with caloric restriction and weight loss may prevent cardiac dysfunction in obese patients.

Topics: Adipose Tissue; Cardiovascular Diseases; Coronary Artery Disease; Heart Rate; Humans; Hypertension; Hypertrophy, Left Ventricular; Leptin; Myocardium; Myocytes, Cardiac; Obesity; Ventricular Remodeling; Weight Loss

Helicobacter pylori (H. pylori) infection is reported to be associated with many extragastrointestinal manifestations, such as hematological diseases [idiopathic thrombocytopenic purpura (ITP) and unexplained iron deficiency anemia (IDA)], cardiovascular diseases (ischemic heart diseases), neurological disorders (stroke, Parkinson's disease, Alzheimer's disease), obesity and skin disorders. Among these, the best evidence so far is in ITP and unexplained IDA, with high-quality studies showing the improvement of IDA and ITP after H. pylori eradication. The evidence of its association with coronary artery disease is weak and many of the results may be erroneous. The role of H. pylori infection in affecting serum leptin and ghrelin levels has attracted a lot of attention recently and available data to date have been conflicting. There have also been many uncontrolled, small sample studies suggesting an association between H. pylori infection and neurological disorders or chronic urticaria. However, more studies are required to clarify such proposed causal links.

Topics: Anemia, Iron-Deficiency; Cardiovascular Diseases; Ghrelin; Helicobacter Infections; Helicobacter pylori; Humans; Leptin; Nervous System Diseases; Obesity; Purpura, Thrombocytopenic, Idiopathic

Functional magnetic resonance imaging (fMRI) has provided the opportunity to safely investigate the workings of the human brain. This paper focuses on its use in the field of human appetitive behaviour and its impact in obesity research. In the present absence of any safe or effective centrally acting appetite suppressants, a better understanding of how appetite is controlled is vital for the development of new antiobesity pharmacotherapies. Early functional imaging techniques revealed an attenuation of brain reward area activity in response to visual food stimuli when humans are fed-in other words, the physiological state of hunger somehow increases the appeal value of food. Later studies have investigated the action of appetite modulating hormones on the fMRI signal, showing how the attenuation of brain reward region activity that follows feeding can be recreated in the fasted state by the administration of anorectic gut hormones. Furthermore, differences in brain activity between obese and lean individuals have provided clues about the possible aetiology of overeating. The hypothalamus acts as a central gateway modulating homeostatic and nonhomeostatic drives to eat. As fMRI techniques constantly improve, functional data regarding the role of this small but hugely important structure in appetite control is emerging.

Topics: Appetite; Appetite Regulation; Blood Glucose; Brain; Brain Mapping; Eating; Food; Ghrelin; Homeostasis; Humans; Hunger; Hypothalamus; Image Processing, Computer-Assisted; Insulin; Leptin; Magnetic Resonance Imaging; Obesity; Reward; Satiation

Inflammation in the white adipose tissue (WAT) is considered a major player in the development of insulin resistance. The role of macrophages accumulating in the WAT during obesity, promoting WAT inflammation and insulin resistance is well established. In contrast, less is known about the role of lymphocytes. Recent studies have implicated different lymphocyte subsets in WAT inflammation. For instance, cytotoxic CD8(+) T cells infiltrating the WAT may contribute to the recruitment, differentiation and activation of macrophages. On the other hand, a differential role for CD4(+) Th1 and CD4(+) Th2 cells has been suggested. Levels of WAT regulatory T cells decrease during the course of obesity and may represent a crucial factor for the maintenance of insulin sensitivity. Moreover, activation of natural killer T cells, an innate-like T cell population, which recognises lipid antigens, promotes insulin resistance and WAT inflammation. Finally, B cells may infiltrate WAT very early in response to high-fat feeding and worsen glucose metabolism through modulation of T cells and the production of pathogenic antibodies. These interesting new findings however bear controversies and introduce novel, yet unanswered, questions. Here, we review and discuss the impact of the different lymphocyte subsets in obesity-related WAT inflammation and attempt to identify the open questions to be answered by future studies.

Topics: Adipose Tissue, White; Animals; B-Lymphocyte Subsets; Disease Models, Animal; Humans; Inflammation; Leptin; Lymphocytes; Mice; Obesity; T-Lymphocyte Subsets

Two years ago, the Lasker Award was shared by Douglas Coleman and Jeffrey Friedman for their discovery of leptin, a hormone that exerts a key role in the central regulation of appetite and body weight. Douglas Coleman is recognized as the researcher who raised the hypothesis and predicted that a circulating satiety factor was lacking in the ob/ob mouse, and predicted that this factor acted at the hypothalamic level to modulate food intake. After three decades, in an attempt to identify the genes that were mutated in the ob/ob mouse, Jeffrey Friedman found that the ob gene encodes a protein hormone that reverses obesity and other abnormalities of this genetic rodent model of obesity. This discovery was a landmark event in physiology, and revolutionized our understanding of energy homeostasis. This short review aims to summarize the main steps that lead to the identification of leptin, the product of the ob gene.

Topics: Animals; Humans; Leptin; Obesity

Feeding behaviour is crucial for the survival of an organism and is regulated by different brain circuits. Among these circuits the mesolimbic dopamine (DA) system is implicated in the anticipation and motivation for food rewards. This system consists of the dopaminergic neurons in the ventral tegmental area (VTA), and their projections to different cortico-limbic structures such as the nucleus accumbens and medial prefrontal cortex. While the importance of this system in motivational drive for different rewards, including drugs of abuse, has been clearly established, its role in energy balance remains largely unexplored. Evidence suggests that peripheral hormones such as leptin and ghrelin are involved in the anticipation and motivation for food and this might be partially mediated through their effects on the VTA. Yet, it remains to be determined whether these effects are direct effects of ghrelin and leptin onto VTA DA neurons, and to what extent indirect effects through other brain areas contribute. Elucidation of the role of leptin and ghrelin signalling on VTA DA neurons in relation to disruptions of energy balance might provide important insights into the role of this neural circuit in obesity and anorexia nervosa.

Topics: Anorexia Nervosa; Appetite; Dopamine; Energy Metabolism; Feeding Behavior; Ghrelin; Humans; Leptin; Motivation; Obesity; Reward; Signal Transduction; Ventral Tegmental Area

Nearly 35% of adults and 20% of children in the United States are obese, defined as a body mass index ≥ 30 kg/m(2). Obesity, which is accompanied by metabolic dysregulation often manifesting in the metabolic syndrome, is an established risk factor for many cancers. Within the growth-promoting, proinflammatory environment of the obese state, cross talk between macrophages, adipocytes, and epithelial cells occurs via obesity-associated hormones, cytokines, and other mediators that may enhance cancer risk and progression. This review synthesizes the evidence on key biological mechanisms underlying the obesity-cancer link, with particular emphasis on obesity-associated enhancements in growth factor signaling, inflammation, and vascular integrity processes. These interrelated pathways represent possible mechanistic targets for disrupting the obesity-cancer link.

Topics: Adiponectin; Cell Communication; Humans; Inflammation; Insulin; Insulin-Like Growth Factor I; Intercellular Signaling Peptides and Proteins; Leptin; Metabolic Syndrome; Neoplasms; Obesity; Receptor, IGF Type 1; Receptor, Insulin; Signal Transduction; Vascular Endothelial Growth Factor A

In the last 50 years, the average self-reported sleep duration in the United States has decreased by 1.5-2 hours in parallel with an increasing prevalence of obesity and diabetes. Epidemiological studies and meta-analyses report a strong relationship between short or disturbed sleep, obesity, and abnormalities in glucose metabolism. This relationship is likely to be bidirectional and causal in nature, but many aspects remain to be elucidated. Sleep and the internal circadian clock influence a host of endocrine parameters. Sleep curtailment in humans alters multiple metabolic pathways, leading to more insulin resistance, possibly decreased energy expenditure, increased appetite, and immunological changes. On the other hand, psychological, endocrine, and anatomical abnormalities in individuals with obesity and/or diabetes can interfere with sleep duration and quality, thus creating a vicious cycle. In this review, we address mechanisms linking sleep with metabolism, highlight the need for studies conducted in real-life settings, and explore therapeutic interventions to improve sleep, with a potential beneficial effect on obesity and its comorbidities.

Topics: Adiponectin; Appetite; Diabetes Mellitus; Energy Metabolism; Female; Ghrelin; Glucose; Humans; Insulin Resistance; Leptin; Male; Melatonin; Obesity; Risk Factors; Sleep Deprivation; Sleep Wake Disorders

Obesity represents a major risk factor for the development of insulin and leptin resistance, ultimately leading to a pleiotropic spectrum of metabolic alterations. However, resistance to both hormones does not uniformly affect all target cells and intracellular signaling pathways. In contrast, numerous clinical phenotypes arise from selective hormone resistance, leading to inhibition of defined intracellular signaling pathways in some tissues, while in other cell types hormone action is maintained or even overactivated. Here, we review the molecular mechanisms and clinical outcomes resulting from selective insulin and leptin resistance, which should ultimately guide future strategies for the treatment of obesity-associated diseases.

Topics: Central Nervous System; Humans; Insulin Resistance; Leptin; Metabolic Diseases; Obesity; Signal Transduction

The focus of this overview is on the animal models of obesity most commonly utilized in research. The models include monogenic models in the leptin pathway, polygenic diet-dependent models, and, in particular for their historical perspective, surgical and chemical models of obesity. However, there are far too many models to consider all of them comprehensively, especially those caused by selective molecular genetic approaches modifying one or more genes in specific populations of cells. Further, the generation and use of inducible transgenic animals (induced knock-out or knock-in) is not covered, even though they often carry significant advantages compared to traditional transgenic animals, e.g., influences of the genetic modification during the development of the animals can be minimized. The number of these animal models is simply too large to be covered in this unit.

Topics: Animals; Arcuate Nucleus of Hypothalamus; Cricetinae; Diet; Disease Models, Animal; Female; Hypothalamus; Leptin; Lipodystrophy; Male; Mesocricetus; Metabolic Diseases; Mice; Mice, Transgenic; Mutation; Obesity; Ovariectomy; Phodopus; Rats; Rats, Transgenic; Receptors, Leptin; Seasons

Topics: Animals; Brain; Diet; Dietary Fats; Dietary Sucrose; Energy Intake; Humans; Leptin; Obesity; Weight Gain

Obesity, defined as abnormal or excessive fat accumulation that may impair life quality, is one of the major public health problems worldwide. It results from an imbalance between food intake and energy expenditure. The control of energy balance in animals and humans is performed by the central nervous system (CNS) by means of neuroendocrine connections, in which circulating peripheral hormones, such as leptin and insulin, provide signals to specialized neurons of the hypothalamus reflecting body fat stores, and induce appropriate responses to maintain the stability of these stores. The majority of obesity cases are associated with central resistance to both leptin and insulin actions. In experimental animals, high-fat diets can induce an inflammatory process in the hypothalamus, which impairs leptin and insulin intracellular signaling pathways, and results in hyperphagia, decreased energy expenditure and, ultimately, obesity. Recent evidence obtained from neuroimaging studies and assessment of inflammatory markers in the cerebrospinal fluid of obese subjects suggests that similar alterations may be also present in humans. In this review, we briefly present the mechanisms involved with the loss of homeostatic control of energy balance in animal models of obesity, and the current evidence of hypothalamic dysfunction in obese humans.

Topics: Adipose Tissue; Animals; Eating; Energy Metabolism; Homeostasis; Humans; Hypothalamic Diseases; Hypothalamus; Insulin; Insulin Resistance; Leptin; Obesity

Over the past 20 years, genetic studies have illuminated critical pathways in the hypothalamus and brainstem mediating energy homeostasis, such as the melanocortin, leptin, 5-hydroxytryptamine and brain-derived neurotrophic factor signaling axes. The identification of these pathways necessary for appropriate appetitive responses to energy state has yielded insight into normal homeostatic processes. Although monogenic alterations in each of these axes result in severe obesity, such cases remain rare. The major burden of disease is carried by those with common obesity, which has so far resisted yielding meaningful biological insights. Recent progress into the etiology of common obesity has been made with genome-wide association studies. Such studies now reveal more than 32 different candidate obesity genes, most of which are highly expressed or known to act in the CNS, emphasizing, as in rare monogenic forms of obesity, the role of the brain in predisposition to obesity.

Topics: Animals; Appetite Regulation; Brain; Brain-Derived Neurotrophic Factor; Genetic Predisposition to Disease; Genome-Wide Association Study; Homeostasis; Humans; Leptin; Melanocortins; Models, Neurological; Obesity; Pro-Opiomelanocortin; Serotonin

Topics: Adipokines; Adiponectin; Adipose Tissue; Adult; Aged; Animals; Chronic Disease; Clinical Trials as Topic; Cytokines; Diabetes Mellitus, Type 2; Exercise; Female; Humans; Inflammation; Insulin Resistance; Leptin; Male; Metabolic Syndrome; Middle Aged; Nicotinamide Phosphoribosyltransferase; Obesity; Resistin; Serpins

In recent years researchers have become increasingly interested in the particular relation between the function of the thyroid gland and the body mass in the population of obese children. Numerous studies have been conducted and the literature on the related issues has been abounding. Several thereof have strived at pinpointing a significant link between the function of the thyroid axis and the body mass. Yet, it still remains to be clarified whether these subtle changes in the level of thyroid hormones and TSH observed in childhood obesity are responsible for the increased body mass or rather they represent a secondary phenomenon. The mechanism most often put forward by the researchers that links obesity to thyroid function is the increased level of leptin, which affects neurones in the hypothalamus and the thyroid axis causing TRH and TSH secretion. The body mass is positively correlated with serum leptin and elevated level of leptin is connected with an increase in TSH level. However, there is still controversy whether these inconspicuous differences observed in thyroid axis merit the treatment with thyroxine since these changes seem to constitute a consequence rather than a cause of obesity. Therefore, as most authors postulate, primary importance should be placed on lifestyle changes and body weight reduction leaving substitutive treatment as a supplementary option. The purpose of this review is to present the most current issues on child obesity and the related malfunction of the thyroid axis through an overview of international publications from the years 1996-2011.

Topics: Adipose Tissue; Child; Humans; Hypothyroidism; Leptin; Obesity; Risk Reduction Behavior; Thyrotropin; Thyroxine; Triiodothyronine

With the steady rise in the prevalence of obesity and its associated diseases, research aimed at understanding the mechanisms that regulate and control whole body energy homeostasis has gained new interest. Leptin and insulin, two anorectic hormones, have key roles in the regulation of body weight and energy homeostasis, as highlighted by the fact that several obese patients develop resistance to these hormones. Within the brain, the hypothalamic proopiomelanocortin and agouti-related protein neurons have been identified as major targets of leptin and insulin action. Many studies have attempted to discern the individual contributions of various components of the principal pathways that mediate the central effects of leptin and insulin. The aim of this review is to discuss the latest findings that might shed light on, and lead to a better understanding of, energy balance and glucose homeostasis. In addition, recently discovered targets and mechanisms that mediate hormonal action in the brain are highlighted.

Topics: Adipose Tissue; Agouti-Related Protein; Brain; Energy Metabolism; Glucose; Homeostasis; Humans; Insulin; Insulin Secretion; Leptin; Obesity; Proprotein Convertases; Signal Transduction

This review discusses the present view on lipid metabolism regulation with emphasis on polymorphisms of key genes. Relying on the analysis of the literature, the blood lipid specter of carriers of the key genes allelic variants has been described. Therefore, reasonability of a more profound study of the influence of genetic polymorphisms on lipid metabolism regulation is substantiated. It is revealed, that the carriers of one of the abnormal alleles causes a higher risk for obesity and its associated complications. Polymorphic variants of the genes, that regulated lipid metabolism are widely presented in human population. It explains the big interest to studying of communication between dyslipidemia, adiposity and other pathologies with features of a genotype. However, abnormality of metabolic process and associated diseases in most cases represent multifactorial diseases. For today, the important problem for researchers still is a definition of a role of individual genetic features in development of pathological processes. The special attention in researches of last years is given to the genes, which products concern to leptin-melanokortin system of regulation of a energy metabolism; proteins-carriers lipid's blood fractions and cholesterol; and also the enzymes splitting lipids. Lipid metabolism is closely connected with an exchange of carbohydrates, especially a glucose metabolism. That is why genes mediating actions of insulin represent the greatest interest. Today, more than 400 genes are the potential candidates, capable to regulate lipid exchange. However, the further careful and extensive researches in this area are necessary.

Topics: Adiposity; Animals; Apolipoproteins; Cholesterol; Dyslipidemias; Energy Metabolism; Genetic Predisposition to Disease; Humans; Insulin; Leptin; Lipid Metabolism; Mice; Obesity; Polymorphism, Genetic

During the development of type 2 diabetes mellitus, skeletal muscle is a major site of insulin resistance. The latter has been linked to mitochondrial dysfunction and impaired fatty acid oxidation. Some hormones like insulin, thyroid hormones and adipokines (e.g., leptin, adiponectin) have positive effects on muscle mitochondrial bioenergetics through their direct or indirect effects on mitochondrial biogenesis, mitochondrial protein expression, mitochondrial enzyme activities and/or AMPK pathway activation--all of which can improve fatty acid oxidation. It is therefore not surprising that treatment with these hormones has been proposed to improve muscle and whole body insulin sensitivity. However, treatment of diabetic patients with leptin and adiponectin has no effect on muscle mitochondrial bioenergetics showing resistance to these hormones during type 2 diabetes. Furthermore, treatment with most thyroid hormones has unexpectedly revealed negative effects on muscle insulin sensitivity. Future research should focus on development of agents that improve metabolic dysfunction downstream of hormone receptors.

Topics: Adiponectin; Diabetes Mellitus, Type 2; Energy Metabolism; Humans; Insulin; Insulin Resistance; Leptin; Mitochondria, Muscle; Muscle, Skeletal; Obesity

The purpose of this review was to highlight, in relation to the currently accepted pathophysiology of non-alcoholic fatty liver disease (NAFLD), the known exercise habits of patients with NAFLD and to detail the benefits of lifestyle modification with exercise (and/or physical activity) on parameters of metabolic syndrome. More rigorous, controlled studies of longer duration and defined histopathological end-points comparing exercise alone and other treatment are needed before better, evidence-based physical activity modification guidelines can be established, since several questions remain unanswered.

Topics: Diet; Exercise; Fatty Liver; Hormones; Humans; Insulin Resistance; Leptin; Life Style; Lipids; Liver; Metabolic Syndrome; Motor Activity; Non-alcoholic Fatty Liver Disease; Obesity; Practice Guidelines as Topic; Treatment Outcome

The role of genetic factors involved in the etiology of human obesity is beyond question. The identification of the hypothalamic leptin-melanocortin signaling pathway as a critical regulator in energy homeostasis and food intake has been essential for genetic research. In this review, we discuss the involvement of established and novel genes from this pathway in the pathogenesis of obesity. Their roles in monogenic and complex forms of obesity are illustrated by discussing the results of mutation analysis, candidate gene and genome-wide association studies, as well as copy number analysis. While we can conclude from these outcomes that the leptin-melanocortin pathway is of immense importance, there is still a lot of heritability that currently cannot be explained. Future studies implementing genome-wide association studies, genome-wide copy number variant analysis, and whole exome and whole-genome sequencing might aid in finding new variation in the conventional pathways and might reveal new biological pathways implicated in the pathogenesis of obesity.

Topics: Genetic Predisposition to Disease; Humans; Leptin; Melanocortins; Obesity; Signal Transduction

Obesity is the most critical factor in the pathology of metabolic syndrome (MetS), and is associated with an increased risk of depression. The imbalance of hormones and neural peptides which are involved in energy regulation are observed in obesity. It becomes evident that these hormones and neural peptides also affect mood. Leptin plays a pivotal role in energy regulation mainly acting in the hypothalamus of the brain. Although obese humans and rodents usually have high circulating levels of leptin, leptin neither reduces food intake nor increases energy expenditure. This paradoxical situation in obesity has been termed "leptin resistance", which is considered to be a central dogma for obesity. Based on these observations, we examined the functional significance of leptin in the regulation of the depressive state in diet-induced obese (DIO) mice. Our recent study demonstrated that DIO mice showed severe depressive behavior without response to the antidepressant effect of leptin, which is, in part, due to the impairment of leptin action in the hippocampus (Yamada, et al., Endocrinology, 2011). MetS and CNS dysfunction might have common pathological bases vulnerable to these disorders. Our future direction is to investigate a new treatment strategy of MetS by analyzing CNS dysfunction associated with obesity.

Topics: Animals; Central Nervous System Diseases; Depression; Disease Models, Animal; Humans; Leptin; Metabolic Syndrome; Obesity

The protein nucleobindin 2 (NUCB2) or NEFA (DNA binding/EF-hand/acidic amino acid rich region) was identified over a decade ago and implicated in intracellular processes. New developments came with the report that post-translational processing of hypothalamic NUCB2 may result in nesfatin-1, nesfatin-2 and nesfatin-3 and convergent studies showing that nesfatin-1 and full length NUCB2 injected in the brain potently inhibit the dark phase food intake in rodents including leptin receptor deficient Zucker rats. Nesfatin-1 also reduces body weight gain, suggesting a role as a new anorexigenic factor and modulator of energy balance. In light of the obesity epidemic and its associated diseases, underlying new mechanisms regulating food intake may be promising targets in the drug treatment of obese patients particularly as the vast majority of them display reduced leptin sensitivity or leptin resistance while nesfatin-1's mechanism of action is leptin independent. Although much progress on the localization of NUCB2/nesfatin-1 in the brain and periphery as well as on the understanding of nesfatin-1's anorexic effect have been achieved during the past three years, several important mechanisms have yet to be unraveled such as the identification of the nesfatin-1 receptor and the regulation of NUCB2 processing and nesfatin-1 release.

Topics: Animals; Appetite Regulation; Body Weight; Calcium-Binding Proteins; Disease Models, Animal; DNA-Binding Proteins; Eating; Energy Intake; Humans; Hypothalamus; Leptin; Nerve Tissue Proteins; Nucleobindins; Obesity; Peptide Hormones; Rats; Satiety Response; Signal Transduction

Obesity is associated with an increased risk of breast cancer in postmenopausal women. Accumulating evidence suggests that adipose tissue, which is an endocrine organ producing a large range of factors, may interfere with breast cancer development. Leptin and adiponectin are two major adipocyte-secreted hormones. The pro-carcinogenic effect of leptin and conversely, the anti-carcinogenic effect of adiponectin result from two main mechanisms: a modulation in the signalling pathways involved in proliferation process and a subtle regulation of the apoptotic response. This review provides insight into recent findings on the molecular mechanisms of leptin and adiponectin in mammary tumours, and discusses the potential interplay between these two adipokines in breast cancer.

Topics: Adiponectin; Adipose Tissue; Animals; Breast Neoplasms; Cell Communication; Female; Humans; Leptin; Mice; Obesity; Receptors, Leptin; Tumor Cells, Cultured

Reducing myocardial damage resulting from ischaemia-reperfusion (I/R) is vital in ensuring patient recovery and survival. It relies upon the activation of the so-called Reperfusion Injury Salvage Kinase (RISK) pathway. Experimentally various treatments, both mechanical and chemical, have been shown to protect the myocardium against I/R injury. Chemical facilitators of myocardial preservation include endogenous factors such as insulin, erythropoietin and glucagon-like peptide 1. The adipocytokines, products of white adipose tissue, are important peptide hormones with respect to metabolic control and satiety, and were formerly considered in the context of obesity and metabolic disease. More recently, however, evidence has been presented indicating that the adipocytokines play significant roles in cardiac function and, as we have suggested, in myocardial protection. To date leptin, adiponectin, apelin and visfatin have all been shown to protect against I/R injury. Significantly, the protection afforded by these peptides involves the activation of kinases which are key elements of the mechanisms underlying tissue preservation, including the RISK pathway components PI3K-Akt and p44/42, and inhibition of the mitochondrial permeability transition pore (MPTP). In this article we examine the roles played by the adipocytokines in cardiovascular function and disease. In particular, we focus on the evidence that these peptides promote myocardial survival, much of it having been obtained in this laboratory. To conclude, we discuss some future directions in the field, including the prospects for some of the adipocytokines finding application as therapeutic agents in myocardial infarction.

Topics: Adipokines; Adiponectin; Apoptosis; Cardiovascular System; Humans; Leptin; Myocardial Reperfusion Injury; Myocardium; Obesity; Signal Transduction

Numerous investigations have shown that mitochondrial dysfunction is a major mechanism of drug-induced liver injury, which involves the parent drug or a reactive metabolite generated through cytochromes P450. Depending of their nature and their severity, the mitochondrial alterations are able to induce mild to fulminant hepatic cytolysis and steatosis (lipid accumulation), which can have different clinical and pathological features. Microvesicular steatosis, a potentially severe liver lesion usually associated with liver failure and profound hypoglycemia, is due to a major inhibition of mitochondrial fatty acid oxidation (FAO). Macrovacuolar steatosis, a relatively benign liver lesion in the short term, can be induced not only by a moderate reduction of mitochondrial FAO but also by an increased hepatic de novo lipid synthesis and a decreased secretion of VLDL-associated triglycerides. Moreover, recent investigations suggest that some drugs could favor lipid deposition in the liver through primary alterations of white adipose tissue (WAT) homeostasis. If the treatment is not interrupted, steatosis can evolve toward steatohepatitis, which is characterized not only by lipid accumulation but also by necroinflammation and fibrosis. Although the mechanisms involved in this aggravation are not fully characterized, it appears that overproduction of reactive oxygen species by the damaged mitochondria could play a salient role. Numerous factors could favor drug-induced mitochondrial and metabolic toxicity, such as the structure of the parent molecule, genetic predispositions (in particular those involving mitochondrial enzymes), alcohol intoxication, hepatitis virus C infection, and obesity. In obese and diabetic patients, some drugs may induce acute liver injury more frequently while others may worsen the pre-existent steatosis (or steatohepatitis).

Topics: Adiponectin; Adipose Tissue; Alcoholic Intoxication; Animals; Carbohydrate Metabolism; Cell Death; Chemical and Drug Induced Liver Injury; Diabetes Mellitus, Type 2; Energy Metabolism; Fatty Acids; Fatty Liver; Genetic Predisposition to Disease; Genome, Mitochondrial; Hepatitis C; Humans; Insulin Resistance; Leptin; Lipid Metabolism; Mitochondria, Liver; Mitochondrial Membrane Transport Proteins; Mitochondrial Permeability Transition Pore; Models, Biological; Obesity; Oxidation-Reduction; Oxidative Phosphorylation; Reactive Oxygen Species

Increased evidence suggests that obesity-related glomerulopathy and chronic kidney diseases should be identified as isolated complications of obesity. It is questioned if the numerous adipose tissue productions could play a role in the initiation/maintenance of such kidney diseases. This review will provide a sum-up of recent advances on fat cell metabolism and adipose tissue physiology. The adipose tissue behaves as an endocrine organ with multiple activities. It is secreting hormones (leptin, adiponectin, apelin) and numerous factors with autocrine, paracrine and systemic effects. These secretions are coming from adipocytes themselves or from cells present in the stroma-vascular fraction of the adipose tissue. When expanding, the adipose tissue of the obese is infiltrated by immune cells such as macrophages and lymphocytes; the role of which is not fully clarified. An attempt will be done to delineate if alterations of lipid storage/fatty acid release or of the secretion potencies of adipose tissue could contribute to kidney lipotoxicity and other chronic kidney diseases described in the obese.

Topics: Adipocytes; Adiponectin; Adipose Tissue, White; Apelin; Biomarkers; Body Mass Index; Cytokines; Evidence-Based Medicine; Glomerulonephritis; Humans; Intercellular Signaling Peptides and Proteins; Leptin; Metabolic Syndrome; Obesity; Renal Insufficiency, Chronic

Chronic uremia is often characterized by wasting of muscle and fat mass, which has been defined as protein-energy wasting (PEW), and is responsible for substantial worsening of patient outcome in terms of morbidity and mortality, mostly from cardiovascular events. Despite major advances in patient treatment, nutritional outcome in patients with end-stage renal disease has not improved substantially in recent years. Extensive research in this field has provided plausible explanations for this limitation by indicating that the pathogenesis of PEW in kidney disease is complex and multifactorial. Complexity involves underlying metabolic alterations, including inflammation, oxidative stress, and insulin resistance. In addition, patient heterogeneity is increasing with large numbers of obese individuals as a result of the ongoing obesity epidemics. Several tissues are involved in cross-talk and contribute to metabolic derangements, including adipose tissue, the gut, and the central nervous system, with novel mediators including the gastric hormone ghrelin. Acknowledging its complex pathogenesis may favor the development of novel and more effective therapeutic tools for PEW. These should ideally be effective in treating the underlying common mechanisms of wasting, which appear to include oxidative stress, inflammation, and insulin resistance.

Topics: Animals; Ghrelin; Humans; Inflammation; Insulin Resistance; Kidney Failure, Chronic; Leptin; Obesity; Oxidative Stress; Protein-Energy Malnutrition

There is increasing evidence that obesity may have pathophysiological effects that extend beyond its well-known co-morbidities; in particular its role in cancer has received considerable epidemiological support. As adipose tissue becomes strongly established as an endocrine organ, two of its most abundant and most investigated adipokines, leptin and adiponectin, are also taken beyond their traditional roles in energy homeostasis, and are implicated as mediators of the effects of obesity on cancer development. This review examines these adipokines in relation to the prostate, breast, colorectal, thyroid, renal, pancreatic, endometrial and oesophageal cancers, and how they may orchestrate the influence of obesity on the development of these malignancies.

Topics: Adiponectin; Body Mass Index; Breast Neoplasms; Colorectal Neoplasms; Endometrial Neoplasms; Esophageal Neoplasms; Female; Humans; Kidney Neoplasms; Leptin; Male; Neoplasms; Obesity; Pancreatic Neoplasms; Prostatic Neoplasms; Thyroid Neoplasms

Elevated blood glucose, obesity, high blood pressure, elevated triglycerides and low high density lipoprotein (HDL) cholesterol are well accepted risk factors in the development of coronary artery disease. Clustering of at least three of these factors in an individual is defined as metabolic syndrome (MetS). Obesity is a central pathological mechanism in the disease and it is expected that the incidence of this condition will increase dramatically within the next years. The visceral adipose tissue is not only an energy depot but also an endocrine organ which produces a large number of bioactive molecules, the so called adipokines. In the setting of obesity, the over-production of proinflammatory and pro-thrombotic adipokines is associated with insulin resistance. This mechanism represents the pathophysiological basis for the development of MetS. Inflammation has a central role in the pathogenesis of MetS and in mediating its impact on the development of cardiovascular disease. Knowledge of these mechanisms has relevance in the context of preventive and therapeutic strategies.

Topics: Adiponectin; Adolescent; Adult; Angiotensinogen; Atherosclerosis; Biomarkers; Cardiovascular Diseases; Chemokine CCL2; Endothelium, Vascular; Humans; Inflammation; Insulin Resistance; Interleukin-6; Intra-Abdominal Fat; Leptin; Life Style; Metabolic Syndrome; Obesity; Plaque, Atherosclerotic; Plasminogen Activator Inhibitor 1; Prognosis; Resistin; Risk; Tumor Necrosis Factor-alpha

The regulation of energy homeostasis by thyroid hormones is unquestionable, and iodothyronine deiodinases are enzymes involved in the metabolic activation or inactivation of these hormones at the cellular level. T3 is produced through the outer ring deiodination of the prohormone T4, which is catalyzed by types 1 and 2 iodothyronine deiodinases, D1 and D2. Conversely, type 3 iodothyronine deiodinase (D3) catalyzes the inner ring deiodination, leading to the inactivation of T4 into reverse triiodothyronine (rT3). Leptin acts as an important modulator of central and peripheral iodothyronine deiodinases, thus regulating cellular availability of T3. Decreased serum leptin during negative energy balance is involved in the down regulation of liver and kidney D1 and BAT D2 activities. Moreover, in high fat diet induced obesity, instead of increased serum T(3) and T(4) secondary to higher circulating leptin and thyrotropin levels, elevated serum rT3 is found, a mechanism that might impair the further increase in oxygen consumption.

Topics: Energy Metabolism; Homeostasis; Humans; Iodide Peroxidase; Kidney; Leptin; Liver; Molecular Structure; Nutrition Disorders; Obesity; Oxygen Consumption; Thyroid Hormones

Hypothalamic inflammation and dysfunction are common features of experimental obesity. An imbalance between caloric intake and energy expenditure is generated as a consequence of this inflammation, leading to the progressive increase of body adiposity. Thermogenesis, is one of the main functions affected by obesity-linked hypothalamic dysfunction and the complete characterization of the mechanisms involved in this process may offer new therapeutic perspectives for obesity. The brown adipose tissue is an important target for hypothalamic action in thermogenesis. This tissue has been thoroughly studied in rodents and hibernating mammals; however, until recently, its advocated role in human thermogenesis was neglected due to the lack of substantial evidence of its presence in adult humans. The recent demonstration of the presence of functional brown adipose tissue in adult humans has renovated the interest in this tissue. Here, we review some of the work that shows how inflammation and dysfunction of the hypothalamus can control brown adipose tissue activity and how this can impact on whole body thermogenesis and energy expenditure.

Topics: Adipose Tissue, Brown; Adult; Humans; Hypothalamus; Inflammation; Insulin; Leptin; Models, Biological; Obesity; Thermogenesis

Although the state of prediabetes is defined by its role as a diabetes risk factor, it also carries a significant risk of cardiovascular disease, independent of progression to diabetes. Typical diabetic microvascular complications also occur, albeit at low rates, in prediabetes. There is evidence that both glucose-related and glucose-independent mechanisms contribute to these vascular complications. Effective preventive strategies will likely require control of glycemia, as well as other metabolic risk factors. This article reviews some of the proposed mechanisms for the vascular complications of the prediabetic state.

Topics: Adiponectin; Adipose Tissue; Blood Glucose; Cardiovascular Diseases; Diabetes Complications; Endothelium, Vascular; Glucose Intolerance; Humans; Insulin Resistance; Leptin; Obesity; Oxidative Stress; Prediabetic State

Calorie restriction (CR)-induced weight loss has been shown to lower the risk of chronic disease in obese individuals. Although the mechanisms that link weight loss to disease risk reduction remain unclear, evidence suggests adipokines may play a role. What has yet to be determined, however, is the dose-response effect of body weight loss and visceral fat mass loss on adipokines. Accordingly, this review examines how varying degrees of CR-induced weight loss (i.e., >10%, 5-10%, and <5% from baseline) impact plasma levels and expression of adiponectin, leptin, resistin, interleukin 6 (IL-6), interleukin 8 (IL-8), monocyte chemotactic protein 1 (MCP-1), and retinol-binding protein 4 (RBP-4). The dose-response relationship between visceral fat mass loss and adipokine profile improvement will also be explored. Results from this review demonstrate that even mild weight loss induced by CR may have beneficial effects on leptin levels, but it has no clear impact on adiponectin, resistin, IL-6, IL-8, MCP-1, or RBP-4 concentrations.

Topics: Adiponectin; Biomarkers; Caloric Restriction; Humans; Leptin; Obesity; Weight Loss

Recent research indicates similarities between obesity and addictive disorders on both the phenomenological and neurobiological level. In particular, neuroendocrine and imaging studies suggest a close link between the homeostatic regulation of appetite on the on hand, and motivation and reward expectancy on the other. In addition, findings from neuropsychological studies additionally demonstrate alterations of cognitive function in both obesity and addictive disorders that possibly contribute to a lack of control in resisting consumption. In this review, recent findings on overlapping neurobiological and phenomenological pathways are summarized and the impact with regard to new treatment approaches for obesity is discussed.

Topics: Animals; Appetite; Behavior Therapy; Brain; Cognition Disorders; Cognitive Behavioral Therapy; Conditioning, Psychological; Energy Metabolism; Evidence-Based Practice; Genetic Predisposition to Disease; Ghrelin; Humans; Hunger; Intracellular Signaling Peptides and Proteins; Leptin; Motivation; Neuropeptides; Obesity; Orexins; Prefrontal Cortex; Receptors, Dopamine D2; Self-Help Groups; Substance-Related Disorders

Energy homeostasis involves a complex network of hypothalamic and extra-hypothalamic neurons that transduce hormonal, nutrient and neuronal signals into responses that ultimately match caloric intake to energy expenditure and thereby promote stability of body fat stores. Growing evidence suggests that rather than reflecting a failure to regulate caloric intake, common forms of obesity involve fundamental changes to this homeostatic system that favor the defense of an elevated level of body adiposity. This article reviews emerging evidence that during high-fat feeding, obesity pathogenesis involves fundamental alteration of hypothalamic systems that regulate food intake and energy expenditure.

Topics: Animals; Energy Intake; Energy Metabolism; Homeostasis; Hypothalamus; Leptin; Mice; Obesity; Signal Transduction

The brain is continuously supplied with information about the distribution and amount of energy stores from the body periphery. Endocrine, autonomic and cognitive-hedonic signals are centrally integrated and exert effects on the whole organism via anabolic and catabolic pathways. The adiposity signals insulin and leptin reflect the amount of body fat and are part of a negative feedback mechanism between the periphery and the central nervous system. The hypothalamic arcuate nucleus is the most important central nervous structure, which integrates this information. Furthermore, the CNS is able to directly measure and to respond to changes in the concentration of certain nutrients. In order to develop effective therapies for the treatment of disorders of energy balance the further elucidation of these neuro-biological processes is of crucial importance. This article provides an overview of the CNS regulation of metabolism and its underlying molecular mechanisms.

Topics: Adiposity; Animals; Central Nervous System; Energy Metabolism; Homeostasis; Humans; Insulin; Leptin; Nutritional Physiological Phenomena; Obesity; Satiety Response

Obesity and its associated co-morbidities represent one of the biggest public health challenges facing the western world today. Although environmental factors have driven the recent rise in the prevalence of obesity, the heritability of body weight is high and there is evidence that genetic variation plays a major role in determining the susceptibility to weight gain.. Genetic approaches can be used to investigate the mechanisms underlying the regulation of weight and the development of obesity.. The discovery that leptin, a hormone that is secreted by adipocytes, could regulate weight through effects on food intake and energy expenditure represented a major breakthrough in our understanding of the molecular components of the systems involved in energy homeostasis.. I discuss how the identification of humans with mutations in the genes encoding leptin and its downstream targets has provided insights into the role of leptin responsive pathways in the regulation of body weight, neuroendocrine axes and immunity.

Topics: Animals; Appetite; Body Weight; Energy Metabolism; Female; Genetic Variation; Humans; Leptin; Male; Obesity; Rats; Risk Factors; Weight Gain

Leptin is a pleiotropic cytokine-like hormone that is involved in the regulation of energy intake and expenditure, neuroendocrine function, immunity and lipid and glucose metabolism. The few humans with genetically based leptin deficiency provide a unique model to assess those effects. We have identified five Turkish patients (one male and two female adults; one boy and one girl) with congenital leptin deficiency due to a missense mutation in the leptin gene. Four of these patients were treated with physiological doses of recombinant methionyl human leptin. Body composition, brain structure and function, behaviour, immunity and endocrine and metabolic parameters were evaluated before and during treatment. Our results showed that leptin has peripheral, hypothalamic and extra-hypothalamic effects. Within the endocrine system, leptin regulates the circadian rhythms of cortisol, thyroid-stimulating hormone, luteinizing hormone and follicle-stimulating hormone. In the brain, leptin controls energy balance and body weight, and plays a role on neurogenesis and brain function. Leptin is a key element of the adiposinsular axis, enhances immune response, and regulates inflammation, coagulation, fibrinolysis and platelet aggregation. Our 10-year experience in treating these unique patients provided valuable data on the peripheral and central effects of leptin. Those results can be taken into account for the development of leptin-based therapies for other diseases.

Topics: Adult; Body Composition; Child; Energy Intake; Energy Metabolism; Female; Humans; Leptin; Male; Mutation, Missense; Obesity; Pedigree; Weight Loss

The 2010 Lasker Award for basic medical research was shared by Douglas Coleman and Jeffery Friedman for their discovery of leptin, a breakthrough that revealed insight into the genetic basis of obesity. This mini-review aims to review landmark studies on the physiologic system of body weight control. The basic research on the leptin system has broad implications for the genetic control of body weight, thus contributing to solve the global obesity crisis.

Topics: Animals; Awards and Prizes; Body Weight; Endocrine System; Homeostasis; Humans; Hypothalamus; Leptin; Neural Pathways; Obesity

Bardet-Biedl Syndrome (BBS) is a rare human hereditary disorder associated with several features including obesity, retinopathy, renal defects, polydactyly, learning disabilities and hypogenitalism. This article discusses the abnormalities accounting for energy imbalance leading to obesity in BBS, with emphasis on the recent evidence pointing to aberrations in hypothalamic action of leptin. Indeed, BBS proteins have emerged as important mediators of leptin receptor trafficking, and loss of BBS genes results in leptin resistance that could be due to abnormal leptin receptor handling in a subset of leptin-responsive neurons. These recent discoveries hold promise for improved clinical management of BBS patients. The relevance of these findings to non-syndromic common obesity is also discussed.

Topics: Animals; Bardet-Biedl Syndrome; Cilia; Disease Models, Animal; Ependyma; Humans; Leptin; Obesity

The regulation of body fat stores and blood glucose levels is critical for survival. This review highlights growing evidence that leptin action in the central nervous system plays a key role in both processes. Investigation into underlying mechanisms has begun to clarify the physiological role of leptin in the control of glucose metabolism and raises interesting new possibilities for the treatment of diabetes and related disorders.

Topics: Adipose Tissue; Adiposity; Animals; Central Nervous System; Diabetes Mellitus; Glucose; Homeostasis; Humans; Insulin; Janus Kinases; Leptin; Nerve Net; Nutritional Physiological Phenomena; Obesity; Phosphatidylinositol 3-Kinases; Signal Transduction

For decades, obesity has been considered to be the result of the complex interaction between genes and the environment and its pathogenesis is still unresolved. The discovery of hormones and neural mediators responsible for the control of food intake and metabolism at the hypothalamic level has provided fundamental insights into the complicated pathways that control food intake. However, the molecular basis for the association between obesity and low-degree chronic inflammation is still unknown. More recently, the discovery of leptin, one of the most abundant adipocyte-derived hormones, has suggested that nutritional status, through leptin secretion, can control immune self-tolerance modulating Treg suppressive function and responsiveness. Furthermore, recent experimental evidence has shown the presence of an abundant adipose tissue-resident Treg population responsible for the control of metabolic parameters and glucose homeostasis. Better knowledge of the intricate network of interactions among leptin-related energy regulation, Treg activities and obesity could lead to valuable strategies for therapeutic intervention in obesity and obesity-associated insulin resistance.

Topics: Autoimmune Diseases; Basic Helix-Loop-Helix Transcription Factors; Genetic Predisposition to Disease; Humans; Leptin; Obesity; Receptor, Melanocortin, Type 4; Repressor Proteins; T-Lymphocytes, Regulatory

Obesity is a highly prevalent health problem in Western countries that leads to many important diseases such as type 2 diabetes and metabolic syndrome being now considered an inflammatory chronic disease. Adipocytes are no longer considered passive cells storing fat since they are major producers of inflammatory cytokines during obesity. Adipocytes and macrophages share many biological properties including the synthesis of similar molecules regulating inflammation. Fatty acid levels are elevated in obesity and induce inflammatory pathways by yet a mostly unknown mechanism, leading to the development of insulin and leptin resistance. Recent studies suggest that these effects could be mediated through the activation of toll-like receptors (TLR). TLR signalling pathways might contribute to the development of obesity-associated insulin resistance, thus representing a connection between innate immunity and metabolism. Here, we summarize the recent evidence for the important role that TLRs play in adipose tissue, obesity and insulin resistance.

Topics: Adipocytes; Adipose Tissue; Animals; Cytokines; Diabetes Mellitus, Type 2; Humans; Inflammation; Insulin Resistance; Leptin; Macrophages; Metabolic Syndrome; Obesity; Signal Transduction; Toll-Like Receptors

The identification of spontaneous mutations in the leptin- and leptin receptor (ObR)-encoding ob and db gene, respectively, opened up a new field in obesity research. Leptin, an adipocyte-derived hormone, mirrors the body's fat stores and thereby informs the brain about the body's energy status. In the hypothalamus, leptin triggers specific neuronal subpopulations, like POMC and AgRP/NPY neurons, and activates several intracellular signaling events, including the JAK/STAT, MAPK, PI3K and mTOR pathway, which eventually translates into decreased food intake and increased energy expenditure. Leptin is also involved in the regulation of other physiological processes including reproduction, bone homeostasis and immune function. Here, we review the pathways that are activated upon ObR activation, how ObR expression is controlled and the molecular mechanisms leading to leptin resistance, i.e. the inability to adequately respond to elevated leptin levels and therefore a primary risk factor for obesity.

Topics: AMP-Activated Protein Kinases; Animals; Blood-Brain Barrier; Endoplasmic Reticulum; Humans; Janus Kinases; Leptin; MAP Kinase Signaling System; Models, Biological; Obesity; Protein Tyrosine Phosphatase, Non-Receptor Type 11; Receptors, Leptin; Signal Transduction; STAT Transcription Factors; Stress, Physiological; TOR Serine-Threonine Kinases

Obesity and its associated comorbidities represent one of the biggest public health challenges facing the world today. The heritability of body weight is high, and genetic variation plays a major role in determining the interindividual differences in susceptibility or resistance to the obesogenic environment. Here we discuss how genetic studies in humans have contributed to our understanding of the central pathways that govern energy homeostasis. We discuss how the arrival of technological advances such as next-generation sequencing will result in a major acceleration in the pace of gene discovery. The study of patients harboring these genetic variants has informed our understanding of the molecular and physiological pathways involved in energy homeostasis. We anticipate that future studies will provide the framework for the development of a more rational targeted approach to the prevention and treatment of genetically susceptible individuals.

Topics: Adaptation, Physiological; Animals; Body Weight; Dietary Fats; Energy Metabolism; Environment; Gene Dosage; Genetic Association Studies; Genome-Wide Association Study; Genomic Imprinting; Humans; Leptin; Melanocortins; Mice; Mice, Mutant Strains; Obesity; Receptor, Melanocortin, Type 4; Receptors, Leptin; Syndrome

This review summarizes the most recent evidence linking decreased sleep duration and poor sleep quality to obesity, focusing upon studies in adults.. Published and unpublished health examination surveys and epidemiological studies suggest that the worldwide prevalence of obesity has doubled since 1980. In 2008, 1 in 10 adults was obese, with women more likely to be obese than men. This obesity epidemic has been paralleled by a trend of reduced sleep duration. Poor sleep quality, which leads to overall sleep loss has also become a frequent complaint. Growing evidence from both laboratory and epidemiological studies points to short sleep duration and poor sleep quality as new risk factors for the development of obesity.. Sleep is an important modulator of neuroendocrine function and glucose metabolism and sleep loss has been shown to result in metabolic and endocrine alterations, including decreased glucose tolerance, decreased insulin sensitivity, increased evening concentrations of cortisol, increased levels of ghrelin, decreased levels of leptin, and increased hunger and appetite. Recent epidemiological and laboratory evidence confirm previous findings of an association between sleep loss and increased risk of obesity.

Topics: Adult; Appetite; Blood Glucose; Female; Ghrelin; Glucose Intolerance; Homeostasis; Humans; Insulin Resistance; Leptin; Male; Neurosecretory Systems; Obesity; Prevalence; Risk Factors; Sleep; Sleep Apnea, Obstructive

Resistance to the hormones insulin and leptin are hallmarks in common for type 2 diabetes mellitus and obesity. Both conditions are associated with increased activity and expression of protein tyrosine phosphatase (PTP)1B. Therefore, inhibition of PTP1B activity or down-regulation of its expression should ameliorate insulin and leptin resistance, and may hold therapeutic utility in type 2 diabetes mellitus and obesity control. This background has motivated the fervent search for PTP1B inhibitors, carried out in the recent years. The purpose of this review is to provide the most recent advances in understanding the structural details of PTP1B molecule relevant to the interactions with inhibitors, and the progress towards compounds with enhanced membrane permeability, affinity, specificity, and potency on intracellular PTP1B; several inhibitors of benefit in type 2 diabetes mellitus and obesity control are presented and discussed.

Topics: Diabetes Mellitus, Type 2; Enzyme Inhibitors; Humans; Insulin Resistance; Leptin; Molecular Structure; Obesity; Protein Tyrosine Phosphatase, Non-Receptor Type 1

Fatty acids released from white adipose tissue (WAT) provide important energy substrates during fasting. However, uncontrolled fatty acid release from WAT during non-fasting states causes lipotoxicity and promotes inflammation and insulin resistance, which can lead to and worsen type 2 diabetes (DM2). WAT is also a source for insulin sensitizing fatty acids such as palmitoleate produced during de novo lipogenesis. Insulin and leptin are two major hormonal adiposity signals that control energy homeostasis through signaling in the central nervous system. Both hormones have been implicated to regulate both WAT lipolysis and de novo lipogenesis through the mediobasal hypothalamus (MBH) in an opposing fashion independent of their respective peripheral receptors. Here, we review the current literature on brain leptin and insulin action in regulating WAT metabolism and discuss potential mechanisms and neuro-anatomical substrates that could explain the opposing effects of central leptin and insulin. Finally, we discuss the role of impaired hypothalamic control of WAT metabolism in the pathogenesis of insulin resistance, metabolic inflexibility and type 2 diabetes.

Topics: Adipose Tissue, White; Homeostasis; Humans; Hypothalamus; Insulin; Insulin Resistance; Leptin; Obesity; Signal Transduction

Asthma and obesity have been increasing in prevalence internationally among children. Evidence points to an association between these chronic morbidities, suggesting the development of an 'obese asthma' phenotype in childhood. This review summarises the evidence that the proinflammatory environment created by excess adiposity may provide a mechanism leading to obese asthma in children and adolescents. Weight loss studies conducted in children without asthma have demonstrated a reduction in systemic inflammation. However, the impact of weight loss in the obese paediatric population with asthma has not been investigated. The paucity of information highlights the need for high quality randomised controlled trials of weight loss in this population that include assessment of systemic and airway inflammation, and clinical asthma outcomes. This will lead to refinements in management approaches for these patients.

Topics: Adiponectin; Adolescent; Asthma; C-Reactive Protein; Child; Comorbidity; Humans; Inflammation; Leptin; Obesity; Phenotype; Tumor Necrosis Factor-alpha; Weight Loss

Topics: Adiponectin; Animals; Humans; Leptin; Metabolic Syndrome; Obesity; Receptors, Leptin

Topics: Animals; Drug Therapy, Combination; Humans; Islet Amyloid Polypeptide; Leptin; Metabolic Syndrome; Mice; Obesity

Second-generation antipsychotics can greatly improve symptoms of psychosis-spectrum disorders. Unfortunately, these drugs are associated with weight gain, which increases a patient's risk for developing chronic diseases including Type 2 diabetes, cardiovascular diseases or other obesity-related complications. There are interindividual differences in weight gain resulting from antipsychotic drug use that may be explained by pharmacodynamic characteristics of these agents as well as clinical factors. In addition, genetic variations in pathways associated with satiety are increasingly recognized as potential contributors to antipsychotic-associated weight gain. Polymorphisms in the leptin gene, as well as the leptin receptor gene, are potential pharmacogenetic markers associated with these outcomes. This article summarizes evidence for the associations of the leptin gene and the leptin receptor gene polymorphisms with antipsychotic-induced weight gain, potential mechanisms underlying these relationships, and discusses areas for future pharmacogenetic investigation.

Topics: Antipsychotic Agents; Humans; Leptin; Obesity; Polymorphism, Genetic; Receptor, Serotonin, 5-HT2C; Receptors, Dopamine; Receptors, Leptin; Schizophrenia; Weight Gain

The US is facing an obesity epidemic. Recognizing the biomarkers associated with adipose tissue may impact physicians' management of cardiometabolic disease greatly. EVIDENCE OF ACQUISITION: We searched PubMed for keywords 'obesity', 'leptin', and 'adiponectin', reviewed national surveys, and searched reference articles used in review articles retrieved via the PubMed search. We included articles with multiple relevant citations. Observational data acquired from two sources, not previously published, were also used to support our conclusion.. Literature review and analysis of observational data showed that the level of leptin increases with the increase in weight gain, while adiponectin decreases. The roles of these adipokines in the body have been defined. With the increase in leptin levels, the incidence and prevalence of the components of the metabolic syndrome were seen to be higher, resulting in higher cardiovascular disease, while adiponectin was seen to play a more protective role in the body against developing such disease.. Measuring circulating levels of leptin and adiponectin as a screening tool may help recognize those individuals who do not only have obesity as a major risk factor toward developing cardiometabolic disease but also may have an unfavorable 'biomarker profile', putting them at highest risk. This may encourage the mobilization of resources to help these individuals lose weight rapidly with possibly aggressive measures such as bariatric surgery.

Topics: Adiponectin; Biomarkers; Cardiovascular Diseases; Humans; Leptin; Obesity

Obesity is associated to significant disturbances in endocrine function. Hyper insulinemia and insulin resistance are the best known changes in obesity, but their mechanisms and clinical significance are not clearly established. Adipose tissue is considered to be a hormone-secreting endocrine organ; and increased leptin secretion from the adipocyte, a satiety signal, is a well-established endocrine change in obesity. In obesity there is a decreased GH secretion. Impairment of somatotropic function in obesity is functional and may be reversed in certain circumstances. The pathophysiological mechanism responsible for low GH secretion in obesity is probably multifactorial. There are many data suggesting that a chronic state of somatostatin hypersecretion results in inhibition of GH release. Increased FFA levels, as well as a deficient ghrelin secretion, probably contribute to the impaired GH secretion. In women, abdominal obesity is associated to hyperandrogenism and low sex hormone-binding globulin levels. Obese men, particularly those with morbid obesity, have decreased testosterone and gonadotropin levels. Obesity is associated to an increased cortisol production rate, which is compensated for by a higher cortisol clearance, resulting in plasma free cortisol levels that do not change when body weight increases. Ghrelin is the only known circulating orexigenic factor, and has been found to be decreased in obese people. In obesity there is also a trend to increased TSH and free T3 levels.

Topics: Adiponectin; Adipose Tissue; Endocrine System; Female; Ghrelin; Gonadal Steroid Hormones; Human Growth Hormone; Humans; Hydrocortisone; Hyperinsulinism; Leptin; Male; Obesity; Sex Hormone-Binding Globulin; Somatostatin; Thyroid Hormones

Common genetic variations in the leptin (LEP), leptin receptor (LEPR), and paraoxonase 1 (PON1) genes have been considered to be implicated in the development of breast cancer. However, the results were inconsistent. In this study, a meta-analysis was performed to assess the associations of five polymorphisms, including LEP G2548A, LEPR Q223R, LEPR Lys109Arg, PON1 L55M, and PON1 Q192R polymorphisms, with breast cancer risk. Published literature from PubMed, ISI Web of Science, Embase databases, CNKI, and Wanfang Data were retrieved. All studies evaluating the association between LEP G2548A, LEPR Q223R, LEPR Lys109Arg, PON1 L55M, or PON1 Q192R polymorphism and breast cancer risk were included. Pooled odds ratio (OR) with 95% confidence interval (CI) was calculated using fixed- or random-effects model. Three studies (2,003 cases and 1,967 controls) for LEP G2548A polymorphism, nine studies (4,627 cases and 5,476 controls) for LEPR Q223R polymorphism, five studies (2,759 cases and 2,573 controls) for LEPR Lys109Arg polymorphism, four studies (1,517 cases and 1,379 controls) for PON1 L55M polymorphism, and five studies (1,575 cases and 2,283 controls) for PON1 Q192R polymorphism were included in the meta-analysis. Overall, the results showed null significant association between LEP G2548A, LEPR Q223R, LEPR Lys109Arg, or PON1 Q192R polymorphism and breast cancer risk; however, PON1 L55M was significantly associated with breast cancer risk overall (MM vs. LL: OR = 2.16; 95% CI, 1.76-2.66). For LEPR Q223R polymorphism, further subgroup analysis suggested that the association was only statistically significant in East Asians (OR = 0.50; 95% CI, 0.36-0.70) but not in Caucasians (OR = 1.06; 95% CI, 0.77-1.45) or Africans (OR = 1.30; 95% CI, 0.83-2.03). The present meta-analysis suggested that LEPR Q223R polymorphism might be implicated in the development of breast cancer in East Asians; PON1 L55M might increase breast cancer risk. However, given the limited sample size, the findings warrant further investigation.

Topics: Aryldialkylphosphatase; Asian People; Breast Neoplasms; Female; Gene Frequency; Genetic Predisposition to Disease; Genotype; Humans; Leptin; Obesity; Odds Ratio; Polymorphism, Genetic; Receptors, Leptin; Risk Assessment; Risk Factors; White People

Obesity is a chronic disease and a major global health challenge. Apart from bariatric surgery, which is costly and not without risk, there are currently no successful long-term treatment options for obesity. The history of pharmacological agents for obesity has been turbulent with many examples of drugs being removed from the market due to significant side effects. Orlistat and sibutramine (the latest drugs on the market) provide only modest weight loss and are both associated with high attrition rates due to intolerable side effects. Furthermore, sibutramine was recently withdrawn from the market. There is a need for the development of safe and efficacious drug treatments for obesity.. This review covers the history of leptin therapy as an orphan drug, leptin-replacement therapy as a treatment for obesity, preclinical studies showing the efficacy of leptin/amylin combination and finally, the very promising early clinical findings using pramlintide/meteleptin combination therapy in overweight to obese individuals.. Combination pharmacological therapy, such as pramlintide/metreleptin, for the treatment of obesity is very promising and is supported by encouraging weight loss results and improvement in metabolic makers in early-phase clinical studies. However, the latest randomized clinical trial on pramlintide/metreleptin was recently stopped due to safety concerns.

Topics: Animals; Anti-Obesity Agents; Drug Therapy, Combination; Humans; Islet Amyloid Polypeptide; Leptin; Obesity; Treatment Outcome; Weight Loss

Leptin, the protein product of the ob gene, is primarily an adipocyte-secreted hormone, whose functional significance is rapidly expanding. Although early research efforts were focused on defining leptin's role in reversing obesity in rodents, there is now substantial evidence indicating that its influence extends to a number of hypothalamic-pituitaryendocrine axes, including adrenal, gonadal, growth hormone, pancreatic islets, and thyroid. The pleiotropic nature of leptin has been confirmed by demonstration of a role for leptin in hematopoiesis, angiogenesis, immune function, osteogenesis, reproduction, and wound healing. Unfortunately, the results of the majority of clinical trials with recombinant human leptin indicated that its effectiveness in restoring energy balance and correcting obesity-related endocrinopathies in genetically obese rodent models extended only to the management of those rare forms of human obesity caused by mutation in the ob gene. Failure of leptin in the clinic, and withdrawal of phentermine from Europe, and fenfluramine and sibutrimine from clinical use in the United States, have stimulated new approaches in the development of anti-obesity and anti-diabetes pharmacophores. These efforts are focused on utilizing leptin-related synthetic peptides as leptin receptor antagonists or leptin-related synthetic peptide analogs or mimetics. This review summarizes patents on leptin-related peptide analogs, antagonists and mimetics.

Topics: Animals; Anti-Obesity Agents; Diabetes Mellitus, Type 2; Drug Evaluation, Preclinical; Drug Therapy, Combination; Humans; Hypoglycemic Agents; Leptin; Obesity; Patents as Topic; Peptides

Obesity due to endocrine and metabolic disorders causing dysfunctions of appetite-regulating pathways and energy balance is an increasingly concerning issue. Such form of obesity is mainly caused by the failure of elevated levels of the hormone leptin (LEP) to suppress feeding and mediate weight loss; the syndrome, caused by disruptions of signal transduction processes at the level of leptin receptors (LEPR), has been named as leptin resistance. Alterations in genes coding for LEPR and other hypothalamic factors in obese individuals have been related to low rates of pregnancies and deliveries. Fertility depends mainly on the success of processes involving ovulation, fertilization, implantation, placentation and embryo development; processes that seem to be affected in obese females. However, mechanistical research in human beings is very difficult to undertake, especially in reproductive issues, for both technical and ethical reasons. Thus, investigation is usually taken on animal models. Most of the studies have been carried out in mice, in which mutations in LEP and LEPR genes cause severe obese phenotypes (Leprob/ob and Leprdb/db mouse); in addition, such genotypes are infertile. However, total loss of LEPR function by monogenic disorders in humans, unlike mice, are really scarce. Functional alterations by LEPR gene polymorphisms are more common; the same has been found in the swine, an animal model very close to human. This review outlines, from results of translational animal research and clinical studies, the factors, mechanisms and pathways involved in the reproductive failures of individuals with metabolic disorders during the critical period from ovulation to completion of placentation and early-embryo development.

Topics: Animals; Embryo Implantation; Female; Humans; Leptin; Metabolic Diseases; Obesity; Ovulation; Placentation; Pregnancy; Pregnancy Complications; Receptors, Leptin

1. Leptin is a 16-kDa hormone, synthesized primarily by adipocyte, which acts as a key factor for maintenance of energy homeostasis in central and peripheral tissues. In most obese individuals, serum leptin levels are increased and correlate with the individual's body mass index. 2. Abundant investigations ranging from clinical and animal model studies to in vitro analyses show that leptin plays a pivotal role in obesity-related cardiovascular diseases (CVD). Hyperleptinaemia has been confirmed to be a predictor of acute cardiovascular events. However, some studies have shown that leptin has a cardioprotective effect in leptin-deficient models. These data suggest the influences of leptin on the pathophysiology of cardiovascular diseases are complex and not completely understood. 3. In the present review, we summarize the major leptin signalling pathways, including Janus-activated kinase/signal transducers and activators of transcription (Jak/STAT), mitogen-activated protein kinases (MAPK), and phosphatidylinositol 3-kinase (PI-3K) signalling pathways, and analyse the probable mechanisms of selective leptin resistance. We then provide a detailed review of the effects of leptin on the cardiovascular system, including sympathoactivation, oxidative stress, vascular inflammation, endothelial dysfunction, vascular cell proliferation, cardiomyocytes hypertrophy, as well as fatty acid metabolism, all of which contribute to the pathogenesis of cardiovascular diseases (e.g. ischaemic heart disease). The central premise of this review is to elucidate the mechanisms by which leptin affects the cardiovascular function and provide insight into obesity-related CVD.

Topics: Animals; Cardiomegaly; Cardiovascular Diseases; Endothelium, Vascular; Extracellular Matrix; Female; Humans; Inflammation; Leptin; Male; Mice; Myocardium; Obesity; Rats; Receptors, Leptin; Risk Factors; Signal Transduction; Thrombosis

Obesity is associated with metabolic syndrome, a cluster of symptoms including diabetes, hyperlipidemia, hypertension and arteriosclerosis, which can cause serious health problems. Accumulating evidence suggests that endoplasmic reticulum stress (ER stress) is associated with metabolic syndrome. Leptin is an anti-obesity hormone, which is secreted from adipose tissue. Circulating leptin acts at the brain hypothalamus and reduces food intake. As most forms of obesity indicate a state of leptin resistance, elucidation of the mechanisms of leptin resistance would be an important subject. We and other groups have recently suggested that leptin resistance may be derived from ER stress. These results raised the possibility that attenuating ER stress would be effective treatment for the disease. In the present review article, recent understanding of the mechanisms of the development of obesity and the potential novel therapeutic approaches targeting ER stress are discussed.

Topics: Adipose Tissue; Animals; Drug Design; Eating; Endoplasmic Reticulum Stress; Humans; Hypothalamus; Leptin; Life Style; Metabolic Syndrome; Mice; Molecular Targeted Therapy; Obesity; STAT3 Transcription Factor

Nocturnal sleep patterns may be a contributing factor for the epidemic of obesity. Epidemiologic ana experimental studies have reported that sleep restriction is an independent risk factor for weight gain and obesity. Moreover, sleep restriction is significantly associated with incidence and prevalence of obesity and several non-transmissible chronic diseases. Experimental sleep restriction is related to altered plasma leptin and ghrelin concentrations. Both hormones are directly related to appetite and satiety mechanisms. Also, a higher activity of the orexin/hypocretin system has been reported, as well as changes in glucose metabolism and autonomic nervous system. Some studies indicate that these endocrine changes could be associated with a higher diurnal food intake and preference for energy- dense foods. All these changes could result in a positive energy balance, leading to weight gain and a higher obesity risk in the long-term. The present article summarizes the epidemiologic and experimental evidence related to sleep deprivation and higher obesity risk. The possible mechanisms are highlighted.

Topics: Appetite; Energy Metabolism; Ghrelin; Humans; Leptin; Obesity; Risk Factors; Sleep Deprivation

Obesity plays a major role in the development of type 2 diabetes mellitus, and it has long been accepted that weight loss plays a significant role in diabetes therapy. This weight loss has traditionally been accomplished through lifestyle changes including diet and exercise. What has only more recently gained acceptance is that bariatric surgery may have a role to play in diabetes therapy as well. This article discusses the pathophysiology of type 2 diabetes mellitus and obesity and provides a basic understanding of these diseases, which forms the basis for understanding the importance of weight loss in their treatment.

Topics: Animals; Bariatric Surgery; Body Mass Index; Comorbidity; Diabetes Mellitus, Type 2; Disease Progression; Energy Intake; Energy Metabolism; Humans; Insulin Resistance; Leptin; Obesity; Risk Factors; Weight Loss

The current epidemic of obesity and its associated metabolic syndromes impose unprecedented challenges to our society. Despite intensive research on obesity pathogenesis, an effective therapeutic strategy to treat and cure obesity is still lacking. Exciting studies in last decades have established the importance of the leptin neural pathway in the hypothalamus in the regulation of body weight homeostasis. Important hypothalamic neuropeptides have been identified as critical neurotransmitters from leptin-sensitive neurons to mediate leptin action. Recent research advance has significantly expanded the list of neurotransmitters involved in body weight-regulating neural pathways, including fast-acting neurotransmitters, gamma-aminobutyric acid (GABA) and glutamate. Given the limited knowledge on the leptin neural pathway for body weight homeostasis, understanding the function of neurotransmitters released from key neurons for energy balance regulation is essential for delineating leptin neural pathway and eventually for designing effective therapeutic drugs against the obesity epidemic.

Topics: Animals; Energy Metabolism; Gene Expression; Humans; Hunger; Hypothalamus; Leptin; Neural Pathways; Neuropeptides; Obesity

Osteoarthritis (OA), the most common form of arthritis, is associated with joint malfunction and chronic disability in the aged population. It is a multifactorial disorder to which several factors-such as age, sex, trauma, and obesity-contribute significantly. Obesity is one of the most influential but modifiable risk factors because it exerts an increased mechanical stress on the tibiofemoral cartilage. However, the high prevalence of OA in obese individuals in non-weightbearing areas, like finger joints, suggests that the link between being overweight and OA lies with factors other than simple biomechanics. An important correlation has been made between obesity and inflammation. Adipose tissues (and the infrapatellar fat pad) play an important role in this context because they are the major source of cytokines, chemokines, and metabolically active mediators called adipokines (or adipocytokines). These metabolic factors are known to possess catabolic and proinflammatory properties and to orchestrate the pathophysiological processes in OA. This review provides information on the relationship between obesity and OA through biomechanical and biochemical factors and highlights the functions of important obesity-related inflammatory products in the initiation and progression of OA. This information will broaden our thinking in identifying the targets for both prevention and intervention for OA.

Topics: Adiponectin; Adipose Tissue; Animals; Cytokines; Disease Models, Animal; Humans; Inflammation; Inflammation Mediators; Interleukin-1beta; Interleukin-6; Interleukin-8; Leptin; Obesity; Osteoarthritis; Prevalence; Resistin; Risk Factors; Tumor Necrosis Factor-alpha

Obesity has various deleterious effects on health largely associated with metabolic abnormalities including abnormal glucose and lipid homeostasis that are associated with vascular injury and known cardiac, renal, and cerebrovascular complications. Advanced age is also associated with increased adiposity, decreased lean mass, and increased risk for obesity-related diseases. Although many of these obesity- and age-related disease processes have long been subsumed to be secondary to metabolic or vascular dysfunction, increasing evidence indicates that obesity also modulates nonvascular diseases such as Alzheimer's disease (AD) dementia. The link between peripheral obesity and neurodegeneration will be explored, using adipokines and AD as a template. After an introduction to the neuropathology of AD, the relationship between body weight, obesity, and dementia will be reviewed. Then, population-based and experimental studies that address whether leptin modulates brain health and mitigates AD pathways will be explored. These studies will serve as a framework for understanding the role of adipokines in brain health.

Topics: Aging; Alzheimer Disease; Animals; Biomarkers; Body Weight; Brain; Disease Models, Animal; Female; Humans; Leptin; Male; Mice; Models, Neurological; Obesity; Receptors, Leptin; Risk Factors; Signal Transduction

Orexin-A (hypocretin-1) and orexin-B (hypocretin-2) are hypothalamic neuropeptides that play key roles in the regulation of wakefulness, feeding, reward, autonomic functions and energy homeostasis. To control these functions indispensable for survival, orexin-expressing neurones integrate peripheral metabolic signals, interact with many types of neurones in the brain and modulate their activities via the activation of orexin-1 receptor or orexin-2 receptor. In addition, a new functional role of orexin is emerging in the regulation of insulin and leptin sensitivities responsible for whole-body glucose metabolism. Recent evidence indicates that orexin efficiently protects against the development of peripheral insulin resistance induced by ageing or high-fat feeding in mice. In particular, the orexin receptor-2 signalling appears to confer resistance to diet-induced obesity and insulin insensitivity by improving leptin sensitivity. In fact, the expression of orexin gene is known to be down-regulated by hyperglycaemia in the rodent model of diabetes, such as ob/ob and db/db mice. Moreover, the levels of orexin receptor-2 mRNA have been shown to decline in the brain of mice along with ageing. These suggest that hyperglycaemia due to insulin insensitivity during ageing or by habitual consumption of a high-fat diet leads to the reduction in orexin expression in the hypothalamus, thereby further exacerbating peripheral insulin resistance. Therefore, orexin receptor controlling hypothalamic insulin/leptin actions may be a new target for possible future treatment of hyperglycaemia in patients with type 2 diabetes.

Topics: Aging; Animals; Diet; Energy Intake; Energy Metabolism; Glucose; Homeostasis; Humans; Hypothalamus; Insulin; Insulin Resistance; Intracellular Signaling Peptides and Proteins; Leptin; Neurons; Neuropeptides; Neurotransmitter Agents; Obesity; Orexin Receptors; Orexins; Receptors, G-Protein-Coupled; Receptors, Neuropeptide; RNA, Messenger; Signal Transduction; Thermogenesis

A moderate elevation of thyrotropin (TSH) concentrations, which is associated with triiodothyronine (T3) values in or slightly above the upper normal range, is frequently found in obese humans. These alterations seem rather a consequence than a cause of obesity since weight loss leads to a normalization of elevated thyroid hormone levels. Elevated thyroid hormone concentrations increase the resting energy expenditure (REE). The underlying pathways are not fully understood. As a consequence of the increased REE, the availability of accumulated energy for conversion into fat is diminished. In conclusion, the alterations of thyroid hormones in obesity suggest an adaptation process. Since rapid weight loss is associated with a decrease of TSH and T3, the resulting decrease in REE may contribute towards the difficulties maintaining weight loss. Leptin seems to be a promising link between obesity and alterations of thyroid hormones since leptin concentrations influence TSH release.

Topics: Adipokines; Animals; Anorexia Nervosa; Body Weight; Energy Metabolism; Humans; Leptin; Obesity; Thyroid Function Tests; Thyroid Gland; Thyrotropin; Triiodothyronine

Obesity in men, particularly when central, is associated with lower total testosterone [TT], free testosterone [FT] and sex hormone-binding globulin [SHBG], and a greater decline in TT and FT with increasing age compared with lean men. Obesity-related conditions such as obstructive sleep apnea, insulin resistance and type 2 diabetes mellitus are independently associated with decreased plasma testosterone. Possible mechanisms include decreased LH pulse amplitude, inhibitory effects of oestrogen at the hypothalamus and pituitary and the effects of leptin and other peptides centrally and on Leydig cells. Obese men have reduced sperm concentration and total sperm count compared to lean men but sperm motility and morphology appear unaffected. The cause and effect relationships between low plasma androgen levels, obesity and the metabolic syndrome, and associated cardiometabolic risk remain unclear. While weight loss normalizes TT and FT in obese men, androgen replacement in the short term does not significantly improve cardiometabolic risk profile despite reducing fat mass.

Topics: Aging; Animals; Body Mass Index; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Humans; Hypogonadism; Hypothalamo-Hypophyseal System; Leptin; Luteinizing Hormone; Male; Metabolic Syndrome; Obesity; Risk Factors; Signal Transduction; Sleep Apnea, Obstructive; Spermatogenesis; Testis; Testosterone; Weight Loss

Topics: Animals; Blood-Brain Barrier; Body Weight; Brain; Feeding Behavior; Humans; Leptin; Neuronal Plasticity; Obesity; Receptors, Leptin; Reward; Satiety Response; Signal Transduction; Synaptic Transmission

Obesity is characterized by increased storage of fatty acids in an expanded adipose tissue mass and is closely associated with the development of insulin resistance in peripheral tissues such as skeletal muscle and the liver. In addition to being the largest source of fuel in the body, adipose tissue and resident macrophages are also the source of a number of secreted proteins. Cloning of the obese gene and the identification of its product, leptin, was one of the first discoveries of an adipocyte-derived signaling molecule and established an important role for adipose tissue as an endocrine organ. Since then, leptin has been found to have a profound role in the regulation of whole-body metabolism by stimulating energy expenditure, inhibiting food intake and restoring euglycemia, however, in most cases of obesity leptin resistance limits its biological efficacy. In contrast to leptin, adiponectin secretion is often diminished in obesity. Adiponectin acts to increase insulin sensitivity, fatty acid oxidation, as well as energy expenditure and reduces the production of glucose by the liver. Resistin and retinol binding protein-4 are less well described. Their expression levels are positively correlated with adiposity and they are both implicated in the development of insulin resistance. More recently it has been acknowledged that macrophages are an important part of the secretory function of adipose tissue and the main source of inflammatory cyokines, such as TNFalpha and IL-6. An increase in circulating levels of these macrophage-derived factors in obesity leads to a chronic low-grade inflammatory state that has been linked to the development of insulin resistance and diabetes. These proteins commonly known as adipokines are central to the dynamic control of energy metabolism, communicating the nutrient status of the organism with the tissues responsible for controlling both energy intake and expenditure as well as insulin sensitivity.

Topics: Adiponectin; Adipose Tissue; Animals; Endocrine Glands; Energy Metabolism; Humans; Insulin Resistance; Interleukin-6; Leptin; Macrophages; Obesity; Protein Conformation; Resistin; Retinol-Binding Proteins, Plasma; Signal Transduction; Tumor Necrosis Factor-alpha

Body weight is tightly controlled in a species-specific range from insects to vertebrates and organisms have developed a complex regulatory network in order to avoid either excessive weight gain or chronic weight loss. Energy homeostasis, a term comprising all processes that aim to maintain stability of the metabolic state, requires a constant communication of the different organs involved; i.e. adipose tissue, skeletal muscle, liver, pancreas and the central nervous system (CNS). A tight hormonal network ensures rapid communication to control initiation and cessation of eating, nutrient processing and partitioning of the available energy within different organs and metabolic pathways. Moreover, recent experiments indicate that many of these homeostatic signals modulate the neural circuitry of food reward and motivation. Disturbances in each individual system can affect the maintenance and regulation of the others, making the analysis of energy homeostasis and its dysregulation highly complex. Though this cross-talk has been intensively studied for many years now, we are far from a complete understanding of how energy balance is maintained and multiple key questions remain unanswered. This review summarizes some of the latest developments in the field and focuses on the effects of leptin, insulin, and nutrient-related signals in the central regulation of feeding behavior. The integrated view, how these signals interact and the definition of functional neurocircuits in control of energy homeostasis, will ultimately help to develop new therapeutic interventions within the current obesity epidemic.

Topics: Animals; Body Weight; Brain; Diabetes Mellitus; Eating; Energy Metabolism; Glucose; Homeostasis; Humans; Hypothalamus; Insulin; Leptin; Neurosecretory Systems; Nutritional Physiological Phenomena; Obesity; Signal Transduction

Beta-aminoisobutyric acid (BAIBA) is a catabolite of thymine and antiretroviral thymine analogues AZT and d4T. We recently discovered that this beta-amino acid is able to enhance fatty acid oxidation and reduce body weight in mice through an increased production of leptin by the white adipose tissue (WAT). Furthermore, BAIBA could have favourable effects on nonalcoholic steatohepatitis in a leptin-independent manner. In the present review, we shall recall the circumstances that led us to discover the effects of BAIBA on body fat mass and lipid homeostasis. In addition, we put forward several hypothetical mechanisms whereby BAIBA could enhance leptin secretion by WAT and present some anti-inflammatory effects in the liver. We also discuss in this review (i) the deleterious impacts caused by the absence of, or low leptin expression on lipid homeostasis and body weight in humans and animals and (ii) recent data from other investigators suggesting that increasing leptin levels and/or responsiveness may be indeed an attractive pharmacological strategy in order to prevent (and/or treat) obesity, at least in some individuals.

Topics: Aminoisobutyric Acids; Animals; Homeostasis; Humans; Leptin; Lipid Metabolism; Mice; Mice, Obese; Obesity

Determining the effect of hypothalamic inflammatory signals on energy balance presents a paradox. On the one hand, a large body of work has identified inflammatory signaling in the hypothalamus as an essential mediator of the sickness response--the anorexia, cachexia, fever, inactivity, lethargy, anhedonia and adipsia that are triggered by systemic inflammatory stimuli and promote negative energy balance. On the other hand, numerous recent studies implicate inflammatory activation within the hypothalamus as a key factor whereby high-fat diets--and saturated fats in particular--cause central leptin and insulin resistance and thereby promote the defense of elevated body weight. This paradox will likely remain unresolved until several issues have been addressed. Firstly, the hypothalamus--unlike many peripheral inflamed tissues--is an extremely heterogeneous tissue comprised of astrocytes, oligodendrocytes, microglia, endothelial cells, ependymal cells as well as numerous neuronal subgroups. Determining exactly which cells activate defined inflammatory signals in response to a particular stimulus--i.e. sepsis vs. nutrient excess--may yield critical clues. Secondly, for the sake of simplicity many studies evaluate inflammation as an on/off phenomenon. More realistically, inflammatory signaling occurs as a cascade or cycle that changes and progresses over time. Accordingly, even within the same cell type, the low-grade, chronic signal induced by nutrient excess may invoke a different cascade of signals than a strong, acute signal such as sepsis. In addition, because tolerance can develop to certain inflammatory mediators, physiological outcomes may not correlate with early biochemical markers. Lastly, the neuroanatomical location, magnitude, and duration of the inflammatory stimulus can undoubtedly influence the net CNS response. Rigorously evaluating the progression of the inflammatory signaling cascade within specific hypothalamic cell types is a key next step towards resolving the paradox surrounding the effect of inflammatory signaling on energy homeostasis.

Topics: Animals; Dietary Fats; Eating; Energy Metabolism; Homeostasis; Humans; Hypothalamus; Inflammation; Insulin Resistance; Leptin; Melanocortins; Obesity; Signal Transduction; Weight Gain

Acute or long-term energy deficit in lean or obese rodents or humans stimulates food intake or appetite and reduces metabolic rate or energy expenditure. These changes contribute to weight regain in post-obese animals and humans. Some studies show that the reduction in metabolic rate with energy deficit in overweight people is transient. Energy restriction has been shown in some but not all studies to reduce physical activity, and this may represent an additional energy-conserving adaptation. Energy restriction up-regulates expression of the orexigenic neuropeptide Y, agouti related peptide and opioids and down-regulates that of the anorexigenic alpha-melanocyte stimulating hormone or its precursor pro-opioomelanocortin and the co-expressed cocaine and amphetamine-regulated transcript in the arcuate nucleus of the hypothalamus. Recapitulating these hypothalamic changes in sated animals mimics the effects of energy deficit, namely increased food intake, reduced physical activity and reduced metabolic rate, suggesting that these energy-conserving adaptations are at least partially mediated by the hypothalamus.

Topics: Agouti-Related Protein; Animals; Appetite; Arcuate Nucleus of Hypothalamus; Body Weight; Eating; Energy Metabolism; Fasting; Humans; Leptin; Motor Activity; Nerve Tissue Proteins; Neuropeptide Y; Obesity; Oxygen Consumption; Pro-Opiomelanocortin; Signal Transduction; Weight Loss

The worldwide pandemic of obesity is creating unique challenges for the diagnosis and treatment of asthma. A wealth of epidemiologic literature has established that whereas asthma can lead to obesity, obesity is a risk factor for asthma, but mechanisms are unclear. This review assesses the current understanding of the relationship between obesity and asthma.. Recent studies are developing a more sophisticated understanding of the possible inflammatory, immunologic, genetic, and mechanical mechanisms underlying the association between obesity and asthma. Obese asthma may be a unique phenotype of asthma, with a more difficult clinical course and altered response to asthma controller therapy. Adipokines such as leptin and adiponectin are thought to be important, but there is new interest in other inflammatory mechanisms related to visceral obesity, insulin resistance, and the metabolic syndrome.. There are still far more questions than answers as to how obesity might cause or worsen asthma. It is clear that weight gain and obesity are particularly troublesome in asthmatics, and clinicians should target these individuals for aggressive intervention. Randomized controlled trials are needed to determine the best treatment approaches for obese asthma, and prospective studies in which both obesity and asthma are well characterized are needed to better understand the underlying mechanisms.

Topics: Adipokines; Asthma; Humans; Insulin Resistance; Leptin; Obesity; Protein Kinase C-alpha

Adipose tissue is now considered to be an active physiologic system operating in concert with multiple other organs. Leptin is a peptide hormone that is primarily synthesized and secreted by adipose tissue whose principal action is the control of appetite and energy balance. However, current information suggests that leptin exerts pleiotropic effects on several organ systems. Herein, we review the potential role of leptin in cardiovascular and renal physiological conditions as well as pathophysiological situations including obesity and hypertension.. Increasing evidence suggests that leptin may function as a pressure and volume-regulating factor under conditions of health; however, in situations characterized by chronic hyperleptinemia such as obesity, it may function pathophysiologically for the development of hypertension and possibly also for adverse renal, vascular and cardiac remodeling.. Adipose tissue should be regarded as a potentially important mediator of cardiorenal physiology. Further research awaits the characterization of additional mechanisms of action of leptin, including its interface with other important endocrine and hemodynamic sodium-volume regulatory systems, in both health and disease, particularly in obesity and related comorbidities. This information could lead to the development of leptin analogues as well as leptin receptor blockers that given specific circumstances could optimize the beneficial actions of the hormone and minimize its deleterious effects.

Topics: Adipose Tissue; Animals; Blood Pressure; Cardiovascular Diseases; Cardiovascular System; Homeostasis; Humans; Hypertension; Kidney; Leptin; Models, Biological; Models, Cardiovascular; Obesity; Receptors, Leptin; Renal Insufficiency, Chronic; Water-Electrolyte Balance

Epidemiological data indicate that obesity is a risk factor for asthma, but the mechanistic basis for this relationship is not established. Here we review data from human subjects and animal models investigating the relationship between obesity and airway hyperresponsiveness, a characteristic feature of asthma. We discuss obesity as a state of chronic systemic inflammation resulting from interactions between adipocytes and adipose tissue macrophages that are recruited to obese adipose tissue. Finally, we focus on the possibility that aspects of this inflammation, particularly obesity-related changes in TNF-alpha, leptin, and adiponectin, may contribute to airway hyperresponsiveness in obesity. Determining how obesity promotes asthma may uncover novel therapeutic strategies that are effective in the obese asthmatic subject.

Topics: Adiponectin; Adipose Tissue; Adult; Animals; Asthma; Bronchial Hyperreactivity; Child; Female; Humans; Inflammation; Inflammation Mediators; Leptin; Male; Obesity; Risk Factors; Tumor Necrosis Factor-alpha

Obesity is a universal health problem of increasing prevalence and represents a major public health concern. Obesity is associated with a high risk of developing cardiovascular and metabolic diseases such as hypertension, coronary atherosclerosis, myocardial hypertrophy, diabetes, dyslipidemia, and increased cardiovascular morbidity and mortality. There has been an ongoing search for mediators between obesity and cardiovascular disease. Leptin is a novel and very promising molecule of research that may link these pathologic conditions. Since its discovery in 1994, major advances have been made in the understanding of neuroendocrine mechanisms regulating appetite, metabolism, adiposity, sympathetic tone and blood pressure. In this review, we discuss the physiological and pathophysiological roles of leptin in the causation of various cardiovascular diseases.

Topics: Cardiovascular Diseases; Diabetes Mellitus; Homeostasis; Humans; Hypertension; Leptin; Obesity; Risk Factors

In the 20th century industrialized nations have become afflicted with an unprecedented pandemic of increased adiposity. In the United States, the epicenter of the epidemic, over 2/3 of the population, is overweight and 1 of every 6 Americans carries the diagnosis of metabolic syndrome. Although genes determine susceptibility to environmental factors, the epidemic is clearly due to increased consumption of calorie-dense, highly lipogenic foods, coupled with a marked decrease in physical exertion resulting from modern technologies. If this lifestyle continues, morbid consequences are virtually inevitable. They include type II diabetes and a cluster of disorders known as "the metabolic syndrome" usually appearing in middle age. The morbid consequences of the chronic caloric surplus are buffered before middle age by the partitioning of these calories as fat in the adipocyte compartment which is specifically designed to store triglycerides. Leptin has been proposed as the major hormonal regulator of the partitioning of surplus calories. However, multiple factors can determine the storage capacity of the fat tissue and when it is exceeded ectopic lipid deposition begins. The organs affected in metabolic syndrome include skeletal muscle, liver, heart and pancreas, which are now known to contain abnormal levels of triglycerides. While neutral fat is probably harmless, it is an index of ectopic lipid overload. Fatty acid derivatives can interfere with the function of the cell and ultimately lead to its demise through lipoapoptosis, the consequences of which are gradual organ failure.

Topics: Animals; Homeostasis; Humans; Leptin; Lipid Metabolism; Metabolic Syndrome; Obesity

A wealth of investigations, ranging from clinical and animal model studies to in vitro analyses, have generated great interest in the cardiovascular effects of leptin. Accordingly, many studies have examined the contribution of leptin to cardiac remodeling in heart failure and whether the effects of leptin on metabolism, apoptosis, extracellular matrix remodeling, and hypertrophy could explain the so-called obesity paradox. Furthermore, obesity and hyperleptinemia have often been associated with hypertension, and regulation of sympathetic tone or direct effects of leptin on contributors such as atherosclerosis, endothelial dysfunction, and thrombosis have been documented. Unfortunately, translating basic research studies in vitro, or in animal models, to human physiology has proven difficult. The degree of leptin resistance in obesity is one intriguing issue that must be resolved. Furthermore, the importance of autocrine and paracrine effects of leptin derived from the heart and perivascular adipose tissue must be further studied. Carefully planned and executed research to conclusively establish distinct effects of leptin on the cardiovascular system in normal and diseased states will be essential to harness any therapeutic potential associated with leptin's effects.

Topics: Adipose Tissue; Animals; Apoptosis; Atherosclerosis; Cardiovascular Diseases; Cardiovascular Physiological Phenomena; Endothelium, Vascular; Extracellular Matrix; Humans; Hypertension; Inflammation; Leptin; Myocardium; Obesity

Leptin acts as an anorexigenic hormone in the brain, where the long form of the leptin receptor (LRb) is widely expressed in hypothalamic and extra-hypothalamic sites that are known to participate in diverse feeding circuits. The important role of leptin in energy homeostasis is demonstrated by the profound hyperphagia and morbid obesity in humans and rodents null for leptin or LRb. However, common forms of obesity are associated with high leptin levels and a failure to respond effectively to exogenous leptin; indicating a state of leptin resistance. Leptin resistance is thought to be an important component in the development of obesity. Several defects may contribute to the leptin resistant state, including a defective leptin transport across the blood-brain barrier, which reduces the availability of leptin at its receptor. Furthermore, defects in LRb signal transduction involving reduced LRb expression or the induction of feedback inhibitors have been found in leptin resistance; these defects are commonly termed cellular leptin resistance,. Finally, reduced leptin action can result in the disruption of proper neuronal interactions, by altering neuronal wiring. Interestingly, some leptin functions remain intact in the leptin-resistant state, such as cardiovascular leptin effects. The appearance of selective leptin resistance is mirrored by the observation that cellular leptin resistance has been found only in some subpopulations of hypothalamic LRb neurons. Current efforts to dissect leptin function in specific populations of LRb neurons will increase our understanding of these complexities of leptin physiology.

Topics: Adipose Tissue; Animals; Energy Metabolism; Feedback, Physiological; Humans; Leptin; Obesity; Receptors, Leptin; Signal Transduction

Puberty, as the end-point of a complex series of maturational events affecting the components of the hypothalamic-pituitary-gonadal (HPG) axis, is gated by the state of body energy reserves and sensitive to different metabolic cues; conditions of severe metabolic stress and energy unbalance (from anorexia to morbid obesity) being commonly linked to perturbation of the onset of puberty. In the last two decades, the neuroendocrine mechanisms responsible for the tight coupling between energy homeostasis and puberty onset have begun to be deciphered. These seemingly involve a plethora of metabolic hormones and neuropeptides, which impinge and integrate (mostly) at the hypothalamic centers governing reproduction. Yet, characterization of the mechanisms of action of such regulators (and even their nature and physiological relevance) still remains incomplete. In this review, we will summarize some recent developments in our knowledge of the effects and mechanisms of action of two key metabolic hormones, leptin and ghrelin, in the control of puberty onset. In addition, the roles of the hypothalamic Kiss1 system in the metabolic gating of puberty will be reviewed, with special attention to its regulation by leptin and the recent identification of the putative roles of Crtc1 and mTOR signaling as molecular conduits for the metabolic control of Kiss1 expression. Elucidation of these novel players and regulatory mechanisms will help for a better understanding of the determinants of the timing of puberty, and its eventual alterations in adverse metabolic conditions.

Topics: Animals; Ghrelin; Humans; Leptin; Obesity; Puberty; Sexual Maturation; Signal Transduction; Tumor Suppressor Proteins

A majority of human obesity is inherited as a polygenic trait. Once obesity develops, over 90% of individuals repeatedly regain lost weight after dieting. Only surgical interventions offer long lasting weight loss. Thus, clinical data suggest that some individuals have a predisposition to develop and maintain an elevated body weight set-point once they are provided with sufficient calories to gain weight. This set-point is mediated by an integrated neural network that controls energy homeostasis. Unfortunately, currently available tools for identifying obesity-prone individuals and examining the functioning of these neural systems have insufficient resolution to identify specific neural factors that cause humans to develop and maintain the obese state. However, rodent models of polygenically inherited obesity allow us to investigate the factors that both predispose them to become obese and that prevent or enhance the development of such obesity. Maternal obesity during gestation and lactation in obesity-prone rodents enhances offspring obesity and alters their neural pathways involved in energy homeostasis regulation. Early postnatal exposure of obesity-resistant offspring to the milk of genetically obese dams alters their hypothalamic pathways involved in energy homeostasis causing them to become obese when fed a high fat diet as adults. Finally, short-term exercise begun in the early post-weaning period increases the sensitivity to the anorectic effects of leptin and protects obesity-prone offspring from becoming obese for months exercise cessation. Such studies suggest that early identification of obesity-prone humans and of the factors that can prevent them from becoming obese could provide an effective strategy for preventing the world wide epidemic of obesity.

Topics: Animals; Brain; Energy Metabolism; Homeostasis; Humans; Leptin; Neural Pathways; Obesity

Body fat distribution is an important metabolic and cardiovascular risk factor, because the proportion of abdominal to gluteofemoral body fat correlates with obesity-associated diseases and mortality. Here, we review the evidence and possible mechanisms that support a specific protective role of gluteofemoral body fat. Population studies show that an increased gluteofemoral fat mass is independently associated with a protective lipid and glucose profile, as well as a decrease in cardiovascular and metabolic risk. Studies of adipose tissue physiology in vitro and in vivo confirm distinct properties of the gluteofemoral fat depot with regards to lipolysis and fatty acid uptake: in day-to-day metabolism it appears to be more passive than the abdominal depot and it exerts its protective properties by long-term fatty acid storage. Further, a beneficial adipokine profile is associated with gluteofemoral fat. Leptin and adiponectin levels are positively associated with gluteofemoral fat while the level of inflammatory cytokines is negatively associated. Finally, loss of gluteofemoral fat, as observed in Cushing's syndrome and lipodystrophy is associated with an increased metabolic and cardiovascular risk. This underlines gluteofemoral fat's role as a determinant of health by the long-term entrapment of excess fatty acids, thus protecting from the adverse effects associated with ectopic fat deposition.

Topics: Adipokines; Adipose Tissue; Adult; Aged; Body Fat Distribution; Buttocks; Cardiovascular Diseases; Female; Health Behavior; Humans; Leptin; Male; Middle Aged; Obesity; Risk Factors; Thigh; Tumor Necrosis Factor-alpha

Leptin is a hormone secreted by adipose tissue in direct proportion to amount of body fat. The circulating leptin levels serve as a gauge of energy stores, thereby directing the regulation of energy homeostasis, neuroendocrine function, and metabolism. Persons with congenital deficiency are obese, and treatment with leptin results in dramatic weight loss through decreased food intake and possible increased energy expenditure. However, most obese persons are resistant to the weight-reducing effects of leptin. Recent studies suggest that leptin is physiologically more important as an indicator of energy deficiency, rather than energy excess, and may mediate adaptation by driving increased food intake and directing neuroendocrine function to converse energy, such as inducing hypothalamic hypogonadism to prevent fertilization. Current studies investigate the role of leptin in weight-loss management because persons who have recently lost weight have relative leptin deficiency that may drive them to regain weight. Leptin deficiency is also evident in patients with diet- or exercise-induced hypothalamic amenorrhea and lipoatrophy. Replacement of leptin in physiologic doses restores ovulatory menstruation in women with hypothalamic amenorrhea and improves metabolic dysfunction in patients with lipoatrophy, including lipoatrophy associated with HIV or highly active antiretroviral therapy. The applications of leptin continue to grow and will hopefully soon be used therapeutically.

Topics: Adipose Tissue; Amenorrhea; Animals; Atrophy; Energy Metabolism; Female; Humans; Insulin Resistance; Leptin; Male; Metabolic Syndrome; Neurosecretory Systems; Obesity; Recombinant Proteins; Weight Loss

Active weight loss and the maintenance of a weight-reduced state elicit potent counter-regulatory responses in multiple neurochemical pathways rendering monotherapy-based anti-obesity agents relatively ineffective. Herein, we highlight potential strategies for overcoming counter-regulatory responses to states of negative energy balance using combinatorial approaches. We discuss methodological and practical considerations for preclinical modeling of additive/synergistic weight loss combinations that have emerged in our translational research program aimed at identifying naturally occurring neurohormonal synergies. As an example of synergy, pharmacological and mechanistic findings with the combined administration of the beta-cell hormone amylin and the adipokine leptin are reviewed. Finally, we briefly discuss what the future landscape of neurohormonal anti-obesity combinations may hold.

Topics: Anti-Obesity Agents; Combined Modality Therapy; Humans; Islet Amyloid Polypeptide; Leptin; Obesity; Weight Loss

Topics: Animals; Cloning, Molecular; Diabetes Mellitus, Type 2; Energy Metabolism; Genetic Predisposition to Disease; Humans; Leptin; Mice; Models, Genetic; Obesity; Phenotype; Publications; Receptors, Leptin; Thinness

In recent years, obesity has been identified as a risk factor for the development of breast cancer in postmenopausal women, and it has been associated with a poor outcome. Many factors appear to be important in the mechanism of this increased risk, including estrogen, estrogen receptors, and the adipokines leptin and adiponectin. Estrogen, a potent mitogen for mammary cells, has long been implicated in the development of mammary tumors. Because adipose-associated aromatase activity increases the conversion of androgen to estrogen, mammary adipose tissue is thought to be an important source of local estrogen production. Leptin, which increases in the circulation in proportion to body fat stores, has been demonstrated in vitro to promote breast cancer cell growth. Animal models have also identified leptin as an important factor for the development of mammary tumors. In contrast to leptin, serum adiponectin concentrations are inversely related to body fat stores, and the addition of adiponectin to human breast cancer cells reduces cell proliferation and enhances apoptosis. This review explores the relationship between these factors and the development of mammary cancer in humans and mouse models.

Topics: Adiponectin; Animals; Breast Neoplasms; Cell Transformation, Neoplastic; Disease Models, Animal; Estrogens; Female; Humans; Leptin; Mice; Obesity; Receptors, Estrogen

A large body of epidemiological data suggests that adverse early environments, including obesity during pregnancy or early postnatal life, are linked to an elevated prevalence of metabolic disease in adult offspring. The mechanisms underlying these effects are still poorly understood, but recent data from rodents provide insight into a potential role for the brain in this 'metabolic programming.' This review summarizes the developmental changes that have been observed in the hypothalamus in response to changes in the early nutritional and hormonal environment. It also discusses how resetting a diverse array of neuroendocrine systems may have long-term effects on the regulation of metabolism and energy balance.

Topics: Animals; Child Development; Energy Metabolism; Female; Humans; Hypothalamus; Infant; Infant Nutritional Physiological Phenomena; Leptin; Maternal Nutritional Physiological Phenomena; Metabolic Diseases; Neurosecretory Systems; Obesity; Pregnancy; Pregnancy Complications; Prenatal Exposure Delayed Effects

Obesity is a well-established risk factor for the development and mortality from several cancers, including adenocarcinoma of the oesophagus, oesophago-gastric junction and colorectum. Despite a large body of epidemiological evidence describing this relationship, the mechanisms relating obesity and cancer are only starting to be uncovered. The altered secretion of metabolically active, pro-inflammatory adipocytokines from adipose tissue is believed to play a key role, and leptin is believed to be a key player in obesity-related carcinogenesis, as well as being the most extensively studied of the adipokines. In this literature review, we aim to examine the association between leptin and cancers of the gastro-intestinal tract. For each individual cancer, we examine and present the published data examining the role of leptin in both cell and animal models, the association between circulating leptin levels and cancer risk, and finally the expression of the leptin system in human gastro-intestinal tract tumours, in relation to tumour biology, stage and patient outcome.

Topics: Gastrointestinal Neoplasms; Humans; Leptin; Obesity; Receptors, Leptin; Risk Factors

From hot dogs to Hashimoto's and inheritance to inactivity, many "entrance ramps" converge onto the "Highway to Obesity", each contributing caloric intake that exceeds expenditure. Initially, the hypothalamus regulates appetite and energy based on leptin feedback, until feedback failure increases appetite, and allows deposition of abdominal fat, metabolic dysregulation, and metabolic syndrome. Without feedback controls, progress toward obesity is unimpeded unless diet, exercise, and/or medications provide an exit ramp.

Topics: Adult; Animals; Feedback, Physiological; Genetic Predisposition to Disease; Humans; Leptin; Obesity

Obesity as a pathogenic disorder is a predisposing factor for cardiovascular diseases and shows an increasing incidence in the industrialized countries. Adipokines such as leptin, adiponectin and resistin have a great impact on the development of atherosclerosis in obesity. Elevated levels of leptin have been found to be atherogenic whereas decreased levels of adiponectin have been proved to be anti-atherogenic in recent studies. The exact role of resistin in the process of atherosclerosis has so far remained uncertain and controversial. In our recent work, we studied the alteration in human paraoxonase-1 (PON1) activity and adipokine levels; furthermore, we also aimed at identifying the potential correlation between these parameters in this metabolic disorder. We investigated the above-mentioned parameters both in adults and in children, with regard to the emerging role of childhood obesity and to get a clearer view of these factors during a whole lifetime. Investigating the adult population with a broad range of body mass index (BMI) we found significantly increased leptin and significantly decreased adiponectin and resistin levels and PON1 activity in the obese group compared to the lean controls. Adiponectin and resistin levels showed significantly positive correlation, while leptin and BMI showed significantly negative correlation with PON1 activity. Our findings were similar in childhood obesity: leptin showed significantly negative correlation, while adiponectin showed significantly positive correlation with PON1 activity. We found gender differences in the univariate correlations of leptin and adiponectin levels with PON1 activity in the adult population. In multiple regression analysis, adiponectin proved to be an independent factor of PON1 activity both in childhood and adult obesity, furthermore thiobarbituric acid-reactive substances (TBARS) also proved to be an independent predictor of the enzyme in adults, reflecting the important role of oxidative stress in obesity. Investigating PON 192 Q/R polymorphism by phenotypic distribution (A/B isoenzyme) in obese children, we found a significant correlation of PON1 arylesterase activity with leptin and adiponectin levels, and of body fat percentage with PON1 192 B isoenzyme. According to our studies, these metabolic changes in obesity predispose to the early development of atherosclerosis throughout our whole lifetime. Decreased activity of PON1 and alterations in adipokine levels in childhood obes

Topics: Adipokines; Adult; Animals; Aryldialkylphosphatase; Atherosclerosis; Child; Gene Expression Regulation, Enzymologic; Humans; Leptin; Lipid Peroxidation; Models, Biological; Obesity; Phenotype; Polymorphism, Genetic; Thiobarbituric Acid Reactive Substances

Once considered divine retribution for sins, comorbidities of obesity (metabolic syndrome) are today attributed to obesity-induced metabolic defects. Here, we propose that obesity and hyperleptinemia protect lipid-intolerant nonadipose organs against lipotoxic lipid spillover during sustained caloric surplus. Metabolic syndrome is ascribed to lipotoxicity caused by age-related resistance to antilipotoxic protection by leptin.

Topics: Adipose Tissue; Energy Intake; Humans; Hyperphagia; Leptin; Lipids; Metabolic Syndrome; Obesity

Obesity is considered to be an important risk factor for postmenopausal breast cancer. Elevated estrogen levels are thought to be a growth factor associated with this relationship. However, there is increasing evidence that factors produced directly in adipose tissue, adipokines, can also affect breast cancer development. Leptin is one of the adipokines that is measured in serum/plasma in increasing amounts as body weight/body fat increases.. We highlight important aspects of leptin in relationship to mammary/breast tumor development. This includes findings from human, in vitro and animal studies. Information on leptin-related compounds which may have therapeutic use is presented. Additionally strategies to alter serum leptin levels by dietary and pharmacological interventions are discussed.. The reader will gain insights into the relationship of an adipose tissue protein and its potential role in breast cancer development as well as ways to intervene in leptin's actions.. Continued research will determine if interfering with the action of leptin has preventive or therapeutic applications in breast cancer.

Topics: Animals; Antineoplastic Agents; Breast Neoplasms; Cell Line, Tumor; Female; Humans; Leptin; Mammary Neoplasms, Experimental; Obesity

To review the pathophysiology, pharmacology, and current or future therapies under study for use in treating diabetes mellitus, inflammation associated with diabetes mellitus, and/or obesity related to diabetes mellitus, through 1 of 4 investigational pathways: adiponectin, ghrelin, resveratrol, or leptin.. A literature search using MEDLINE (1966-December 12, 2009), PubMed (1950-December 12, 2009), Science Direct (1994-December 12, 2009), and International Pharmaceutical Abstracts (1970-December 12, 2009) was performed using the terms adiponectin, ghrelin, resveratrol, leptin, inflammation, obesity, and diabetes mellitus. English-language, original research, and review articles were examined, and citations from these articles were assessed as well.. Clinical studies and in vitro studies were included in addition to any Phase 1, 2, or 3 clinical trials.. Mechanistic pathways regarding adiponectin, ghrelin, resveratrol, and leptin are of interest as future treatment options for diabetes mellitus. Each of these pathways has produced significant in vitro and in vivo clinical data warranting further research as a possible treatment pathway for diabetes-related inflammation and/or obesity reduction. While research is still underway to determine the exact effects these pathways have on metabolic function, current data suggest that each of these compounds may be of interest for future therapies.. While several pathways under investigation may offer additional benefits in the treatment of diabetes mellitus and associated impairments, further investigation is necessary for both investigational and approved therapies to ensure that the impact in new pathways does not increase risks to patient safety and outcomes.

Topics: Adiponectin; Animals; Anti-Inflammatory Agents; Anti-Obesity Agents; Antioxidants; Diabetes Mellitus; Ghrelin; Humans; Hypoglycemic Agents; Inflammation; Leptin; Obesity; Resveratrol; Stilbenes

Excess weight gain contributes to increased blood pressure in most patients with essential hypertension. Although the mechanisms of obesity hypertension are not fully understood, increased renal sodium reabsorption and impaired pressure natriuresis play key roles. Several mechanisms contribute to altered kidney function and hypertension in obesity, including activation of the sympathetic nervous system, which appears to be mediated in part by increased levels of the adipocyte-derived hormone leptin, stimulation of pro-opiomelanocortin neurons, and subsequent activation of central nervous system melanocortin 4 receptors.

Topics: Adipocytes; Adipose Tissue; Animals; Body Weight; Humans; Hypertension; Kidney; Leptin; Melanocortins; Mice; Models, Biological; Neurons; Obesity; Pro-Opiomelanocortin; Rats; Receptor, Melanocortin, Type 4; Sympathetic Nervous System

Adipose tissue is an active endocrine organ that secretes various humoral factors (adipokines), and its shift to production of proinflammatory cytokines in obesity likely contributes to the low-level systemic inflammation that may be present in metabolic syndrome-associated chronic pathologies such as atherosclerosis. Leptin is one of the most important hormones secreted by adipocytes, with a variety of physiological roles related to the control of metabolism and energy homeostasis. One of these functions is the connection between nutritional status and immune competence. The adipocyte-derived hormone leptin has been shown to regulate the immune response, innate and adaptive response, both in normal and pathological conditions. The role of leptin in regulating immune response has been assessed in vitro as well as in clinical studies. It has been shown that conditions of reduced leptin production are associated with increased infection susceptibility. Conversely, immune-mediated disorders such as autoimmune diseases are associated with increased secretion of leptin and production of proinflammatory pathogenic cytokines. Thus, leptin is a mediator of the inflammatory response.

Topics: Adaptive Immunity; Adipokines; Adipose Tissue; Animals; Humans; Immunity, Innate; Inflammation; Leptin; Lymphocyte Activation; Obesity

That adult humans possess active brown adipose tissue potentially leads to a paradigm shift in the understanding of human metabolism and of obesity. Adaptive adrenergic thermogenesis in humans represents brown adipose tissue activity, the absence of which may contribute to middle-age obesity.

Topics: Adipose Tissue, Brown; Aging; Energy Metabolism; Humans; Ion Channels; Leptin; Mitochondrial Proteins; Models, Biological; Obesity; Thermogenesis; Uncoupling Protein 1

Leptin is well known as an important hormone in the central control of feeding behavior. During development, fetuses and newborns are exposed to leptin and recent evidence has shown that leptin receptors are widespread throughout the developing brain. Accordingly, leptin affects brain development during both pre- and postnatal life. The actions of leptin in the developing brain are generally permanent and range from the establishment of hypothalamic circuits to plasticity in cortical pathways. The cellular events mediated by leptin include the following: neurogenesis, axon growth, and synaptogenesis. Nutritional manipulation of leptin secretion during perinatal life has generated considerable concern, and the developing brain appears to be a particularly sensitive target for these environmental changes.

Topics: Brain; Feeding Behavior; Humans; Leptin; Obesity; Receptors, Leptin

Multiple epidemiologic studies have linked the development of renal cancer to obesity. In this chapter, we begin with a review of selected population studies, followed by recent mechanistic discoveries that further link lipid deregulation to the RCC development. The upregulation of leptin and downregulation of adiponectin pathways in obesity fit well with our molecular understanding of RCC pathogenesis. In addition, two forms of hereditary RCC involve proteins, Folliculin and TRC8, that are positioned to coordinately regulate lipid and protein biosynthesis. Both of these biosynthetic pathways have important downstream consequences on HIF-1/2alpha levels and angiogenesis, key aspects in the disease pathogenesis. The role of lipid biology and its interface with protein translation regulation represents a new dimension in RCC research with potential therapeutic implications.

Topics: Adiponectin; Basic Helix-Loop-Helix Transcription Factors; Carcinoma, Renal Cell; Carrier Proteins; Cholesterol; Cytoskeletal Proteins; Estrone; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Kidney Neoplasms; Leptin; Lipids; Molecular Chaperones; Neoplastic Syndromes, Hereditary; Obesity; Receptors, Cell Surface; Sterol Regulatory Element Binding Proteins

Although the adipokine leptin is regarded as the prototypical long-term signal of energy balance, obese individuals are largely nonresponsive to exogenous leptin administration. Restoration of leptin responsiveness in obesity has been elusive despite a detailed understanding of the molecular mechanisms of leptin signaling. Recent translational research findings point to a potential therapeutic approach that incorporates amylin (a beta-cell hormone) and leptin agonism, with amylin restoring or enhancing leptin sensitivity. Here we hypothesize various physiological, neurobiological and molecular mechanisms that could mediate the interaction of these two neurohormonal signals and discuss several methodological challenges. Understanding how amylin agonism improves leptin function could point to general therapeutic strategies for combating leptin resistance and associated obesity.

Topics: Animals; Body Weight; Drug Synergism; Humans; Hypothalamus; Islet Amyloid Polypeptide; Leptin; Obesity; Rhombencephalon

Obesity is becoming a global epidemic. Around 1.1 billion adults and 10% of the world's children are currently overweight or considered obese. Generally associated with risk factors for cardiovascular disease, such as Diabetes Mellitus and systemic arterial high blood pressure, the obesity has been more and more seen as an independent risk factor for Coronary Artery Disease (CAD). Coronary arteriosclerosis comprises a series of inflammatory responses at cellular and molecular level, whose reactions are stronger in obese patients. In the past, the adipose tissue was regarded as a mere fat deposition. Now it is seen from a totally different standpoint, as an active endocrine and paracrine organ that produces several inflammatory cytokines, such as the adipokines. This article aims to raise awareness about obesity as an increasingly significant public health issue over the past decades, as well as to relate the intense inflammatory process in obese individuals with an increased tendency for this group of individuals to develop CAD.

Topics: Adiponectin; C-Reactive Protein; Coronary Artery Disease; Endothelium, Vascular; Humans; Inflammation Mediators; Leptin; Obesity; Risk Factors; Vasculitis

Obesity and its associated health disorders and costs are increasing. Men and post-menopausal women have greater risk of developing complications of obesity than younger women. Within the brain, the hypothalamus is an important regulator of energy homeostasis. Two of its sub-areas, the ventrolateral portion of the ventral medial nucleus (VL VMN) and the arcuate (ARC) respond to hormones and other signals to control energy intake and expenditure. When large lesions are made in the hypothalamus which includes both the VL VMN and the ARC, animals eat more, have reduced energy expenditure, and become obese. The ARC and the VL VMN, in addition to other regions in the hypothalamus, have been demonstrated to contain estrogen receptors. There are two estrogen receptors, estrogen receptor alpha (ERalpha) and estrogen receptor beta (ERbeta). We and others have previously demonstrated that activation of ERalpha by estrogens reduces food intake and increases body weight. This review focuses on the relative contribution of activation of ERalpha by estrogens in the ARC and the VL VMN in the regulation of food intake and body weight. Additionally, estrogen receptors have been found in many peripheral tissues including adipose tissue. Estrogens are thought to have direct effects on adipose tissue and estrogens may provide anti-inflammatory properties both in the periphery and the in the central nervous system (CNS) which may protect women from diseases associated with inflammation. Understanding the mechanisms by which estrogens regulate body weight and inflammation will assist in determining potential therapeutic agents for menopausal women to decrease the propensity of diseases associated with obesity.

Topics: Body Weight; Eating; Energy Metabolism; Estrogens; Female; Humans; Hypothalamus; Leptin; Male; Obesity; Receptors, Estrogen

The relationship between obesity and hypertension is well established both in children and adults. The mechanisms through which obesity directly causes hypertension are still an area of research. Activation of the sympathetic nervous system has been considered to have an important function in the pathogenesis of obesity-related hypertension. The arterial-pressure control mechanism of diuresis and natriuresis, according to the principle of infinite feedback gain, seems to be shifted toward higher blood-pressure levels in obese individuals. During the early phases of obesity, primary sodium retention exists as a result of increase in renal tubular reabsorption. Extracellular-fluid volume is expanded and the kidney-fluid apparatus is resetted to a hypertensive level, consistent with a model of hypertension because of volume overload. Plasma renin activity, angiotensinogen, angiotensin II and aldosterone values display significant increase during obesity. Insulin resistance and inflammation may promote an altered profile of vascular function and consequently hypertension. Leptin and other neuropeptides are possible links between obesity and the development of hypertension. Obesity should be considered as a chronic medical condition, which is likely to require long-term treatment. Understanding of the mechanisms associated with obesity-related hypertension is essential for successful treatment strategies.

Topics: Blood Pressure; Humans; Hypertension; Insulin Resistance; Leptin; Natriuresis; Obesity; Sympathetic Nervous System

Recent upsurge in research has uncovered distinct circuitries that regulate appetite, energy expenditure and fat accrual under the supervision of hormonal feedback signalling of adipocyte leptin and gastric ghrelin in the hypothalamic integration of energy homeostasis. A host of messenger molecules of diverse chemical composition and origin mediate the crosstalk between the three circuitries. Leptin is now recognized as the mandatory afferent signal in maintenance of weight homeostasis. Leptin insufficiency in the hypothalamus due to diminished transport of leptin across the blood-brain barrier (BBB) imposed by environmental causes, such as consumption of energy-enriched diets and diminished energy expenditure, orchestrates unregulated fat accrual and the attendant disease cluster of metabolic syndrome. Bioavailability of leptin selectively in the hypothalamic targets with the aid of gene therapy successfully averted the environmentally induced metabolic afflictions and normalized lifespan. Thus, sustenance of optimal sufficiency in leptin signalling solely in the hypothalamus is a novel strategy to combat the worldwide epidemic of obesity and metabolic syndrome.

Topics: Animals; Appetite; Body Weight; Energy Metabolism; Ghrelin; Homeostasis; Humans; Hypothalamus; Leptin; Metabolic Syndrome; Neurosecretory Systems; Obesity; Signal Transduction

Acute pancreatitis is an acute inflammatory response to pancreatic injury. In humans, the magnitude of the response and complications are highly variable and unpredictable. Recent clinical studies demonstrate that all major complications are more common and more severe in patients who are obese. This raises the question of how adipose tissue interacts with the immune response to worsen the severity of acute pancreatitis. Here we review the results of a series of new studies focusing on various fat-associated cytokines (adipokines) that are produced and released in proportion to the amount of visceral adipose tissue in the body. The primary adipokines that have been studied in acute pancreatitis include adiponectin, leptin, visfatin, resistin, and adipose tissue related MCP-1, TNF-a and IL-6. These new data provide strong evidence that susceptibility and severity in acute pancreatitis are associated with a number of these adipokines. Although no specific therapy exists to block the effects of these factors, recognizing the high risk and anticipating inflammation-associated complications of adipokine release is an important part of optimal patient management. For this review, a PubMed search was performed with the terms "acute pancreatitis", "severe acute pancreatitis", and "obesity". Additional searches were conducted to identify recent reviews on adipokines, Finally, PubMed searches on specific adipokines, including adiponectin, leptin, visfatin and resistin were conducted focusing on acute pancreatitis and systemic inflammation.

Topics: Adiponectin; Biomarkers; Body Mass Index; Chemokine CCL2; Humans; Interleukin-6; Intra-Abdominal Fat; Leptin; Nicotinamide Phosphoribosyltransferase; Obesity; Pancreatitis, Acute Necrotizing; Resistin; Risk; Severity of Illness Index; Tumor Necrosis Factor-alpha

Studies to understand the pathogenesis of obesity have revealed mediators that are responsible for the control of food intake and metabolism at the hypothalamic level. However, molecular insight explaining the link between obesity and low-degree chronic inflammation remains elusive. The adipocyte-derived hormone leptin, and thereby the nutritional status, could control immune self-tolerance by affecting regulatory T (Treg) cell responsiveness and function. Furthermore, resident Treg cells, which are capable of modulating metabolism and glucose homeostasis, are abundant in adipose tissue. Here, we provide an update on recent findings relating Treg cells to obesity and discuss how the intricate network of interactions among leptin, Treg cells and adipose tissue might provide new strategies for therapeutic interventions.

Topics: Adipose Tissue; Animals; Humans; Leptin; Models, Biological; Obesity; T-Lymphocytes, Regulatory

Melanocortin peptides, derived from POMC (pro-opiomelanocortin) are produced in the ARH (arcuate nucleus of the hypothalamus) neurons and the neurons in the commissural NTS (nucleus of the solitary tract) of the brainstem, in anterior and intermediate lobes of the pituitary, skin and a wide range of peripheral tissues, including reproductive organs. A hypothetical model for functional roles of melanocortin receptors in maintaining energy balance was proposed in 1997. Since this time, there has been an extraordinary amount of knowledge gained about POMC-derived peptides in relation to energy homoeostasis. Development of a Pomc-null mouse provided definitive proof that POMC-derived peptides are critical for the regulation of energy homoeostasis. The melanocortin system consists of endogenous agonists and antagonists, five melanocortin receptor subtypes and receptor accessory proteins. The melanocortin system, as is now known, is far more complex than most of us could have imagined in 1997, and, similarly, the importance of this system for regulating energy homoeostasis in the general human population is much greater than we would have predicted. Of the known factors that can cause human obesity, or protect against it, the melanocortin system is by far the most significant. The present review is a discussion of the current understanding of the roles and mechanism of action of POMC, melanocortin receptors and AgRP (agouti-related peptide) in obesity and Type 2 diabetes and how the central and/or peripheral melanocortin systems mediate nutrient, leptin, insulin, gut hormone and cytokine regulation of energy homoeostasis.

Topics: Animals; Diabetes Mellitus; Energy Metabolism; Homeostasis; Humans; Leptin; Mice; Obesity; Peptides; Pro-Opiomelanocortin; Receptors, Melanocortin

Obesity induced by high-fat (HF) feeding is associated with low-grade inflammation in peripheral tissues that predisposes to insulin resistance. Recent evidence suggests the occurrence of a similar process in the hypothalamus, which favors weight gain through impairment of leptin and insulin signaling. In addition to its implications for obesity pathogenesis, this hypothesis suggests that centrally targeted antiinflammatory therapies may prove effective in prevention and treatment of this disorder. This article highlights molecular and cellular mechanisms by which hypothalamic inflammation predisposes to diet-induced obesity.

Topics: Animals; Glucose Intolerance; Humans; Hypothalamus; Inflammation; Insulin Resistance; Leptin; Models, Biological; Obesity; Weight Gain

Ghrelin and leptin, putative controllers of human appetite, have no effect on human meal-to-meal appetite but respond to variations in energy availability. Nonhomeostatic characteristics of appetite and spontaneous activity stem from inhibition by leptin and ghrelin of brain reward circuit that is responsive to energy deficit, but refractory in obesity, and from the operation of a meal-timing circadian clock.

Topics: Animals; Appetite; Body Weight; Circadian Rhythm; Energy Intake; Energy Metabolism; Female; Ghrelin; Homeostasis; Humans; Leptin; Mice; Motor Activity; Obesity; Rats; Reward

Although energy balance is tightly regulated in order to maintain a specific level of adiposity, the incidence of obesity continues to increase. Consequently, it is essential that effective therapeutics for the treatment and prevention of obesity be developed. This review provides a brief update on some recent advances in the characterization of neuroendocrine targets for obesity therapy.. During the review period, considerable progress occurred in the understanding of previously described neuroendocrine regulators of energy balance, and several novel targets have been identified. Moreover, the understanding of the neural circuitry and molecular mechanisms of the neuroendocrine regulation of energy homeostasis has been expanded.. Energy balance is maintained by neuroendocrine signals arising from many tissues including the gastrointestinal tract and adipose tissue. These signals are integral to the cessation of meals and to the ability of the brain to monitor energy status and respond accordingly. Many current targets for obesity therapy are based on manipulating the activity of these signals and their receptors; however, to date, clinical-weight loss based on this strategy has been minimal and alternative approaches such as combinatorial therapies are emerging.

Topics: Adipose Tissue; Animals; Appetite Regulation; Cholecystokinin; Energy Intake; Gastrointestinal Tract; Ghrelin; Glucagon-Like Peptide 1; Humans; Insulin; Leptin; Mice; Neurosecretory Systems; Obesity; Weight Loss

Leptin regulates energy homeostasis and reproductive, neuroendocrine, immune, and metabolic functions. In this review, we describe the role of leptin in human physiology and review evidence from recent "proof of concept" clinical trials using recombinant human leptin in subjects with congenital leptin deficiency, hypoleptinemia associated with energy-deficient states, and hyperleptinemia associated with garden-variety obesity. Since most obese individuals are largely leptin-tolerant or -resistant, therapeutic uses of leptin are currently limited to patients with complete or partial leptin deficiency, including hypothalamic amenorrhea and lipoatrophy. Leptin administration in these energy-deficient states may help restore associated neuroendocrine, metabolic, and immune function and bone metabolism. Leptin treatment is currently available for individuals with congenital leptin deficiency and congenital lipoatrophy. The long-term efficacy and safety of leptin treatment in hypothalamic amenorrhea and acquired lipoatrophy are currently under investigation. Whether combination therapy with leptin and potential leptin sensitizers will prove effective in the treatment of garden-variety obesity and whether leptin may have a role in weight loss maintenance is being greatly anticipated.

Topics: Energy Metabolism; Homeostasis; Humans; Immune System; Leptin; Metabolic Diseases; Models, Biological; Neurosecretory Systems; Obesity; Reproduction; Signal Transduction

The understanding of the regulation of food intake has become increasingly complex. More than 20 hormones, both orexigenic and anorexigenic, have been identified. After crossing the blood-brain barrier, they reach their main site of action located in several hypothalamic areas and interact to balance satiety and hunger. One of the most significant advances in this matter has been the discovery of leptin. This hormone plays fundamental roles in the control of appetite and in regulating energy expenditure. In accordance with the lipostatic theory stated by Kennedy in 1953, leptin was originally discovered in white adipose tissue. Its expression by other tissues was later established. Among them, the gastric mucosa has been shown to secrete large amounts of leptin. Both the adipose and the gastric tissues share similar characteristics in the synthesis and storage of leptin in granules, in the formation of a complex with the soluble receptor and a secretion modulated by hormones and energy substrates. However while adipose tissue secretes leptin in a slow constitutive endocrine way, the gastric mucosa releases leptin in a rapid regulated exocrine fashion into the gastric juice. Exocrine-secreted leptin survives the extreme hydrolytic conditions of the gastric juice and reach the duodenal lumen in an intact active form. Scrutiny into transport mechanisms revealed that a significant amount of the exocrine leptin crosses the intestinal wall by active transcytosis. Leptin receptors, expressed on the luminal and basal membrane of intestinal epithelial cells, are involved in the control of nutrient absorption by enterocytes, mucus secretion by goblet cells and motility, among other processes, and this control is indeed different depending upon luminal or basal stimulus. Gastric leptin after transcytosis reaches the central nervous system, to control food intake. Studies using the Caco-2, the human intestinal cell line, in vitro allowed analysis of the mechanisms of leptin actions on the intestinal mucosa, identification of the mechanisms of leptin transcytosis and understanding the modulation of leptin receptors by nutrients and hormones. Exocrine-secreted gastric leptin thus participates in a physiological axis independent in terms of time and regulation from that of adipose tissue to rapidly control food intake and nutrient absorption. Adipocytes and gastric epithelial cells are two cell types the metabolism of which is closely linked to food intake and energy st

Topics: Adipose Tissue; Appetite Regulation; Eating; Energy Metabolism; Gastric Mucosa; Humans; Hypothalamus; Leptin; Obesity; Receptors, Leptin

Obesity has been recognized as an important risk factor for many serious medical conditions. The association of obesity with an increased risk of many cancers is of enormous economic importance to the health industry.The metabolic syndrome and visceral obesity have an increasing prevelance and incidence in the general population.The actual prevelance of the metabolic syndrome is 24% in US population and between 24,6% and 30.9% in Europe. Recent evidence from epidemiologic and basic research studies, as well as clinical and intervention studies, supports the emerging hypothesis that metabolic syndrome may be an important etiologic factor for the onset of cancer. In addition, increased body weight has recently been shown to be associated with an increased risk of cancers at multiple specific sites. The close interaction between cancer cells and adipocytes is an intriguing issue in tumor biology. In nowdays, several metabolic markers are implicated in the development and progression of several malignancies. This review describes the emerging data concerning the role of metabolic markes in tumor cell growth and relates them to their future clinical prospects.

Topics: Adiponectin; Animals; Fatty Acids, Nonesterified; Ghrelin; Humans; Insulin Resistance; Leptin; Metabolic Syndrome; Neoplasms; Obesity

It is well recognized that obesity increases the risk of various cancers, including breast malignancies in postmenopausal women. Furthermore, obesity may adversely affect tumor progression, metastasis, and overall prognosis in both pre- and postmenopausal women with breast cancer. However, the precise mechanism(s) through which obesity acts is/are still elusive and this relationship has been the subject of much investigation and speculation. Recently, adipose tissue and its associated cytokine-like proteins, adipokines, particularly leptin and adiponectin, have been investigated as mediators for the association of obesity with breast cancer. Higher circulating levels of leptin found in obese subjects could be a growth-enhancing factor as supported by in vitro and preclinical studies, whereas low adiponectin levels in obese women may be permissive for leptin's growth-promoting effects. These speculations are supported by in vitro studies which indicate that leptin promotes human breast cancer cell proliferation while adiponectin exhibits anti-proliferative actions. Further, estrogen and its receptors have a definite impact on the response of human breast cancer cell lines to leptin and adiponectin. More in-depth studies are needed to provide additional and precise links between the in vivo development of breast cancer and the balance of adiponectin and leptin.

Topics: Adiponectin; Animals; Breast Neoplasms; Cell Transformation, Neoplastic; Disease Progression; Female; Humans; Leptin; Obesity

Because leptin reduces food intake and body weight, the coexistence of elevated leptin levels with obesity is widely interpreted as evidence of 'leptin resistance.' Indeed, obesity promotes a number of cellular processes that attenuate leptin signaling (referred to here as 'cellular leptin resistance') and amplify the extent of weight gain induced by genetic and environmental factors. As commonly used, however, the term 'leptin resistance' embraces a range of phenomena that are distinct in underlying mechanisms and pathophysiological implications. Moreover, the induction of cellular leptin resistance by obesity complicates efforts to distinguish the mechanisms that predispose to weight gain from those that result from it. We suggest a framework for approaching these issues and important avenues for future investigation.

Topics: Animals; Animals, Genetically Modified; Disease Models, Animal; Drug Resistance; Humans; Leptin; Models, Biological; Obesity; Receptors, Leptin; Signal Transduction

The frequency of obesity has been increasing worldwide for 20 years. Many epidemiological studies support a correlation between obesity and increased risk of cancer, particularly digestive cancers in both genders, and gynaecological cancer in women. Currently, about 5% of cancers could be directly related to overweight. Carcinogenesis mechanisms induced by obesity involve insulin resistance, adipokine and angiogenic factor secretions, and inflammation. Experimental and clinical evidence suggest that insulin resistance plays a major role in carcinogenesis. Insulin and non-protein banded IGF-1, whose levels are increased in type 2 diabetes, stimulate cellular growth and inhibit apoptosis. Abnormalities in adipokine secretion by the central adipose tissue play a role at different stages of obesity-induced carcinogenesis. Excess of leptin and PAI-1, associated with a decrease in adiponectin secretion in obese people, contributes to carcinogenesis through cellular growth and angiogenesis stimulation. Remodelling of the extracellular matrix due to metalloproteinase stimulation by PAI-1 is also able to promote cell migration. Obesity not only increases cancer frequency, but is also liable to modify the prognosis and the response to antiangiogenic therapy of digestive cancers. This data suggests the need for clinicians to take into account overweight in cancer risk evaluation and to consider obesity and metabolic disorders as confounding factors in designing therapeutic studies.

Topics: Adipokines; Adipose Tissue; Biological Factors; Body Mass Index; Diabetes Complications; Diabetes Mellitus, Type 2; Evidence-Based Medicine; France; Gastrointestinal Neoplasms; Global Health; Humans; Incidence; Insulin; Insulin Resistance; Insulin-Like Growth Factor I; Leptin; Metalloproteases; Obesity; Plasminogen Activator Inhibitor 1; Prevalence; Prognosis; Risk Assessment; Risk Factors; Serine Proteinase Inhibitors

Obstructive sleep apnea (OSA) is a chronic disease characterized by repetitive partial or complete closure of the upper airway during sleep. OSA tends to be associated with components of metabolic syndrome sharing a common ground of metabolic changes with metabolic syndrome itself. Recent studies showed that subjects with OSA were 6-9 times more likely to have metabolic syndrome than subjects without OSA. Intermittent hypoxia and sleep fragmentation in OSA can initiate intermediary mechanisms (oxidative stress, neurohumoral changes, inflammation) leading to the components of metabolic syndrome. OSA has been suggested to be a novel risk factor, inside the metabolic syndrome, contributing to increased cardiovascular risk. Several studies report that continuous positive airway pressure (CPAP) treatment can reverse pathophysiological changes in OSA, increasing insulin sensitivity and reducing blood pressure. Recent evidences show that CPAP treatment reduces the risk of cardiovascular events and mortality in subjects with OSA. Some subjects with metabolic syndrome can be affected by undiagnosed OSA: CPAP treatment could significantly reduce cardiovascular risk in this subgroup of patients.

Topics: Age Factors; Aged; Blood Glucose; Cardiovascular Diseases; Clinical Trials as Topic; Continuous Positive Airway Pressure; Death, Sudden, Cardiac; Diabetes Mellitus, Type 2; Glucose Tolerance Test; Humans; Hypertension; Insulin Resistance; Leptin; MEDLINE; Metabolic Syndrome; Obesity; Randomized Controlled Trials as Topic; Risk Factors; Sleep Apnea, Obstructive; Stroke

Epidemiological studies have shown a positive relationship between dietary fat intake and obesity. Since rats and mice show a similar relationship, they are considered an appropriate model for studying dietary obesity. The present paper describes the history of using high-fat diets to induce obesity in animals, aims to clarify the consequences of changing the amount and type of dietary fats on weight gain, body composition and adipose tissue cellularity, and explores the contribution of genetics and sex, as well as the biochemical basis and the roles of hormones such as leptin, insulin and ghrelin in animal models of dietary obesity. The major factors that contribute to dietary obesity - hyperphagia, energy density and post-ingestive effects of the dietary fat - are discussed. Other factors that affect dietary obesity including feeding rhythmicity, social factors and stress are highlighted. Finally, we comment on the reversibility of high-fat diet-induced obesity.

Topics: Adipose Tissue; Animals; Body Composition; Dietary Fats; Disease Models, Animal; Energy Intake; Feeding Behavior; Ghrelin; Humans; Hyperphagia; Insulin; Leptin; Obesity; Sex Factors; Social Environment; Stress, Psychological; Weight Gain

Whereas in most cases a fatty liver remains free of inflammation, 10%-20% of patients who have fatty liver develop inflammation and fibrosis (nonalcoholic steatohepatitis [NASH]). Inflammation may precede steatosis in certain instances. Therefore, NASH could reflect a disease where inflammation is followed by steatosis. In contrast, NASH subsequent to simple steatosis may be the consequence of a failure of antilipotoxic protection. In both situations, many parallel hits derived from the gut and/or the adipose tissue may promote liver inflammation. Endoplasmic reticulum stress and related signaling networks, (adipo)cytokines, and innate immunity are emerging as central pathways that regulate key features of NASH.

Topics: Animals; Diet; Disease Progression; Fatty Liver; Humans; Inflammation; Interleukin-5; Leptin; Metabolic Diseases; Models, Biological; Obesity; Trans Fatty Acids; Tumor Necrosis Factor-alpha

Obesity is a growing worldwide health problem affecting both adults and children. Effective prevention and treatment modalities can be achieved by understanding the pathogenesis of obesity better. This review addresses some of the issues related to the hormones and cytokines taking part in the pathogenesis of obesity, energy balance and inflammation.. We reviewed current literature on this broad subject especially concentrating on the functions of the hormones and cytokines taking part in the pathogenesis of the childhood obesity. Using the key words obesity, children, hormones, cytokines publications and cross references were evaluated from PubMed database between 1957 and 2009.. In children, leptin and ghrelin are two hormones which have major influence on energy balance. Leptin is responsible from long term regulation of energy balance and ghrelin functions as an appetite stimulatory signal. In contrast to ghrelin, obestatin acts as an anorexigenic hormone by suppressing food intake. Adipokines secreted from adipose tissue are the key regulators of inflammation in obesity. Increased TNF-alpha and IL-6 levels but decreased levels of adiponectin and IL-10 are associated with increased inflammation, tissue injury and complications of obesity.. Development, pathogenesis and complications of childhood obesity consist of complex mechanisms including numerous cytokines and hormones. New treatment modalities depend on understanding these complex mechanisms.

Topics: Adipokines; Adiponectin; Adipose Tissue; Child; Cytokines; Ghrelin; Humans; Interleukin-10; Interleukin-6; Leptin; Obesity; Tumor Necrosis Factor-alpha

Leptin is a pleiotropic hormone produced mainly by the adipose tissue. Its most well-known effect is to regulate food intake and energy metabolism within the hypothalamus. More recently, several peripheral and extra-hypothalamic effects have been described, expanding leptin's actions far beyond energy balance.. To review the extra-hypothalamic effects of leptin and their possible clinical implications.. We did a PubMed search using the terms "leptin" AND "brain" AND "neuron" AND "glial", and selected the most relevant articles.. In extra-hypothalamic sites, leptin has remarkable effects on neurogenesis, axon growth, synaptogenesis, denditric morphology, development of oligodendroglial cells, neuron excitability, neuroprotection and regulation of beta-amyloid levels. Those effects have been shown to improve cognition and mood in animal models of depression and anxiety. In lean humans, leptin levels have been negatively correlated with the development of Alzheimer's disease.. Leptin has extra-hypothalamic effects that may protect the brain against the development of mood and neurodegenerative disorders, such as Alzheimer's disease. Better understanding of those effects may lead to the development of potential leptin-based therapies against such conditions.

Topics: Alzheimer Disease; Brain; Cognition; Humans; Leptin; Obesity

The world is now experiencing an epidemic of obesity. Although the effects of obesity on the development of metabolic and cardiovascular problems are well studied, much less is known about the impact of obesity on immune function and infectious disease. Studies in obese humans and with obese animal models have repeatedly demonstrated impaired immune function, including decreased cytokine production, decreased response to antigen/mitogen stimulation, reduced macrophage and dendritic cell function, and natural killer cell impairment. Recent studies have demonstrated that the impaired immune response in the obese host leads to increased susceptibility to infection with a number of different pathogens such as community-acquired tuberculosis, influenza, Mycobacterium tuberculosis, coxsackievirus, Helicobacter pylori and encephalomyocarditis virus. While no specific mechanism has been defined for the decreased immune response to infectious disease in the obese host, several obesity-associated changes such as excessive inflammation, altered adipokine signaling, metabolic changes and even epigenetic regulation could affect the immune response. This review will discuss what is currently known about the relationship between obesity and infectious disease.

Topics: Animals; Communicable Diseases; Epigenesis, Genetic; Humans; Immunity, Cellular; Immunologic Memory; Leptin; Obesity; Risk Factors; Vaccination

Mendelian forms of obesity are already known to account for approximately 5% of the severely obese but are currently underinvestigated. In contrast, there has been much recent concentration on genome-wide single nucleotide polymorphism (SNP) associations in obesity, with particular emphasis given to the role of the fat mass and obesity associated (FTO) gene. Unfortunately, despite the enormous resources devoted to this work, none of the SNP markers in the ∼30 genes discovered to have associations with common obesity have meaningful predictive power. This is very different from the situation for Mendelian obesity, where mutations have very clear effects on phenotype. Study of Mendelian obesity has also added significantly to our understanding of mechanisms of appetite regulation, with all known causative genes being active in the brain and most forming part of the leptin-melanocortin signaling pathway. Investigation of genomic structural variation has also recently revealed deletions causing obesity, sometimes with concomitant neurocognitive dysfunction. Advances in next-generation sequencing are expected to uncover additional highly penetrant causes of obesity. Screening for Mendelian forms of obesity is rarely carried out but holds considerable promise for improved clinical care of these high-risk patients.

Topics: Alpha-Ketoglutarate-Dependent Dioxygenase FTO; Humans; Leptin; Melanocortins; Mutation; Obesity; Phenotype; Polymorphism, Single Nucleotide; Precision Medicine; Proteins; Signal Transduction

Insulin and leptin play complementary roles in regulating the consumption, uptake, oxidation and storage of nutrients. Chronic consumption of diets that contain a high proportion of calories from saturated fat induces a progressive deterioration in function of both hormones. Certain rat lines and strains of mice are particularly sensitive to the obesogenic and diabetogenic effects of high fat diets, and have been used extensively to study the developmental progression of insulin and leptin resistance in relation to the increasing adiposity that is characteristic of their response to these diets. Some aspects of the diminished efficacy of each hormone are secondary to increased adiposity but a consensus is emerging to support the view that direct effects of dietary components or their metabolites, independent of the resulting obesity, play important roles in development of insulin and leptin resistance. In this minireview, we will examine the implications of crosstalk between leptin and insulin signaling during the development of diet-induced obesity, emphasizing potential interactions between pathways that occur among target sites, and exploring how these interactions may influence the progression of obesity and diabetes.

Topics: Adiposity; Animals; Dietary Fats; Energy Intake; Humans; Insulin; Insulin Resistance; Leptin; Mice; Obesity; Rats; Signal Transduction

Breast milk is practically the only food ingested during the first months of life in fully breastfed infants and it is assumed to match the infant's nutritional needs. Epidemiological data suggest that breastfeeding compared with infant formula feeding confers protection against several chronic diseases later on in life and, particularly, against obesity and related medical complications. However, causality has not been related to any specific compound of breast milk. Recent data in our laboratory have identified leptin as the specific compound that is responsible for some of these beneficial effects of breastfeeding. The hormone leptin was identified as a key candidate because it is present in breast milk, but is not present in infant formula, and when ingested during the suckling period can be absorbed by the immature stomach exerting biological effects. Evidence of the beneficial effects of breast milk leptin was obtained from human studies, showing that milk-borne maternal leptin appeared to give moderate protection to infants from excess weight gain. Direct cause-effect evidence was obtained in rats, where oral leptin supplementation during the suckling period resulted in a decrease in food intake, affected food preferences in favour of carbohydrates versus fat, and protected against overweight in adulthood, with an improvement of related parameters such as leptin and insulin sensitivity. These findings open a new area of research on the use of leptin in the design of more appropriate infant formula, which is significant considering the increasing incidence of obesity and its associated medical complications.

Topics: Eating; Female; Food Preferences; Humans; Insulin; Lactation; Leptin; Male; Milk, Human; Obesity

The hormones insulin and leptin have been demonstrated to act in the central nervous system (CNS) as regulators of energy homeostasis at medial hypothalamic sites. In a previous review, we described new research demonstrating that, in addition to these direct homeostatic actions at the hypothalamus, CNS circuitry that subserves reward and motivation is also a direct and an indirect target for insulin and leptin action. Specifically, insulin and leptin can decrease food reward behaviors and modulate the function of neurotransmitter systems and neural circuitry that mediate food reward, i.e., midbrain dopamine and opioidergic pathways. Here we summarize new behavioral, systems, and cellular evidence in support of this hypothesis and in the context of research into the homeostatic roles of both hormones in the CNS. We discuss some current issues in the field that should provide additional insight into this hypothetical model. The understanding of neuroendocrine modulation of food reward, as well as food reward modulation by diet and obesity, may point to new directions for therapeutic approaches to overeating or eating disorders.

Topics: Adiposity; Animals; Disease Models, Animal; Dopamine; Eating; Feeding Behavior; Food Preferences; Homeostasis; Humans; Insulin; Leptin; Mesencephalon; Motivation; Neural Pathways; Obesity; Opioid Peptides; Reward; Signal Transduction

Recent studies consistently support a hypoxia response in the adipose tissue in obese animals. The observations have led to the formation of an exciting concept, adipose tissue hypoxia (ATH), in the understanding of major disorders associated with obesity. ATH may provide cellular mechanisms for chronic inflammation, macrophage infiltration, adiponectin reduction, leptin elevation, adipocyte death, endoplasmic reticulum stress and mitochondrial dysfunction in white adipose tissue in obesity. The concept suggests that inhibition of adipogenesis and triglyceride synthesis by hypoxia may be a new mechanism for elevated free fatty acids in the circulation in obesity. ATH may represent a unified cellular mechanism for a variety of metabolic disorders and insulin resistance in patients with metabolic syndrome. It suggests a new mechanism of pathogenesis of insulin resistance and inflammation in obstructive sleep apnea. In addition, it may help us to understand the beneficial effects of caloric restriction, physical exercise and angiotensin II inhibitors in the improvement of insulin sensitivity. In this review article, literatures are reviewed to summarize the evidence and possible cellular mechanisms of ATH. The directions and road blocks in the future studies are analyzed.

Topics: Adiponectin; Adipose Tissue; Animals; Humans; Hypoxia; Inflammation; Insulin Resistance; Leptin; Mice; Neovascularization, Physiologic; Obesity; Signal Transduction

Obesity is a resilient and complex chronic disease. One potential causative factor in the obesity syndrome is leptin resistance. Leptin behaves as a potent anorexic and energy-enhancing hormone in most young or lean animals, but its effects are diminished or lacking in the obese state associated with a normal genetic background. Emerging evidence suggests that leptin resistance predisposes the animal to exacerbated diet-induced obesity (DIO). Elevation of central leptin in young, lean rats induces a leptin resistance that precludes obesity on a chow diet but accelerates high-fat (HF)-induced obesity. Similarly, chronic dietary fructose consumption evokes a leptin resistance that causes obesity only upon HF exposure. Inherent central leptin insensitivity also contributes to dietary weight gain in certain obesity-prone rats. Conversely, aged, leptin-resistant animals are obese with continuous chow feeding and demonstrate aggravated obesity when challenged with an HF diet. Additionally, a submaximal central blockade with a leptin antagonist leads to obesity on both chow and HF diets, as is the case in rodents with leptin receptor deficiency of genetic origin. Despite the differences in the incidence of obesity on a chow diet, all of these forms of leptin resistance predispose rodents to aggravated HF-mediated obesity. Moreover, once leptin resistance takes hold, it aggravates DIO, and the leptin resistance and obesity compound one another, promoting a vicious cycle of escalating weight gain.

Topics: Aging; Animals; Body Composition; Diet; Humans; Leptin; Obesity

Obesity is associated with an increased risk of breast cancer. interleukin-1 (IL-1), a pro-inflammatory cytokine secreted by adipose tissue, is involved in breast cancer development. There is also convincing evidence that other adipocytokines including leptin not only have a role in haematopoiesis, reproduction and immunity but are also growth factors in cancer. Therefore, IL-1 family and leptin family are adipocytokines which could represent a major link between obesity and breast cancer progression. This minireview provides insight into recent findings on the prognostic significance of IL-1 and leptin in mammary tumours, and discusses the potential interplay between IL-1 family members and adipocyte-derived hormones in breast cancer.

Topics: Adipokines; Breast Neoplasms; Female; Humans; Interleukin-1; Leptin; Obesity

Leptin, a protein containing 167 amino acids, demonstrates structural similarities with cytokine family and is mainly produced by adipocytes. The leptin receptor (OB-R) is a large membrane spanning protein that belongs to the gp 130 family of cytokine class I receptors. Besides the neuroendocrine effects of leptin in the control of food intake and energy expenditure, binding of this hormone has been proven in intestine, liver, kidney, skin, stomach, heart, spleen, lung, and so on. Thus leptin affects maternal, fetal and placental function, it appears to act as an endocrine and paracrine factor for the regulation of reproduction and puberty, prevents ectopic lipid deposition, modifies insulin sensitivity in the muscle or liver, and links the immune and endocrine systems. The LEP gene encodes for leptin. It has been localized in humans on the 7 alpha 31.3 chromosome and consists of three exons separated by two introns. In humans, a mutation in the LEP gene was reported in two children with the same cosanguineous pedigree. Other studies reported a polymorphism in the promoter untranslated exon 1 of the LEP gene (A19G), a polymorphism C(-188)A in the promoter region of the LEP gene (17) and a mutation at codon V110M. The biologic activities of leptin on target tissues are carried out through binding to a specific receptor, LEPR. LEPR maps in humans to the 1p31 chromosome. Variants commonly occur, which cause two nonconservative changes:lysine to asparagine at codon 656 (AAG to AAC) in exon 14 (K656N); lysine to arginine at codon 109 (AAG to AGG) in exon 4 (K109R); a nonconservative change glutamine to arginine at codon 223 (CAG to CGG); a silent TC change at codon 343; and a silent GA transition at codon 1019. Leptin is related with obesity and its metabolic disorders. However, new relation ships have been described; inflammatory bowel disease, cancer, bone formation, asthma and so on. In conclusion, despite the great advances in our knowledge of leptin physiology, many areas of investigation remain. Future research is expected to discover new molecules in the leptin pathway, to treat obesity and its related diseases.

Topics: Animals; Cardiovascular Diseases; Humans; Leptin; Metabolic Syndrome; Mice; Obesity; Receptors, Leptin; Sequence Homology, Amino Acid

Synthesized and released by the adipose tissue, leptin is the widely studied 167-amino acid hormonal protein product of the obesity gene. Originally leptin was defined in association with satiety and energy balance and claimed to be an anti-obesity factor that functioned via a feedback effect from adipocytes to hypothalamus. There is a growing body of evidence that emphasizes the importance of leptin in the regulation of food intake and body weight in animals and humans, alike. Other research findings point out that it plays a role in the regulation of the metabolism, sexual development, reproduction, hematopoiesis, immunity, gastrointestinal functions, sympathetic activation, and angiogenesis. The aim of this review is to evaluate the relation between leptin and the central nervous system (CNS).

Topics: Adipose Tissue; Animals; Blood-Brain Barrier; Central Nervous System; Humans; Leptin; Obesity; Receptors, Leptin

The incidence of obesity is increasing at an alarming rate and this worldwide epidemic represents an ominous predictor of increases in diseases such as type 2 diabetes and metabolic syndrome. Epidemiological and animals studies suggest that maternal obesity and alterations in postnatal nutrition are associated with increased risks for obesity, hypertension, and type 2 diabetes in the offspring. Furthermore, there is also growing appreciation that developmental programming of neuroendocrine systems by the perinatal environment represents a possible cause for these diseases. This review article provides a synthesis of recent evidence concerning the actions of perinatal hormones and nutrition in programming the development and organization of hypothalamic circuits that regulate body weight and energy balance. Particular attention is given to the neurodevelopmental actions of insulin and leptin.

Topics: Energy Metabolism; Female; Homeostasis; Humans; Hypothalamus; Infant; Insulin; Leptin; Male; Obesity; Pregnancy; Prenatal Exposure Delayed Effects; Prenatal Nutritional Physiological Phenomena

Common obesity is a multi-factorial trait, contributed by the "obesogenic" environment of caloric abundance and increasing automation, sedentary lifestyle and an underlying genetic susceptibility. There have been major advances in the past decade in our understanding of the human weight regulation mechanism and pathogenesis of obesity, abetted by discoveries of genetic defects which lead to human obesity.. Reports of genetic mutations causing obesity in humans and murine models were reviewed.. Humans with genetic defects resulting in leptin deficiency, leptin receptor deficiency, proopiomelanocortin deficiency (POMC), and melanocortin 4 receptor (MC4R) deficiency developed severe obesity as the dominant phenotypic feature, though these are rare autosomal recessive conditions, except MC4R deficiency which is inherited in an autosomal co-dominant fashion. Common and rare variants of the POMC and melanocortin 3 receptor genes may be predisposing factors in the development of common obesity. Recent reports of human obesity associated with thyrosine kinase B (TrkB) defect and brain derived neurotrophic factor (BDNF) disruption, coupled with other murine studies, supported the role of BDNF/TrkB as effectors downstream of the melanocortin receptors.. Despite exciting discoveries of single gene mutations resulting in human obesity, most cases of obesity are likely the result of subtle interactions of several related genetic variants with environmental factors which favour the net deposition of calories as fat, culminating in the obese phenotype. The mechanisms of action of these genes in the development of obesity are now being examined, with the aim of eventually discovering a therapeutic intervention for obesity.

Topics: Animals; Body Weight; Disease Models, Animal; Humans; Leptin; Melanocortins; Mice; Mutation; Obesity

Obesity is a major risk factor for hypertension. Adipose tissue releases numerous substances that act on the pathophysiologic mechanisms of blood pressure. Management of obese patients with high blood pressure includes weight loss efforts, but antihypertensive treatment is most often necessary. Beta-blockers, alone or with thiazide diuretics, increase the risk of diabetes in hypertensive patients. Treatment against hypertension must include a renin-angiotensin system blocker, with a calcium channel blocker or a thiazide diuretic, if necessary.

Topics: Adiponectin; Adipose Tissue; Antihypertensive Agents; Blood Pressure; Combined Modality Therapy; Humans; Hypertension; Insulin Resistance; Leptin; Obesity; Sympathetic Nervous System; Weight Loss

This review summarises current experimental adipokine investigations and will focus on some of the procedures and techniques that are currently important in the clinical research laboratory. The complexity of measuring adipokines is discussed and the relative success of the various applications in the transition from the laboratory to clinical diagnosis assessed. In addition, as new adipokines continue to emerge, this review will consider the direction research is taking at the cutting edge of novel adipokine discovery. Finally, how a more comprehensive understanding of the pathobiology related to adipokines may enhance innovative therapeutic strategies designed to attenuate the predicted explosion in obesity related diseases will be discussed.

Topics: Adipokines; Adipose Tissue; Biomarkers; Humans; Leptin; Obesity

Endocannabinoids (ECs) regulate energy balance by modulating hypothalamic circuits controlling food intake and energy expenditure. However, convincing evidence has accumulated indicating that the EC system is present also in peripheral tissues, in particular in adipose tissue. Fat cells produce and are targets of ECs. Glucose uptake and lipoprotein lipase (LPL) activity, lipogenesis and adipogenesis are stimulated by ECs through cannabinoid 1 (CB1) receptors. Moreover, CB1 activation leads to a decreased mitochondrial biogenesis and function through inhibition of endothelial nitric oxide synthase (eNOS). All these effects are blocked by the CB1 antagonist rimonabant, suggesting that the weight-reducing effect of CB1 blockade is due not only to the transient suppression of food intake and reduction of lipogenesis but also to an increased mitochondrial biogenesis and oxidative metabolism which counteracts the inhibitory effects of ECs, levels of which are increased in fat tissues of obese rodents and humans. This review focuses on the role of ECs in adipose tissue metabolism, adipokine production, and interactions between ECs and peroxisome proliferator-activated receptors (PPARs) during adipogenesis.

Topics: Adipocytes; Adipokines; Adipose Tissue; Animals; Cannabinoid Receptor Modulators; Cell Differentiation; Endocannabinoids; Energy Metabolism; Glucose; Humans; Leptin; Lipid Metabolism; Models, Biological; Obesity; Peroxisome Proliferator-Activated Receptors; Receptor, Cannabinoid, CB1

Endocannabinoids, a lipid-derived signaling system, regulate appetite and motivation to eat via effects in the hypothalamus and nucleus accumbens. Not all the effects of endocannabinoids on fat mass can be explained by the regulation of food intake alone. Endocannabinoids and their receptors are located in areas of the central nervous system and multiple peripheral tissues involved in the regulation of intermediary metabolism and energy expenditure. In addition to regulating food intake by both central and peripherally mediated effects, endocannabinoids modify glucose and lipid metabolism so as to promote energy storage via lipogenesis and reduce energy expenditure. The endocannabinoid system appears to be overactive in obesity and may serve to maintain fat mass and underlies some of the metabolic consequences of obesity. Inhibition of the cannabinoid type-1 receptor ameliorates the effects of endocannabinoids on food intake and energy metabolism; lipogenesis is inhibited, lipolysis, fatty acid oxidation and glucose uptake increase.

Topics: Adipose Tissue; Animals; Cannabinoid Receptor Modulators; Eating; Endocannabinoids; Energy Metabolism; Humans; Intestinal Absorption; Leptin; Liver; Muscle, Skeletal; Obesity; Pancreas; Receptor, Cannabinoid, CB1; Ventromedial Hypothalamic Nucleus

The prevalence of Diabetes Mellitus (DM) is becoming a serious public health problem. The use of atypical antipsychotics has been associated with disruption of the glucose metabolism and therefore with causing DM. The underlying mechanisms are unknown, but knowledge of the differences between the pharmacological features of various antipsychotics combined with their diabetogenic profile might help us to understand those mechanisms. This article describes how the binding of various essential receptors or transporters in essential body tissues, adipose tissue, pancreatic tissue and liver and skeletal muscle tissue can cause disruption of the glucose metabolism. With such knowledge in mind one can try to explain the differences between the diabetogenic propensities of various antipsychotics. It is well known that clozapine and olanzapine cause weight gain and DM, whereas aripiprazole and ziprasidone have much less disruptive clinical profiles. The most significant risk factor for adiposity seems to be strong blocking of histaminergic receptors. An agonistic activity on serotonergic-1a receptors, with a very low affinity for muscarinergic-3 receptors, might protect against the development of DM. More data will become available which may help to solve the puzzle.

Topics: Adiponectin; Antipsychotic Agents; Aripiprazole; Benzodiazepines; Blood Glucose; Clozapine; Diabetes Mellitus; Humans; Leptin; Obesity; Olanzapine; Piperazines; Quinolones; Receptor, Muscarinic M3; Receptor, Serotonin, 5-HT1A; Receptors, Dopamine D2; Receptors, Histamine; Serotonin 5-HT1 Receptor Agonists; Thiazoles; Weight Gain

Collapsible pharyngeal airway size is determined by interaction between structural properties of the pharyngeal airway and neural regulation of the pharyngeal dilating muscles. Obesity seems to have two distinct mechanical influences on the pharyngeal airway collapsibility. First, obesity increases soft tissue surrounding the pharyngeal airway within limited maxillomandible enclosure occupying and narrowing its space (pharyngeal anatomical imbalance). Second, obesity, particularly central obesity, increases visceral fat volume decreasing lung volume. Pharyngeal wall collapsibility is increased by the lung volume reduction, possibly through decreased longitudinal tracheal traction (lung volume hypothesis). Neural compensation for functioning structural abnormalities operating during wakefulness is lost during sleep, leading to pharyngeal obstruction. Instability of the negative feedback of the respiratory system may accelerate cycling of pharyngeal closure and opening. Improvement of the pharyngeal anatomical imbalance and maintenance of lung volume are the keys for safe perioperative airway managements of obese patients with obstructive sleep apnea.

Topics: Airway Resistance; Anesthesia; Functional Residual Capacity; Humans; Hypercapnia; Leptin; Obesity; Perioperative Care; Pharyngeal Muscles; Pharynx; Sleep Apnea, Obstructive; Tongue

Nutrition and growth during infancy are an emerging issue because of their potential link to metabolic health disorders in later life. Moreover, prolonged breast-feeding appears to be associated with a lower risk of obesity than formula feeding. Human milk is a source of various hormones and growth factors, namely adipokines (leptin and adiponectin), ghrelin, resistin and obestatin, which are involved in food intake regulation and energy balance. These compounds are either not found in commercial milk formulas or their presence is still controversial. Diet-related differences during infancy in serum levels of factors involved in energy metabolism might explain anthropometric differences and also differences in dietary habits between breast-fed (BF) and formula-fed (FF) infants later in life, and may thus have long-term health consequences. In this context, the recent finding of higher leptin levels and lower ghrelin levels in BF than in FF infants suggests that differences in hormonal values together with different protein intake could account for the differences in growth between BF and FF infants both during infancy and later in life. In this review, we examine the data related to hormones contained in mothers' milk and their potential protective effect on subsequent obesity and metabolic-related disorders.

Topics: Breast Feeding; Ghrelin; Hormones; Humans; Infant; Infant, Newborn; Leptin; Milk, Human; Obesity

The prevalence of obesity among children in the United States represents a pool of latent morbidity. Though the prevalence of obesity has increased in both boys and girls, the causes and consequences differ between the sexes. Thus, interventions proposed to treat and prevent childhood obesity will need to account for these differences.. This review examines gender differences in the presentation of obesity in children and describes environmental, hormonal, and genetic factors that contribute to observed gender differences.. A search of peer-reviewed, published literature was performed with PubMed for articles published from January 1974 through October 2008. Search terms used were obesity, sex, gender, hormones, family environment, body composition, adiposity, and genes. Studies of children aged 0 to 18 years were included, and only articles published in English were reviewed for consideration. Articles that illustrated gender differences in either the presentation or underlying mechanisms of obesity in children were reviewed for content, and their bibliographies were used to identify other relevant literature.. Gender differences in childhood obesity have been understudied partially because of how we define the categories of overweight and obesity. Close examination of studies revealed that gender differences were common, both before and during puberty. Boys and girls differ in body composition, patterns of weight gain, hormone biology, and the susceptibility to certain social, ethnic, genetic, and environmental factors.. Our understanding of how gender differences in pediatric populations relate to the pathogenesis of obesity and the subsequent development of associated comorbid states is critical to developing and implementing both therapeutic and preventive interventions.

Topics: Alpha-Ketoglutarate-Dependent Dioxygenase FTO; Family Health; Female; Genetic Predisposition to Disease; Hormones; Humans; Insulin; Insulin Resistance; Leptin; Male; Obesity; Proteins; Receptor, Melanocortin, Type 4; Receptors, Leptin; Sex Factors; Social Environment

This review summarizes recent advances in our understanding of the pre- and posttranscriptional mechanisms that regulate leptin production and secretion in adipocytes. Basal leptin production is proportional to the status of energy stores, i.e., fat cell size, and this is mainly regulated by alterations in leptin mRNA levels. Leptin mRNA levels are regulated by hormones, including glucocorticoids and catecholamines, but little is known about the transcriptional mechanisms involved. Leptin synthesis and secretion is also acutely modulated in response to hormones such as insulin and the availability of metabolic fuels. Acute variations in leptin production over a time course of minutes to hours are mediated at the levels of both translation and secretion. Increases in amino acids and insulin after a meal activate the mammalian target of rapamycin (mTOR) pathway, leading to an increase in specific rates of leptin biosynthesis. Cross-talk among mTOR, PKA, and AMP-activated protein kinase pathways appears to integrate hormonal and nutrient signals that regulate leptin mRNA translation, at least in part through mechanisms involving its 5'- and 3'-untranslated regions. In addition, the rate of leptin secretion from preformed stores in response to hormonal cues is also regulated. Insulin stimulates, and adrenergic agonists inhibit, leptin secretion, and this likely contributes to variations in the magnitude of nutrition-related leptin excursions and oscillations. Overall, the study of leptin production has contributed to a deepening understanding of leptin biology and, more broadly, to our understanding of the cellular and molecular mechanisms by which the adipocyte integrates hormonal and nutrient signals to regulate adipokine production.

Topics: Adipose Tissue; Animals; Eating; Food; Hormones; Humans; Leptin; Obesity; Signal Transduction

Adipose tissue cells express and secrete numerous proteins influencing the signal transduction pathways of insulin receptor by auto-, para- and endocrine manner. Several cytokines, tumor necrosis factor-alpha and its soluble receptor forms, sTNFR1 and sTNFR2, resistin, retinol-binding protein 4, plasminogen activator inhibitor, lipocain 1 inhibit the signalization of insulin receptor causing insulin resistance in target tissues, mainly in adipose, liver and muscle, brain, endothelial as well as in pancreatic beta-cells. However, many other proteins produced by the fat tissue, such as adiponectin, visfatin, vaspin, apelin, omentin and chemerin enhance the signal transmission of the receptor. Recently discovered common mechanisms leading to insulin and cytokine resistance in obesity and type 2 diabetes mellitus, e.g. protein family of suppressor of cytokine signaling (SOCS) are also discussed.

Topics: Adipokines; Animals; Diabetes Mellitus, Type 2; Humans; Insulin Resistance; Leptin; Lipocalin 1; Mutation; Obesity; Plasminogen Inactivators; Receptor, Insulin; Resistin; Retinol-Binding Proteins, Plasma; Signal Transduction; Transcription, Genetic; Tumor Necrosis Factor-alpha

Amylin is a pancreatic B-cell hormone that plays an important role in the control of nutrient fluxes because it reduces food intake, slows gastric emptying, and reduces postprandial glucagon secretion. These actions seem to depend on a direct effect on the area postrema (AP). Subsequent to area AP activation, the amylin signal is conveyed to the forebrain via distinct relay stations. Within the lateral hypothalamic area, amylin diminishes the expression of orexigenic neuropeptides. Recent studies suggest that amylin may also play a role as a long term, adiposity signal. Similar to leptin or insulin, an infusion of amylin into the brain resulted in lower body weight gain than in controls, irrespective of the starting body weight. Interestingly, preliminary data also suggest that rats fed an energy-dense diet develop resistance to central amylin. In addition to amylin's action to control meal termination and to act as a potential adiposity signal, amylin and its agonist salmon calcitonin have recently been shown to increase energy expenditure under certain conditions. In summary, amylin may be an interesting target as a body weight lowering drug. In fact, recent studies provide evidence that amylin, especially when combined with other anorectic hormones (for example, peptide YY and leptin) has beneficial long-term effects on body weight.

Topics: Adiposity; Amyloid; Animals; Appetite Depressants; Appetite Regulation; Area Postrema; Dose-Response Relationship, Drug; Energy Metabolism; Feeding Behavior; Humans; Islet Amyloid Polypeptide; Leptin; Obesity; Peptide YY; Proto-Oncogene Proteins c-fos; Rats; Satiety Response; Weight Gain

The current epidemic of childhood obesity will be a serious threat to population health for at least the next several decades. The biology of childhood obesity was the theme of an international symposium held in November 2007. Speakers discussed monogenic causes of obesity, prenatal epigenetic programming, neurobehavioral aspects of obesity, and hormonal and neuroendocrine abnormalities, and the insights provided by non-murine models for understanding the biology of early-onset obesity. Several new developments have been reported in white and brown adipose tissue biology. They are summarized briefly in this review and include observations about cell lineage of adipocytes, the renewal of adipocytes throughout life and the numerous factors that influence adipocyte fatty acid release. The biological underpinnings of childhood obesity are multiple and complex.

Topics: Adipocytes; Adipose Tissue; Adult; Age of Onset; Cardiovascular Diseases; Child; Fatty Acids; Female; Ghrelin; Homeostasis; Humans; Infant, Newborn; Insulin; Leptin; Lipase; Lipolysis; Maternal Nutritional Physiological Phenomena; Obesity; Pregnancy; Prenatal Exposure Delayed Effects; Prenatal Nutritional Physiological Phenomena; Sterol Esterase

Epidemiological studies suggest that maternal undernutrition, obesity and diabetes during gestation and lactation can all produce obesity in human offspring. Animal models provide a means of assessing the independent consequences of altering the pre- vs postnatal environments on a variety of metabolic, physiological and neuroendocrine functions, which lead to the development of offspring obesity, diabetes, hypertension and hyperlipidemia. During the gestational period, maternal malnutrition, obesity, type 1 and type 2 diabetes, and psychological and pharmacological stressors can all promote offspring obesity. Normal postnatal nutrition can sometimes reduce the adverse effect of some of these prenatal factors, but may also exacerbate the development of obesity and diabetes in offspring of dams that are malnourished during gestation. The genetic background of the individual is also an important determinant of outcome when the perinatal environment is perturbed. Individuals with an obesity-prone genotype are more likely to be adversely affected by factors such as maternal obesity and high-fat diets. Many perinatal manipulations are associated with reorganization of the central neural pathways which regulate food intake, energy expenditure and storage in ways that enhance the development of obesity and diabetes in offspring. Both leptin and insulin have strong neurotrophic properties so that an excess or an absence of either of them during the perinatal period may underlie some of these adverse developmental changes. As perinatal manipulations can permanently and adversely alter the systems that regulate energy homeostasis, it behooves us to gain a better understanding of the factors during this period that promote the development of offspring obesity as a means of stemming the tide of the emerging worldwide obesity epidemic.

Topics: Animals; Body Weight; Child; Disease Models, Animal; Energy Metabolism; Exercise; Female; Humans; Infant, Newborn; Insulin; Lactation; Leptin; Maternal Nutritional Physiological Phenomena; Mice; Mice, Inbred Strains; Obesity; Pregnancy; Pregnancy Complications; Prenatal Exposure Delayed Effects; Rats; Rats, Sprague-Dawley; Weaning

Sedentary behavior and sleep may be working in concert to increase the likelihood of a child becoming overweight, but in paradoxical ways. Reduction of sedentary behavior (that is, media screen time) has been extensively researched and touted as an intervention target. Inadequate sleep as a putative risk factor for obesity is only beginning to be explored. In this paper, we review the current state of research regarding these factors, and describe the existing evidence and mechanisms proposed to explain these relationships. Whereas the association between weight and sedentary behavior has been consistently shown in observational studies, effect sizes are small, and multiple mechanisms appear to be operating. Recent cross-sectional and longitudinal evidence suggests a link between short sleep duration and weight. Possible mechanisms here include direct metabolic effects as well as indirect behavioral pathways, including the presence of electronic media in children's bedrooms. Measurement issues present a challenge to both areas of research. Prospective studies that include more accurate measures of both sedentary behavior and of sleep will be needed to clarify causal pathways.

Topics: Adolescent; Child; Child, Preschool; Computers; Epidemiologic Studies; Feeding Behavior; Female; Ghrelin; Growth Hormone; Humans; Leptin; Male; Obesity; Risk Factors; Satiation; Sedentary Behavior; Sleep Deprivation; Social Environment; Television; Time Factors

Energy balance (intake and expenditure) is under the control of complex and redundant neural pathways that regulate feeding behavior and energy metabolism in response to availability of nutrients in the circulation or in fat stores. A number of hormones are secreted from peripheral organs and act in the hypothalamus to influence appetite and energy expenditure. This review will summarize recent progress in the identification of the neural pathways that respond to peripheral signals of energy availability such as leptin and macronutrients. Although the impact of environmental factors on obesity is underscored by the modern obesity epidemic, new insights into the pathophysiology of weight control provide new targets for therapeutic intervention for obesity.

Topics: Animals; Body Weight; Brain; Energy Metabolism; Humans; Hypothalamus; Leptin; Obesity

Women with mood disorders, especially bipolar disorder (BD), have been shown to have high rates of reproductive and metabolic dysfunction. The available data on the functional, anatomic, and clinical neuroendocrine abnormalities in women with BD suggest a two-tiered relationship with mood pathology. First, many of the medications commonly used in the treatment of BD can have deleterious effects on blood levels of reproductive hormones and consequently on the hypothalamic-pituitary-gonadal (HPG) axis and reproductive function. Studies that have specifically addressed the association between psychotropic medications and menstrual abnormalities, polycystic ovary syndrome, and overall reproductive endocrine function in women with BD have found high rates of HPG irregularities in women with BD. Second, there is evidence of reproductive dysfunction in women with BD prior to treatment. In addition, many of the psychotropic medications used in the treatment of BD are associated with weight gain, insulin resistance, and dyslipidemia. These metabolic side effects further compound the neuroendocrine system dysregulation in women with BD. Current understanding of the reproductive and metabolic function in women with BD points to vulnerability, which in turn increases the risk of later-life cardiovascular disease and diabetes, among other morbidities, for women with BD.

Topics: Bipolar Disorder; Dyslipidemias; Endocrine System Diseases; Female; Humans; Hypogonadism; Hypothalamo-Hypophyseal System; Leptin; Lithium Carbonate; Menstruation; Obesity; Pituitary-Adrenal System; Polycystic Ovary Syndrome; Psychotropic Drugs; Valproic Acid

The adipocyte-derived hormone, leptin controls feeding behavior, augments fatty acid beta-oxidation in the skeletal muscle, attenuates insulin secretion but enhances whole body insulin sensitivity and glucose disposal, thereby serving as a promising therapeutic candidate for the treatment of insulin resistance and dyslipidemia. Along with other researchers, we demonstrated the clinical efficacy and safety of leptin in the treatment of diabetes and dyslipidemia for patients with generalized lipodystrophy. However, the clinical application of leptin has been hampered by the notion that leptin does not fully exert its metabolic effects in human obesity and diet-induced obese rodents. We found that the activity of skeletal muscle AMP-activated protein kinase (AMPK) parallels hypothalamic leptin sensitivity and metabolic phenotype in transgenic mice overexpressing leptin. Our data indicate that the activation of skeletal muscle AMPK is mediated by the hypothalamic melanocortin pathway. In fact, intracerebroventricular administration of melanocortin agonist, MT-II in mice robustly overcomes high-fat diet-induced leptin resistance and ameliorates fuel dyshomeostasis and hyperphagia, with a concomitant recovery of AMPK activity in skeletal muscle. Conversely, AMPK/ACC phosphorylation by leptin was abrogated by the co-administration of melanocortin antagonist, SHU9119 and in the KKA(y) mice, which centrally express endogenous melanocortin antagonist. Importantly, high-fat diet-induced attenuation of AMPK/ACC phosphorylation in leptin-overexpressing transgenic mice was not reversed by central leptin per se, but was markedly recovered by MT-II. Our data provide evidence for the critical role of the central melanocortin system in leptin-skeletal muscle AMPK axis, and highlight the system as a therapeutic target for leptin insuffciency in obese humans.

Topics: Animals; Diabetes Mellitus; Humans; Hypothalamus; Leptin; Obesity; Receptor, Melanocortin, Type 4; Signal Transduction

Obesity is the major cause of type 2 diabetes. In the mid 1990s interest in adipose tissue was revived by the discovery of leptin. The association of obesity and diabetes emphasizes their shared physiopathological features. At the end of the 1990s, ghrelin, a potent gastric orexigenic factor, was found to be involved in obesity. Leptin and ghrelin have opposite actions in several tissues including the regulation of feeding in the brain.. To survey the role of leptin and ghrelin in glucose metabolism. We summarize the current state of research and discuss the roles of ghrelin and leptin in glucose homeostases and the potential application of drugs targeting leptin and ghrelin signalling to prevent and treat diabetes.. A pressing challenge is to determine how leptin, ghrelin and other adipokines or gastric factors are involved in metabolic disorders. Answering these questions will require the development of new pharmacological tools that target specific adipokine systems. Hopefully, new therapeutic targets will be identified.

Topics: Adult; Animals; Child; Diabetes Mellitus, Type 2; Drug Delivery Systems; Drug Evaluation, Preclinical; Energy Metabolism; Female; Ghrelin; Glucose; Humans; Hypoglycemic Agents; Insulin Resistance; Islets of Langerhans; Leptin; Mice; Mice, Knockout; Obesity; Receptors, Ghrelin; Receptors, Leptin

Topics: Animals; Brain; Diabetes Mellitus, Type 2; Energy Metabolism; Feedback, Physiological; Ghrelin; Glucose; Glucose Intolerance; Humans; Hypothalamus; Insulin; Leptin; Neurotransmitter Agents; Nutritional Status; Obesity

Leptin (meaning thin) is attracting the attention of many scientists of the world recently. It is an adipocyte-derived protein hormone discovered in 1994. Human leptin gene is located on chromosome 7. It is mainly expressed in adipose tissue but also in skeletal muscle, stomach, placenta and mammary gland. Leptin play key role in food intake, energy balance, and adiposity as well as in immune and endocrine system. It acts as feedback loop to maintain the constant store of body fat. Leptin acts as an antiobesity hormone raising the potential of its use as antiobesity drugs. In future, leptin or its analogue may offer noble therapeutic approach for obesity or other leptin related disorders. This review focuses on current knowledge of leptin biology and the role of leptin in various physiological and pathophysiological states.

Topics: Chromosomes, Human, Pair 7; Humans; Janus Kinases; Leptin; Obesity; Receptors, Leptin; RNA, Messenger

According to the definition (body mass index>97 degrees percentile), overweight and obesity concern 15% of French children. The parallel trends in the increase in asthma and obesity may indicate a potential link between these two conditions. The purpose of this study was to review the epidemiological data indicating a relationship between asthma and obesity, to evaluate the consequences of obesity on asthma and to assess the mechanisms of this association. We conclude with the implications for treatment strategies.

Topics: Adipokines; Adolescent; Adrenal Cortex Hormones; Airway Resistance; Anti-Asthmatic Agents; Asthma; Body Mass Index; Child; Child, Preschool; Comorbidity; Cross-Sectional Studies; Exercise; Humans; Leptin; Longitudinal Studies; Lung Volume Measurements; Obesity; Overweight; Respiratory Hypersensitivity; Risk Factors; Treatment Outcome; Weight Loss

Obesity is currently a worldwide pandemic. It affects more than 300 million humans and it will probably increase over the next 20 years. The consumption of calorie-rich foods is responsible for most of the obesity cases, but not all humans exposed to high-calorie diets develop the disease. This fact has prompted researchers to investigate the mechanisms linking the consumption of high-calorie diets to the generation of an imbalance between energy intake and expenditure. According to recent studies, the exposure to fat-rich diets induces an inflammatory response in the hypothalamic areas involved in the control of feeding and thermogenesis. The inflammatory process damages the neuronal circuitries that maintain the homeostatic control of the body's energy stores, therefore favoring body mass gain. This review will focus on the main advances obtained in this field.

Topics: Animals; Body Composition; Body Mass Index; Diet; Dietary Fats; Eating; Energy Intake; Energy Metabolism; Humans; Hypothalamic Diseases; Hypothalamus; Leptin; Limbic Encephalitis; Obesity; Thermogenesis

Obesity, especially visceral adiposity, is associated with morbidity and mortality through endocrine and mechanical processes. Clinical manifestations due to effects of obesity on the cardiovascular, respiratory, gastrointestinal, musculoskeletal, immune, and integumentary systems have been described. Further studies are needed to understand the pathologic processes underlying these clinical manifestations to improve disease prevention.

Topics: Adipocytes; Adiponectin; Adiposity; Cardiovascular Diseases; Energy Metabolism; Exercise; Gastrointestinal Diseases; Humans; Insulin Resistance; Intra-Abdominal Fat; Leptin; Musculoskeletal Diseases; Neoplasms; Obesity; Respiratory Tract Diseases

Obesity is currently reaching epidemic levels worldwide and is a major predisposing factor for a variety of life-threatening diseases including diabetes, hypertension and cardiovascular diseases. Recently, it has also been suggested to be linked with cancer. Epidemiological studies have shown that obesity increases the risk of colon cancer by 1.5-2 fold with obesity-associated colon cancer accounting for 14-35% of total incidence. Several factors, altered in obesity, may be important in cancer development including increased levels of blood insulin, insulin-like growth factor I, leptin, TNF-alpha, IL-6 as well as decreased adiponectin. A unifying characteristic of all these factors is that they increase the activity of the PI3K/Akt signal pathway. The PI3K/Akt signal pathway in turn activates signals for cell survival, cell growth and cell cycle leading to carcinogenesis. Here we review the evidence that PI3K/Akt and its downstream targets are important in obesity-associated colon cancer and thus, that targeted inhibition of this pathway could be employed for the prevention of obesity-associated colon cancer and incorporated into the therapy regime for those with irremovable colon cancers.

Topics: Cell Proliferation; Cell Survival; Cell Transformation, Neoplastic; Colonic Neoplasms; Comorbidity; Enzyme Inhibitors; Humans; Insulin-Like Growth Factor I; Interleukin-6; Leptin; Obesity; Proto-Oncogene Proteins c-akt; Signal Transduction; Tumor Necrosis Factor-alpha

The increasing incidence of obesity and obesity-linked disease presents a serious global health threat. To develop truly effective therapies to modulate food intake and promote weight loss, we must understand the physiological regulators that underlie these processes. One crucial mediator of food intake and energy homeostasis is the adipose-derived hormone, leptin, which acts through neurons expressing the long form of the leptin receptor (LepRb). Although most investigation of leptin action has centered on the large population of LepRb neurons in the arcuate nucleus (ARC), this nucleus does not mediate all aspects of leptin action. Indeed, several hypothalamic and extrahypothalamic loci contain substantial numbers of LepRb neurons, each of which presumably mediates distinct aspects of leptin action, and the collective output of these various LepRb populations produces the totality of leptin function. This review will examine known central nervous system loci that contain LepRb neurons and the potential roles for discrete populations of LepRb neurons in the control of homeostatic and hedonic pathways by leptin. Understanding the unique neuroanatomical and functional roles for each locus of leptin action will be important to identify how specific aspects of food intake contribute to obesity.

Topics: Appetite Regulation; Arcuate Nucleus of Hypothalamus; Energy Metabolism; Homeostasis; Humans; Hypothalamus; Leptin; Neural Pathways; Obesity; Receptors, Leptin; Reward; Signal Transduction

Food intake is regulated by many factors, including sensory information, metabolic hormones and the state of hunger. In modern humans, the drive to eat has proven to be incompatible with the excess food supply present in industrialized societies. A result of this imbalance is the dramatically increased rates of obesity during the last 20 years. The rise in obesity rates poses one of the most significant public health issues facing the United States and yet we do not understand the neural basis of ingestive behavior, and specifically, our motivation to eat. Understanding how the brain controls eating will lay the foundation for systematic dissection, understanding and treatment of obesity and related disorders. The lack of control over food intake bears resemblance to drug addiction, where loss of control over behavior leads to compulsive drug use. Work in laboratory animals has long suggested that there exist common neural substrates underlying both food and drug intake behaviors. Recent studies have shown direct leptin effects on dopamine neuron function and behavior. This provides a new mechanism by which peripheral hormones influence behavior and contribute to a more comprehensive model of neural control over food intake.

Topics: Animals; Dopamine; Eating; Energy Metabolism; Feeding Behavior; Humans; Hunger; Leptin; Motivation; Obesity; Satiety Response

Powerful biological mechanisms evolved to defend adequate nutrient supply and optimal levels of body weight/adiposity. Low levels of leptin indicating food deprivation and depleted fat stores have been identified as the strongest signals to induce adaptive biological actions such as increased energy intake and reduced energy expenditure. In concert with other signals from the gut and metabolically active tissues, low leptin levels trigger powerful activation of multiple peripheral and brain systems to restore energy balance. It is not just neurons in the arcuate nucleus, but many other brain systems involved in finding potential food sources, smelling and tasting food, and learning to maximize rewarding effects of foods, that are affected by low leptin. Food restriction and fat depletion thus lead to a 'hungry' brain, preoccupied with food. By contrast, because of less (adaptive thrifty fuel efficiency) or lost (lack of predators) evolutionary pressure, the upper limits of body weight/adiposity are not as strongly defended by high levels of leptin and other signals. The modern environment is characterized by the increased availability of large amounts of energy-dense foods and increased presence of powerful food cues, together with minimal physical procurement costs and a sedentary lifestyle. Much of these environmental influences affect cortico-limbic brain areas concerned with learning and memory, reward, mood and emotion. Common obesity results when individual predisposition to deal with a restrictive environment, as engraved by genetics, epigenetics and/or early life experience, is confronted with an environment of plenty. Therefore, increased adiposity in prone individuals should be seen as a normal physiological response to a changed environment, not in the pathology of the regulatory system. The first line of defense should ideally lie in modifications to the environment and lifestyle. However, as such modifications will be slow and incomplete, it is equally important to gain better insight into how the brain deals with environmental stimuli and to develop behavioral strategies to better cope with them. Clearly, alternative therapeutic strategies such as drugs and bariatric surgery should also be considered to prevent or treat this debilitating disease. It will be crucial to understand the functional crosstalk between neural systems responding to metabolic and environmental stimuli, i.e. crosstalk between hypothalamic and cortico-limbic circuitry.

Topics: Adiposity; Appetite Regulation; Energy Intake; Energy Metabolism; Feeding Behavior; Homeostasis; Humans; Hypothalamus; Leptin; Limbic System; Neural Pathways; Obesity; Satiety Response

Breast milk is practically the only food eaten during the first months of life in fully breastfed infants and it is assumed to match the nutritional needs during these first months of postnatal life. Breastfeeding compared with infant formula feeding confers protection against several metabolic and physiological changes later on in life and, particularly, against obesity and related medical complications. Recent data from our laboratory, identifying leptin as the first specific compound responsible for these beneficial effects, are reviewed and discussed.

Topics: Adult; Animals; Breast Feeding; Female; Humans; Infant; Infant Nutritional Physiological Phenomena; Infant, Newborn; Leptin; Maternal Nutritional Physiological Phenomena; Obesity; Rats

Although it has long been known that fasting or the consumption of certain foods can trigger headaches, abdominal and total body obesity have only recently been linked to migraine. Several adipocytokines appear to play an integral role in feeding and obesity--and have also been linked to pain. Among these proteins are adiponectin and leptin. The author reviews the regulation of adipose tissue and feeding and provides an in-depth examination of adiponectin and leptin and their association with migraine.

Topics: Adiponectin; Appetite; Biomarkers; Humans; Leptin; Migraine Disorders; Obesity

Adipokines are polypeptides secreted in the adipose tissue in a regulated manner. While some of these molecules are expressed only by adipocytes, resident and infiltrating macrophages and components of the vascular stroma markedly contribute to expression of other adipokines. As a result, adipose tissue inflammation is associated with a modification in the pattern of adipokine secretion. Leptin, adiponectin, and resistin are the best-studied molecules in this class, but cytokines such as tumor necrosis factor or interleukin-6 are also secreted at high levels by the adipose tissue. Several other molecules have been recently identified and are actively investigated. Adipokines interfere with hepatic injury associated with fatty infiltration, differentially modulating steatosis, inflammation, and fibrosis. Several studies have investigated plasma levels of adiponectin in patients with nonalcoholic fatty liver disease, to establish correlations with the underlying state of insulin resistance and with the type and severity of hepatic damage. Hepatitis C is another disease where adipokines may represent a link between viral infection, steatosis, and metabolic disturbances. Identification of the mediators secreted by expanded adipose tissue and their pathogenic role is pivotal in consideration of the alarming increase in the prevalence of obesity and of the detrimental role that this condition exerts on the course of liver diseases.

Topics: Adipocytes; Adipokines; Adiponectin; Adipose Tissue; Apelin; Fatty Liver; Hepatic Stellate Cells; Hepatitis, Viral, Human; Humans; Intercellular Signaling Peptides and Proteins; Leptin; Liver; Liver Cirrhosis; Liver Diseases; Nicotinamide Phosphoribosyltransferase; Obesity; Resistin; Retinol-Binding Proteins, Plasma; Tumor Necrosis Factor-alpha

This review assesses the feasibility of using glycemic index (GI) as a predictor of appetite, hunger and satiety by surveying published human intervention studies. We also discuss the relationship between GI and two appetite/satiety control hormones, leptin and ghrelin. Ingestion of high-GI food increased hunger and lowered satiety in short-term human intervention studies. This effect may be attributed to the rapid decline in blood glucose level following a hyperinsulinemic response caused by a sharp and transient increase in blood glucose level that occurs after the ingestion of high-GI food, which is defined as the glucostatic theory. However, appetite, hunger and satiety after the ingestion of foods with varying GI were inconsistent among long-term human intervention studies. From the few relevant long-term studies available, we selected two recent well-designed examples for analysis, but they failed to elicit clear differences in glycemic and insulinemic responses between high- and low-GI meals (consisting of a combination of different foods or key carbohydrate-rich foods incorporated into habitual diets). One of the reasons that these studies could not predict glycemic response to mixed meals is presumably that the GI of each particular food was not reflected in that of the mixed meals as a whole. Thus, it is difficult to conclude that the GI values of foods or mixed meals are a valid long-term predictor for appetite, hunger and satiety. Both insulin and insulin-mediated glucose uptake and metabolism in adipose tissue affect blood leptin concentration and its diurnal pattern. Circulating ghrelin level is suppressed by carbohydrate-rich meals, presumably via glycemia and insulinemia. Accordingly, low-GI foods may not necessarily increase satiety or suppress appetite and/or hunger because of the lack of insulin-mediated leptin stimulation and ghrelin suppression. However, insulin-mediated leptin stimulation and ghrelin suppression per se is not consistent among studies; thus we were not able to identify a clear relationship among GI, satietogenic leptin, and appetitic ghrelin.

Topics: Adolescent; Adult; Appetite; Blood Glucose; Child; Eating; Female; Ghrelin; Glycemic Index; Humans; Hunger; Insulin; Leptin; Male; Obesity; Satiation

Although its role in energy homeostasis is firmly established, the evidence accumulated over a decade linking the adipocyte leptin-hypothalamus axis in the pathogenesis of diabetes mellitus has received little attention in the contemporary thinking. In this context various lines of evidence are collated here to show that (1) under the direction of leptin two independent relays emanating from the hypothalamus restrain insulin secretion from the pancreas and mobilize peripheral organs--liver, skeletal muscle and brown adipose tissue--to upregulate glucose disposal, and (2), leptin insufficiency in the hypothalamus produced by either leptinopenia or restriction of leptin transport across the blood brain barrier due to hyperleptinemia of obesity and aging, initiate antecedent pathophysiological sequalae of diabetes type 1 and 2. Further, we document here the efficacy of leptin replenishment in vivo, especially by supplying it to the hypothalamus with the aid of gene therapy, in preventing the antecedent pathophysiological sequalae--hyperinsulinemia, insulin resistance and hyperglycemia--in various animal models and clinical paradigms of diabetes type 1 and 2 with or without attendant obesity. Overall, the new insights on the long-lasting antidiabetic potential of two independent hypothalamic relays engendered by central leptin gene therapy and the preclinical safety indicators in rodents warrant further validation in subhuman primates and humans.

Topics: Animals; Appetite Regulation; Body Weight; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Glucose; Humans; Hypothalamus; Insulin; Leptin; Obesity; Signal Transduction

Changes in maternal diet at different stages of reproduction can have pronounced influences on the health and well-being of the resulting offspring, especially following exposure to an obesogenic environment. The mechanisms mediating adaptations in development of the embryo, placenta, fetus and newborn include changes in the maternal metabolic environment. These changes include reductions in a range of maternal counter-regulatory hormones such as cortisol, leptin and insulin. In the sheep, for example, targeted maternal nutrient restriction coincident with the period of maximal placental growth has pronounced effects on the development of the kidney and adipose tissue. As a consequence, the response of these tissues varies greatly following adolescent-onset obesity and ultimately results in these offspring exhibiting all the symptoms of the metabolic syndrome earlier in young adult life. Leptin administration to the offspring after birth can have some long-term differential effects, although much higher amounts are required to cause a response in small compared with large animal models. At the same time, the responsiveness of the offspring is gender dependent, which may relate to the differences in leptin sensitivity around the time of birth. Increasing maternal food intake during pregnancy, either globally or of individual nutrients, has little positive impact on birth weight but does impact on liver development. The challenge now is to establish which components of the maternal diet can be sustainably modified in order to optimise the maternal endocrine environment through pregnancy, thus ensuring feto-placental growth is appropriate in relation to an individual's gender and body composition.

Topics: Adipose Tissue; Animals; Diet; Female; Fetus; Humans; Kidney; Leptin; Liver; Metabolic Syndrome; Models, Animal; Obesity; Pregnancy; Prenatal Nutritional Physiological Phenomena; Sex Factors

The brain controls energy homeostasis and body weight by integrating various metabolic signals. Leptin, an adipose-derived hormone, conveys critical information about peripheral energy storage and availability to the brain. Leptin decreases body weight by both suppressing appetite and promoting energy expenditure. Leptin directly targets hypothalamic neurons, including AgRP and POMC neurons. These leptin-responsive neurons widely connect to other neurons in the brain, forming a sophisticated neurocircuitry that controls energy intake and expenditure. The anorexigenic actions of leptin are mediated by LEPRb, the long form of the leptin receptor, in the hypothalamus. LEPRb activates both JAK2-dependent and -independent pathways, including the STAT3, PI 3-kinase, MAPK, AMPK, and mTOR pathways. These pathways act coordinately to form a network that fully mediates leptin response. LEPRb signaling is regulated by both positive (e.g., SH2B1) and negative (e.g., SOCS3 and PTP1B) regulators and by endoplasmic reticulum stress. Leptin resistance, a primary risk factor for obesity, likely results from impairment in leptin transport, LEPRb signaling, and/or the neurocircuitry of energy balance.

Topics: Animals; Body Weight; Brain; Humans; Leptin; Obesity; Receptors, Leptin; Signal Transduction

In the mid-1990s, interest in adipose tissue - until then generally regarded as a mere energy reserve - was revived by the discovery of leptin. Since then numerous other cytokine-like hormones have been isolated from white adipose tissue. These adipokines have been investigated in relation to obesity, metabolic syndrome, insulin resistance and other pathological conditions and processes. In addition, it is now established that adipokines play a role in the maintenance of an inflammatory state in adipose tissue and in the development of obesity and comorbidities. The contributions of individual adipokines in the pathophysiological features of obesity have yet to be determined in full, but recent data highlight important roles for adipokines in lipid metabolism.

Topics: Adipokines; Adiponectin; Adipose Tissue; Animals; Humans; Leptin; Lipid Metabolism; Obesity; Signal Transduction

Micronutrient deficiencies have been found in obese individuals across age groups worldwide. While the effects of micronutrient deficiencies on human functions have been studied widely in different populations, there is limited information on how these micronutrient deficiencies affect obese populations. An examination of the available literature suggests associations exist between micronutrient deficiencies and obesity in different populations. These associations and possible mechanisms of the deficiencies' metabolic effects, such as their influence on leptin and insulin metabolism, are discussed here. Further studies are needed to clarify the roles of the different micronutrient deficiencies with respect to obesity and its comorbid conditions.

Topics: Adipose Tissue; Animals; Antioxidants; Calcium; Female; Humans; Insulin; Iron; Iron Deficiencies; Leptin; Male; Micronutrients; Nutritional Status; Obesity; Vitamin A; Vitamin A Deficiency; Vitamin D; Vitamin D Deficiency; Zinc

The current alarming spread of obesity in many parts of the world is caused by a sudden environmental shift characterized by replacement of a frugal diet with low cost, energy dense food, and little requests for physical activity during work and leisure time. Yet, not all people exposed to an obesogenic environment become obese, and individual differences in the propensity to gain weight as well as the occurrence of different obese phenotypes within the same environment indicate that the genetic heritage in this regard is significant and heterogeneous. The central melanocortin circuit has received much attention during the past decade, since mutations of genes expressing some key molecules in neurons of this system were discovered, which may cause monogenic forms of obesity in animals and humans. Within the arcuate nucleus of the hypothalamus the prohormone proopiomelanocortin is posttranslationally cleaved to produce the alpha-melanocyte stimulating hormone, a peptide with anorexigenic effects upon activation of the melanocortin-4 receptor (MC4R) expressed on the surface of target neurons. Studies regarding the frequency of MC4R mutations associated with human obesity have provided variable results (up to 6% of obese subjects). Various findings suggest an oligogenic and codominant mode of inheritance for MC4R deficiency, with modulation of expressivity and penetrance of the phenotype. The yield of MC4R testing in clinical diagnosis and treatment of obesity is at present undefined since the relatively low prevalence of MC4R pathogenic variants in the general population, along with the high number of sequence variants, has so far compromised the devising of systematic controlled intervention studies. Hopefully, in the future, MC4R testing will have practical implications for the development of new mechanism-based therapy of obesity as well as for the design of specific and more effective protocols, based on lifestyle intervention and current pharmacological or surgical approaches, for management of obesity in MC4R-mutated individuals.

Topics: Agouti-Related Protein; alpha-MSH; beta-MSH; Body Weight; Central Nervous System; Humans; Leptin; Mutation; Obesity; Receptor, Melanocortin, Type 4

Obesity is one of the most important health problems today. Obesity is mostly caused by a complex interaction between environmental and genetic factors. However, several monogenic forms of obesity also exist. The mutations causing these forms of obesity were all found in genes involved in the leptin-melanocortin pathway: leptin, leptin receptor, proopiomelanocortin, prohormone convertase 1, and melanocortin-4 receptor. Recently, several novel players with a role in this pathway have been identified and have increased our knowledge on the regulation of food intake. These include the melanocortin-3 receptor, BDNF, SIM1, and nesfatin-1. In this review, we will discuss the most important players involved in this pathway. We will focus on genetic studies concerning mouse models involving these genes and reported human variation in these genes. We intend to provide an extensive overview of all currently known proteins with a significant role in this pathway. Together, these data demonstrate the importance of this pathway in the regulation of food intake and the pathogenesis of obesity.

Topics: Agouti-Related Protein; Animals; Basic Helix-Loop-Helix Transcription Factors; Brain-Derived Neurotrophic Factor; Eating; Humans; Leptin; Melanocortins; Mice; Obesity; Receptor, Melanocortin, Type 3; Receptor, Melanocortin, Type 4; Receptor, trkB; Receptors, Leptin; Repressor Proteins; Signal Transduction

Worldwide, the prevalence of overweight and obesity and associated complications is increasing. Cardiovascular complications are the most important factor determining survival and influencing clinical management. However, obesity is also associated with an increased risk of metabolic syndrome, type 2 diabetes, cancer and other diseases. The development of complications depends on the amount of body fat and its endocrine function. The hormones (leptin, adiponectin, resistin) and cytokines (TNF alpha, IL-6, PAI-1) produced by the adipose tissue are the link between obesity and obesity-related complications. The present article discusses the structure, function and clinical significance of adipokines.

Topics: Adipocytes, White; Adipokines; Adiponectin; Humans; Insulin Resistance; Leptin; Obesity; Resistin; Structure-Activity Relationship

Epidemiological studies have suggested that obesity is associated with increased risk of several cancer types including colon, esophagus, breast (in postmenopausal women), endometrium, kidney, liver, gallbladder and pancreas. Suggested mechanisms include increased intake of potentially carcinogenic food ingredients along with excessive amount of calories, loss of cancer protective effects due to reduced physical activity, carcinogenic factors released from increased adipose tissue mass and "secondary" associations via "precursor" condition such as gallstones. The increased cancer risk in patients with obesity is a neglected topic which deserves more scientific attention. Because of its extreme chronicity and co-association with numerous other conditions true causality and underlying mechanisms are difficult to study. Nevertheless, a large body of literature is already available which provides concepts for future research.

Topics: Adiposity; Comorbidity; Energy Intake; Humans; Inflammation; Insulin; Leptin; Neoplasms; Obesity; Risk Factors

Cardiovascular diseases are currently the most frequent cause of death in Poland and their incidence continually rises. This is related to the high incidence of obesity associated with insulin resistance, which is present in type 2 diabetes mellitus. Adipose tissue produces multiple cytokines(TNF-alpha, IL-6, PAI-1, CRP, angiotensinogen, leptin, adiponectin, visfatin, apelin, resistin)which decrease insulin sensitivity and induce inflammatory processes, endothelial dysfunction,and atherosclerosis. This article presents the link between obesity, insulin resistance, and type 2 diabetes mellitus according to studies conducted in vitro and in animal models. In human studies, the influence of resistin on the development of insulin resistance is controversial. The article underlines the role of resisitin in the development of inflammatory processes and endothelial dysfunction in humans. In clinical studies, resistin was shown to be a predictive factor of coronary artery disease and mortality connected with cardiovascular diseases.

Topics: Adipose Tissue; Animals; Biomarkers; Body Mass Index; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Endothelium, Vascular; Humans; Inflammation; Inflammation Mediators; Leptin; Metabolic Diseases; Metabolic Syndrome; Obesity; Resistin

Obesity is a multifactorial disease that is rarely associated to single gene defects. However, due to their direct cause-effect relationships, those genetic defects that cause some forms of monogenic obesity are relevant in the study of mechanisms that contribute to increased energy intake and body fat accumulation. Most of the genes that have been shown to cause monogenic obesity are related to the leptin-melanocortin system. The functionality of this system has been elucidated through natural mutations (Agouti, ob and db) in mice and knock-out models. Mutations related to human monogenic obesity have been described in leptin, leptin receptor, proopiomelanocortin, prohormone convertase 1 or melanocortin receptor 4 genes. Therapy with human recombinant leptin in patients with genetic deficiency of the hormone is an effective medical treatment of obesity, although only applicable to very few families. The use of leptin-melanocortin agonists, drugs to avoid leptin resistance or combinations of treatments with leptin and other satiating peptides are currently being investigated for multifacotiral human obesity.

Topics: Animals; Body Weight; Humans; Leptin; Melanocortins; Mice; Mutation; Obesity

The discovery of leptin in 1994 was a seminal event in obesity research. It helped to establish that body weight is tightly regulated by a complex neurohormonal feedback system and that obesity should be viewed as a disorder with a strong biological basis rather than simply the result of poor lifestyle choices and lack of willpower.Leptin, secreted from adipocytes, acts as a prototypic long-term (tonic) adiposity signal. Although nonclinical and clinical studies have provided unequivocal evidence that leptin plays a unique, pivotal role in body weight regulation, efforts to develop recombinant leptin (metreleptin) as a monotherapy for obesity have proven unsuccessful. Amylin, secreted from pancreatic beta-cells, fulfills the criteria for a short-term (episodic) satiety signal. The amylin analog pramlintide elicits sustained reductions in food intake and body weight in obese rodents and humans.A translational research program aimed at elucidating the interaction between different islet-, gut-, and adipocyte-derived hormones led to the discovery that combined amylin/leptin agonism induces marked, synergistic, fat-specific weight loss in leptin-resistant diet-induced obese rodents. In obese humans, combination treatment with pramlintide/metreleptin led to an approximately 13% weight loss after 24 weeks, significantly more than after treatment with pramlintide or metreleptin alone.Collectively, these findings suggest that combined amylin/leptin agonism may have therapeutic utility as part of an integrated, neurohormonal approach to obesity pharmacotherapy.

Topics: Amyloid; Animals; Anti-Obesity Agents; Drug Design; Drug Therapy, Combination; Feedback, Physiological; Humans; Islet Amyloid Polypeptide; Leptin; Neurotransmitter Agents; Obesity; Satiety Response; Signal Transduction; Weight Loss

The discovery of leptin in 1994 has led to remarkable advances in obesity research. We now know that leptin is a cytokinelike hormone that is produced in adipose tissue and plays a pivotal role in regulation of energy balance and in a variety of additional processes via actions in the central nervous system. This symposium review covers current understandings of neuronal leptin receptor signaling and mechanisms of obesity-related leptin resistance in the central nervous system and provides recent insights into the regulation of peripheral glucose balance by central leptin action in rodents.

Topics: Animals; Brain; Drug Resistance; Leptin; Obesity; Pro-Opiomelanocortin; Receptors, Leptin; Signal Transduction

Leptin is a hormone, which plays a central role in inhibiting food intake and body weight gain. Leptin is secreted from exocrine as well as endocrine cells. Circulating leptin activates JAK-STAT tyrosine kinases through Ob-Rb leptin receptor in the hypothalamus and brain stem. In recent years, "leptin resistance" has been considered to be one of the main causes of obesity. However, the detailed mechanisms of leptin resistance are not well understood. Recently, we hypothesized possibility that endoplasmic reticulum (ER) stress is involved in leptin resistance. In the present manuscript, we would like to mention possible mechanisms of ER stress-induced leptin resistance and possible implication in obesity. In addition, pathophysiological role of leptin's action in regulating endocrine as well as exocrine functions at the state of ER stress are discussed.

Topics: Animals; Endoplasmic Reticulum; Humans; Janus Kinase 2; Leptin; Models, Animal; Obesity; Signal Transduction; STAT3 Transcription Factor; Stress, Physiological

Multiple lines of investigations demonstrated that the melanocortin-4 receptor (MC4R) is a critical regulator of energy homeostasis from fishes to humans. Clinical studies in humans showed that mutations in the MC4R gene are the most prevalent form of monogenic obesity. More than 150 mutations have been identified from subjects of different ethnic backgrounds. Functional analyses of the mutant MC4Rs revealed multiple defects, including cell-surface expression, ligand binding, and signaling. Based on the defects, the mutants can be classified into five classes. Potential therapeutic implications from the analyses of the naturally occurring MC4R mutations, such as novel ligands and pharmacological chaperones, are highlighted.

Topics: Energy Metabolism; Humans; Leptin; Mutation; Obesity; Phenotype; Receptor, Melanocortin, Type 4

The prevalence of obesity has grown to an alarming magnitude, affecting more than 300 million humans worldwide. Although in most instances obesity is caused by excessive caloric consumption, only recently have we begun to understand the mechanisms involved in the loss of balance between caloric intake and energy expenditure. In the hypothalamus, groups of specialized neurons provide the signals that, under physiological conditions, determine the stability of body mass. Recent studies have shown that under certain environmental and genetic conditions, this equilibrium is lost and body adiposity may increase. Here, we review the work that provided the basis for the current understanding of hypothalamic dysfunction and the genesis of obesity.

Topics: Animals; Humans; Hypothalamus; Insulin; Leptin; Obesity

Studies of the role of immune system activation in the pathogenesis of obesity and its concomitant diseases have been conducted for some years. Numerous recent studies revealed an association between increased immune activation in obesity and the development of insulin resistance. On the other hand there is the hypothesis that immune activation in obesity is a homeostatic mechanism to protect the organism from reaching the point at which the over-accumulation of fat decreases the possibility to move. The aim of the present study was to review the current literature on immune activation in obesity and the participation of adipokines produced by adipose tissue in the development of insulin resistance. Attention is drawn to the similarities in function and gene expression of adipocytes and macrophages.

Topics: Adipocytes; Adipokines; Adipose Tissue; Animals; Gene Expression; Humans; Inflammation; Insulin Resistance; Interleukin-6; Leptin; Macrophages; Obesity; Resistin; Tumor Necrosis Factor-alpha

Secreted by adipocytes, leptin is a hormone which regulates appetite and metabolism. Leptin secretion is proportional to the fat mass, and thus leptin concentration is raised in most obese subjects. In recent years, more and more biological effects have been attributed to leptin; one of the most well-known effects is the effect of leptin on the vascular tone. Obesity is very often associated with hypertension, and it has been known that leptin affects the blood pressure by activating the sympathetic nervous system and causing endothelial cell (EC) dysfunction. However, there has been strong evidence that leptin is able to dilate blood vessels. Such vasodilation has been shown to be EC-dependent and EC-independent. Further, both nitric oxide-dependent and nitric oxide-independent mechanisms have been reported. In this mini-review, we summarize the heterogeneous mechanisms by which leptin causes relaxation of vascular smooth muscle. We also argue that while leptin may act as a direct dilator on the vasculature in healthy subjects, hyperleptinemia in obese subjects gradually dysregulates blood pressure control by deteriorating EC functions. How these dual effects of leptin on EC might be related to EC ionic channels is also discussed.

Topics: Animals; Endothelial Cells; Humans; Leptin; Nitric Oxide; Obesity; Receptors, Leptin; Vasodilation

Over the last few years, a series of molecules known to play a function in metabolism has also been shown to play an important role in the regulation of the immune response. In this context, the adipocyte-derived hormone leptin has been shown to regulate the immune response in normal as well as in pathological conditions. More specifically, it has been shown that conditions of reduced leptin production (i.e., genetic leptin deficiency, anorexia nervosa, malnutrition) are associated with increased susceptibility to infections. Conversely, immune-mediated disorders such as autoimmune disorders are associated with increased secretion of leptin and production of proinflammatory, pathogenic cytokines. Leptin could represent the "missing link" among immune response, metabolic function, and nutritional status. Indeed, more recently, leptin-deficient mice have been shown to be resistant to a series of experimentally induced autoimmune disorders including experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. Normal wild-type mice show increased secretion of leptin in serum upon EAE induction, and brain inflammatory infiltrates stain positive for leptin. Finally, leptin neutralization with leptin antagonists improves the EAE course by profoundly altering intracellular signaling of myelin-reactive T cells and increasing the number of regulatory forkhead/winged helix transcription factor 3(+)CD4(+) T cells. These data suggest that leptin can be considered as a link among immune tolerance, metabolic state, and autoimmunity and that strategies aimed at interfering with the leptin axis could represent innovative, therapeutic tools for autoimmune disorders.

Topics: Animals; Autoimmune Diseases; Brain; CD4-Positive T-Lymphocytes; Encephalomyelitis, Autoimmune, Experimental; Homeostasis; Humans; Immunity; Inflammation; Leptin; Metabolism; Multiple Sclerosis; Obesity; T-Lymphocytes, Regulatory

Obesity is one of the risk factors in various chronic diseases and malignancy. It may result from excess accumulation of body fat. This condition may be caused by dysfunction of appetite-regulating pathways and energy balance due to leptin resistance. Leptin, a 16 kDa hormone, is the most important regulator of appetite and energy balance in the body. Most individuals with obesity have leptin resistance characterized by increased leptin blood levels. Some possibilities of mechanism involved in leptin resistance have been proposed by researchers despite the fact that it is still being studied hitherto. One of the mechanisms considered to have a role in leptin resistance is disruption in signal transduction process through Janus-activating kinase2-signal transducer and activator of transcription 3 (JAK2-STAT3) pathway on leptin receptors by suppressor of cytokine signaling-3 (SOCS-3). SOCS-3 is a protein that inhibits the signal transduction process of various cytokines in the body, including leptin. SOCS-3 expression is induced by leptin and SOCS-3 activation will inhibit STAT3 phosphorylation which is important in signal transmission on leptin receptors. Such inhibition will consequently cause leptin resistance characterized by dysfunction of leptin biological function.

Topics: Cytokines; Energy Metabolism; Humans; Leptin; Obesity; Receptors, Leptin; Risk Factors; Signal Transduction; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Calcium Channel Blockers; Cardiovascular Diseases; Diabetes Mellitus; Drug Therapy, Combination; Humans; Hypertension; Insulin Resistance; Leptin; Obesity

Obesity is the most serious long-term health risk currently facing America's adolescents. Weight gain during adolescence carries a higher risk for adult obesity and the metabolic syndrome. This review highlights early adolescence as a particularly high-risk time for weight gain due to the synergy of naturally occurring metabolic changes along with increasing behavioral risk factors. One of the first potential health effects of abnormal weight gain during this period is earlier puberty, usually manifested as thelarche. The obesity epidemic is clearly implicated in the national trend toward earlier thelarche, although the data are not as strong in relation to menarche. Leptin activation of the hypothalamic-pituitary axis, combined with insulin resistance, and increased adiposity may result in the higher estrogen levels that are linked to breast development. Young adolescents also experience a sharp decline in their level of physical activity, worsening nutritional habits, and other important psychosocial and developmental risk factors that may contribute to obesity and estrogen-dependent disease in later life, including polycystic ovary syndrome and breast cancer. Unfortunately, the very psychosocial factors that contribute to abnormal weight gain during early adolescence make prevention and treatment in this population particularly challenging. Therefore, intervening prior to pubertal onset becomes even more important given the risk factors present once puberty begins.

Topics: Adolescent; Adult; Breast Neoplasms; Estrogens; Female; Humans; Hypothalamo-Hypophyseal System; Insulin Resistance; Leptin; Metabolic Syndrome; Obesity; Polycystic Ovary Syndrome; Puberty; Risk Factors; Weight Gain

Over the past decade, adipose tissue has been shown to produce numerous factors that act as hormones. Many of these act on the brain to regulate energy balance via dual effects on food intake and energy expenditure. These include well-characterised hormones such as leptin, oestrogen and glucocorticoids and novel factors such as adiponectin and resistin. This review provides a perspective on the role of these factors as lipostats.

Topics: Adiponectin; Adipose Tissue; Animals; Brain; Eating; Estrogens; Glucocorticoids; Gonadal Steroid Hormones; Hormones; Humans; Leptin; Obesity; Resistin; Signal Transduction

The epidemic of obesity in the United States and around the world is intensifying in severity and scope and has been implicated as an underlying mechanism in systemic hypertension. Obese hypertensive individuals characteristically exhibit volume congestion, relative elevation in heart rate, and high cardiac output with concomitant activation of the renin-angiotensin-aldosterone system. When the metabolic syndrome is present, insulin resistance and hyperinsulinemia may contribute to hypertension through diverse mechanisms. Blood pressure can be lowered when weight control measures are successful, using, for example, caloric restriction, aerobic exercise, weight loss drugs, or bariatric surgery. A major clinical challenge resides in converting short-term weight reduction into a sustained benefit. Pharmacotherapy for the obese hypertensive patient may require multiple agents, with an optimal regimen consisting of inhibitors of the renin-angiotensin-aldosterone system, thiazide diuretics, beta-blockers, and calcium channel blockers if needed to attain contemporary blood pressure treatment goals.

Topics: Antihypertensive Agents; Bariatric Surgery; Blood Pressure; Drug Therapy, Combination; Hemodynamics; Humans; Hypertension; Leptin; Metabolic Syndrome; Obesity; Renin-Angiotensin System; Risk Reduction Behavior; Sympathetic Nervous System; Weight Loss

In this review, we discuss the role of inactivity and exercise on appetite regulation, both in the short and long term, and the potential mechanisms involved. A better short-term appetite control has been described in active compared to sedentary men, and an exercise intervention was shown to improve appetite control in previously sedentary individuals. The mechanisms whereby exercise improves short-term appetite control remain obscure and although the changes in the postprandial release of satiety peptides are attractive hypotheses, it remains unproven. The impact of exercise on habitual food intake is also controversial and likely to be dependent on restraint level and body weight. We hypothesize that the beneficial impact of exercise on appetite regulation can contribute to its well-established efficacy in the prevention of weight regain in obese individuals. However, more studies are needed in the obese population to clearly establish the role of exercise on appetite control in this group.

Topics: Appetite Regulation; Eating; Energy Intake; Energy Metabolism; Exercise; Humans; Leptin; Motivation; Obesity; Weight Loss

Although beta3-adrenoceptor (beta3AR) agonists have not become drugs for the treatment of obesity or diabetes, they offer perspectives on obesity drug discovery, the physiology of energy expenditure and receptor pharmacology. beta3AR agonists, some of which also stimulate other betaARs in humans, selectively stimulate fat oxidation in rodents and humans. This appears to be why they improve insulin sensitivity and reduce body fat whilst preserving lean body mass. Regulatory authorities ask that novel anti-obesity drugs improve insulin sensitivity and reduce mainly body fat. Drugs that act on different targets to stimulate fat oxidation may also offer these benefits. Stimulation of energy expenditure may be easy to detect only when the sympathetic nervous system is activated. Leptin resembles beta3AR agonists in that it increases fat oxidation, energy expenditure and insulin sensitivity. This is partly because it raises sympathetic activity, but it may also promote fat oxidation by directly stimulating muscle leptin receptors. The beta1AR and beta2AR can, like the beta3AR, display atypical pharmacologies. Moreover, the beta3AR can display variable pharmacologies of its own, depending on the radioligand used in binding studies or the functional response measured. Studies on the beta3AR demonstrate both the difficulties of predicting the in vivo effects of agonist drugs from in vitro data and that there may be opportunities for identifying drugs that act at a single receptor but have different profiles in vivo.

Topics: Adrenergic beta-3 Receptor Agonists; Adrenergic beta-Agonists; Animals; Anti-Obesity Agents; Energy Metabolism; History, 20th Century; Humans; Leptin; Lipid Metabolism; Obesity; Oxidation-Reduction; Receptors, Adrenergic, beta-3; Receptors, Leptin

The metabolic syndrome is a common and complex disorder combining obesity, dyslipidemia, hypertension, and insulin resistance. It is a primary risk factor for diabetes and cardiovascular disease. We showed for the first time that the metabolic syndrome is associated with a higher fraction of oxidized LDL and thus with higher levels of circulating oxidized LDL. Hyperinsulinemia and impaired glycaemic control, independent of lipid levels, were associated with increased in vivo LDL oxidation, as reflected by the higher prevalence of high oxidized LDL. High levels of oxidized LDL were associated with increased risk of future myocardial infarction, even after adjustment for LDL-cholesterol and other established cardiovascular risk factors. This association is in agreement with the finding that accumulation of oxidized LDL, which activates/induces subsets of smooth muscle cells and macrophages to gelatinase production, was associated with upstream localization of a vulnerable plaque phenotype. Dyslipidemia and insulin resistance in obese LDL receptor-deficient mice were associated with increased oxidative stress and impaired HDL-associated antioxidant defence associated with accelerated atherosclerosis due to increased macrophage infiltration and accumulation of oxidized LDL in the aorta. The accumulation of oxidized LDL was partly due to an impaired HDL-associated antioxidant defence due to a decrease in PON. Our data in this experimental model are thus the more relevant because a decrease in PON activity was found to be associated with a defective metabolism of oxidized phospholipids by HDL from patients with type 2 diabetes. Weight loss in leptin-deficient, obese, and insulin-resistant mice was associated with expressional changes of key genes regulating adipocyte differentiation, glucose transport and insulin sensitivity, lipid metabolism, oxidative stress and inflammation, most of which are under the transcriptional control of PPARs. We established an important relationship between PPAR-gamma and SOD1 for the prevention of the oxidation of LDL in the arterial wall. For example we showed that rosuvastatin decreased the oxidized LDL accumulation by increasing the expression of PPAR-gamma and SOD1. In addition, we established a relation between increased PPAR-alpha expression in the adipose tissue and a change in the gene expression pattern, which explains the decrease of free fatty acids, triglycerides and the increase in insulin sensitivity. We demonstrated

Topics: Animals; Cardiovascular Diseases; Comorbidity; Humans; Inflammation; Insulin Resistance; Leptin; Lipid Metabolism; Lipoproteins, LDL; Metabolic Syndrome; Mice; Obesity; Oxidation-Reduction; Oxidative Stress; Risk Factors; Weight Loss

The dramatic increase in the number of obese and overweight persons has spurred interest in control of appetite, body weight, and adiposity. Leptin is the humoral component of a negative feedback loop between adipose tissue and brain. Leptin is secreted from fat in proportion to the degree of adiposity, is transported across the blood-brain barrier (BBB), and acts in the brain to decrease appetite and increase thermogenesis, actions that ultimately decrease adiposity. However, leptin fails as an adipostat because leptin resistance arises in obesity. The BBB transporter is the first part of the feedback loop to fail, producing the so called "peripheral resistance" to leptin. In this sense, obesity is a disease of the BBB. Failure of leptin as an adipostat raises the question of what its primary role is as does its effects on reproduction, bone, immunity, breathing, cognition, and neurogenesis. Kinetics analysis shows that the BBB transporter performs most efficiently at low serum levels of leptin, suggesting that the feedback loop evolved to operate at lower leptin levels than those seen in ideal body weight. We suggest that low levels of serum leptin inform the brain that adipose reserves are adequate to expend calories on functions other than feeding, such as reproduction and the immune system. This feedback loop is short-circuited when an animal enters starvation. Hallmarks of starvation include decreased secretion of leptin by adipose tissue and hypertriglyceridemia. Triglycerides inhibit the transport of leptin across the BBB, thus attenuating the leptin signal across the BBB and providing a mechanism for peripheral leptin resistance. Triglycerides are elevated in both starvation and obesity. We postulate that hypertriglyceridemia evolved as a starvation signal to the brain that acts in part to inhibit the transport of the leptin across the BBB. The hypertriglyceridemia of obesity invokes this aspect of the starvation response, inducing leptin resistance at the BBB. Thus, the BBB plays important roles in both obesity and starvation.

Topics: Animals; Blood-Brain Barrier; Cognition; Energy Intake; Humans; Leptin; Obesity; Protein Transport

Obesity is becoming one of the most common health problems in the world. Many other disorders, such as hypertension and diabetes are considered as the consequences of obesity. Since effective remedies are rare (only two drugs, Orlistat and Sibutramine, were officially approved by the US Food and Drug Administration for long-term obesity treatment so far), researchers are trying to discover new therapies for obesity, and acupuncture is among the most popular alternative approaches. To facilitate weight reduction, one can use manual acupuncture, electroacupuncture (EA) or transcutaneous electrical acupoint stimulation (TEAS). As the parameters of the EA or TEAS can be precisely characterized and the results are more or less reproducible, this review will focus on EA as a treatment modality for obesity. Results obtained in this laboratory in recent five years will be summarized in some detail.

Topics: alpha-MSH; AMP-Activated Protein Kinases; Animals; Appetite; Arcuate Nucleus of Hypothalamus; Electroacupuncture; Ghrelin; Humans; Ion Channels; Leptin; Mitochondrial Proteins; Neuropeptide Y; Obesity; Rats; Uncoupling Protein 3

Hypothalamic neuronal histamine and its H(1) receptor (H(1)-R), a leptin signaling pathway in the brain, regulate body weight and adiposity by affecting food intake and energy expenditure. Glucagon-like peptide-1 and/or corticotrophin-releasing hormone mediate leptin signaling to neuronal histamine. Leptin-induced suppression of food intake and upregulation of uncoupling protein-1 expression in brown adipose tissue were partially attenuated in histamine H(1)-R knockout (H(1)KO) mice. H(1)KO mice developed maturity-onset obesity. Hyperphagia and decreased energy expenditure assessed by the expression of uncoupling protein-1 mRNA were observed in older (48-wk-old) obese H(1)KO mice but not in younger (12-wk-old) non-obese H(1)KO mice. However, the diurnal feeding rhythm was impaired even in younger non-obese animals. Specifically, disruption of the feeding rhythm developed before the onset of obesity in H(1)KO mice. Correction of these abnormal feeding rhythms with scheduled feeding improved the obesity and associated metabolic disorders in the H(1)KO mice. These findings suggest that histamine H(1)-R is crucial for regulating the feeding rhythm and in mediating the effects of leptin. Early disruption of H(1)-R-mediated functions in H(1)KO mice may lead to hyperphagia and decreased energy expenditure, which may contribute to the development of obesity in these animals.

Topics: Animals; Appetite Regulation; Behavior, Animal; Body Weight; Circadian Rhythm; Eating; Energy Metabolism; Feeding Behavior; Histamine; Hypothalamus; Leptin; Mice; Obesity

There is general agreement that central, as opposed to peripheral, adipose tissue confers the most cardiometabolic risk. Although the basis of this differential risk has not been established, the pattern of gene expression and secretory products in visceral fat would be predicted to be more atherogenic compared with that in subcutaneous peripheral fat. Adipose tissue is, in fact, now recognized not simply a store of excess energy but a major endocrine and secretory organ, releasing a wide range of protein factors and signals, termed adipokines, in addition to fatty acids and other lipid moieties. These factors are derived from adipocyte or non-adipocyte fractions, and include proteins, metabolites and hormones. This paper reviews some of the advances in the understanding of biologically active molecules produced by adipose tissue and how dysregulated production of these factors could be implicated in the association between central adiposity, cardiovascular pathology and comorbidities, including metabolic syndrome, type 2 diabetes and systemic inflammation.

Topics: Adipocytes; Adipokines; Adiponectin; Adipose Tissue; Animals; Atherosclerosis; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Humans; Leptin; Metabolic Syndrome; Obesity; Systemic Inflammatory Response Syndrome

Hypertension and obesity are major components of the cardiometabolic syndrome and are both on the rise worldwide, with enormous consequences on global health and the economy. The relationship between hypertension and obesity is multifaceted; the etiology is complex and it is not well elucidated. This article, reviews the current knowledge on obesity-related hypertension. Further understanding of the underlying mechanisms of this epidemic will be important in devising future treatment avenues.

Topics: Adipocytes; Adiponectin; Animals; Humans; Hypertension; Insulin Resistance; Kidney; Leptin; Obesity; Renin-Angiotensin System; Sleep Apnea, Obstructive; Sympathetic Nervous System

Human obesity has a strong genetic component. Most genes that influence an individual's predisposition to gain weight are not yet known. However, the study of extreme human obesity caused by single gene defects has provided a glimpse into the long-term regulation of body weight. These monogenic obesity disorders have confirmed that the hypothalamic leptin-melanocortin system is critical for energy balance in humans, because disruption of these pathways causes the most severe obesity phenotypes. Approximately 20 different genes and at least three different mechanisms have been implicated in monogenic causes of obesity; however, they account for fewer than 5% of all severe obesity cases. This finding suggests that the genetic basis for human obesity is likely to be extremely heterogeneous, with contributions from numerous genes acting by various, yet undiscovered, molecular mechanisms.

Topics: Bardet-Biedl Syndrome; Basic Helix-Loop-Helix Transcription Factors; Brain-Derived Neurotrophic Factor; Humans; Leptin; Mutation; Obesity; Pro-Opiomelanocortin; Proprotein Convertase 1; Receptor, Melanocortin, Type 4; Receptors, Leptin; Repressor Proteins

The classical perception of adipose tissue as a storage place of fatty acids has been replaced over the last years by the notion that adipose tissue has a central role in lipid and glucose metabolism and produces a large number of hormones and cytokines, e.g. tumour necrosis factor-alpha, interleukin-6, adiponectin, leptin, and plasminogen activator inhibitor-1. The increased prevalence of excessive visceral obesity and obesity-related cardiovascular risk factors is closely associated with the rising incidence of cardiovascular diseases and type 2 diabetes mellitus. This clustering of vascular risk factors in (visceral) obesity is often referred to as metabolic syndrome. The close relationship between an increased quantity of visceral fat, metabolic disturbances, including low-grade inflammation, and cardiovascular diseases and the unique anatomical relation to the hepatic portal circulation has led to an intense endeavour to unravel the specific endocrine functions of this visceral fat depot. The objective of this paper is to describe adipose tissue dysfunction, delineate the relation between adipose tissue dysfunction and obesity and to describe how adipose tissue dysfunction is involved in the development of diabetes mellitus type 2 and atherosclerotic vascular diseases. First, normal physiology of adipocytes and adipose tissue will be described.

Topics: Adipocytes; Adipose Tissue; Atherosclerosis; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Energy Metabolism; Female; Humans; Intra-Abdominal Fat; Leptin; Male; Metabolic Syndrome; Obesity; Risk Reduction Behavior; Subcutaneous Fat, Abdominal; Transcription Factors

Obesity is associated with increased morbidity and mortality from cardiovascular disease, diabetes mellitus and certain cancers. The prevalence of obesity is increasing rapidly throughout the world and is now recognized as a major global public-health concern. Although the increased prevalence of obesity is undoubtedly driven by environmental factors, the evidence that inherited factors profoundly influence human fat mass is equally compelling. Twin and adoption studies indicate that up to 70% of the interindividual variance in fat mass is determined by genetic factors. Genetic strategies can, therefore, provide a useful tool with which to dissect the complex (and often heterogeneous) molecular and physiologic mechanisms involved in the regulation of body weight. In this Review, we have focused our attention on monogenic disorders, which primarily result in severe, early-onset obesity. The study of these genetic disorders has provided a framework for our understanding of the mechanisms involved in the regulation of body weight in humans and how these mechanisms are disrupted in obesity. The genes affected in these monogenic disorders all encode ligands and receptors of the highly conserved leptin-melanocortin pathway, which is critical for the regulation of food intake and body weight.

Topics: Drug Resistance; Genetic Predisposition to Disease; Humans; Leptin; Ligands; Melanocortins; Models, Biological; Mutation; Obesity; Pro-Opiomelanocortin; Receptors, Leptin; Receptors, Melanocortin; Signal Transduction; Syndrome

Dysfunction of specific hypothalamic neurons is regarded as an important mechanism predisposing to the development of obesity. Recent studies have revealed that the consumption of fat-rich foods can activate an inflammatory response in the hypothalamus, which disturbs the anorexigenic and thermogenic signals generated by the hormones leptin and insulin, leading in turn to anomalous body mass control. Depending on diet composition, cytokines are expressed in the hypothalamus, contributing to the activation of intracellular inflammatory signal transduction. At least 4 distinct signaling pathways have been identified and the molecular mechanisms leading to the impairment of the leptin and insulin actions have been determined. Here, we present the mechanisms involved in diet-induced resistance to leptin and insulin action in the hypothalamus and discuss some of the potential applications of this knowledge in the therapeutics of obesity.

Topics: Animals; Body Weight; Cytokines; Dietary Fats; Encephalitis; Humans; Hypothalamus; Insulin; Insulin Resistance; Insulin Secretion; Leptin; Obesity; Signal Transduction

Obesity and hypertension frequently coexist and both represent important risk factors for cardiovascular disease. The mechanisms implicated in the regulation of food intake have not been completely elucidated. Recent data suggests that peripheral and central neuropeptides play an important role in the maintenance of energy balance. More specifically, leptin, neuropeptide Y (NPY) and alpha-melanocyte-stimulating hormone (a-MSH) appear to be implicated in the pathogenesis of obesity and also contribute to the development of hypertension in obesity.. Analysis of the pertinent bibliography published in PubMed database.. Leptin is produced in the adipose tissue directly correlated with fat tissue mass. Leptin acts on two distinct neural populations in the hypothalamus: the first expresses the orexigenic peptides NPY and agouti-related protein (AgRP), the second pro-opiomelanocortin (POMC). The activation of POMC neurons increases the production of the anorexigenic hormone a-MSH and inhibits the release of NPY and AgRP. In addition, the hypothalamus integrates the neuroendocrine systems with the autonomic nervous system and controls the activity of the latter. Stimulation of hypothalamic nuclei elicits sympathetic responses including blood pressure elevation. Both NPY and a-MSH appears to be implicated in the hypothalamic regulation of sympathetic nervous system (SNS) activity.. Alterations in leptin, NPY and a-MSH are frequently observed in obesity and might stimulate SNS activity, contributing to the development of hypertension in obese patients. These neuropeptides might provide a pathophysiologic link between excess weight and hypertension. However, more research is needed before the pharmacologic manipulation of these complex neuroendocrine systems can be applied in the treatment of obesity and hypertension.

Topics: alpha-MSH; Appetite Regulation; Body Weight; Humans; Hypertension; Leptin; Neuropeptide Y; Obesity; Sympathetic Nervous System

Obesity has been recognized as a worldwide public health problem. It significantly increases the chances of developing several diseases, including Type II diabetes. The roles of insulin and leptin in obesity involve reactions that can be better understood when they are presented step by step. The aim of this work was to design software with data from some of the most recent publications on obesity, especially those concerning the roles of insulin and leptin in this metabolic disturbance. The most notable characteristic of this software is the use of animations representing the cellular response together with the presentation of recently discovered mechanisms on the participation of insulin and leptin in processes leading to obesity. The software was field tested in the Biochemistry of Nutrition web-based course. After using the software and discussing its contents in chatrooms, students were asked to answer an evaluation survey about the whole activity and the usefulness of the software within the learning process. The teaching assistants (TA) evaluated the software as a tool to help in the teaching process. The students' and TAs' satisfaction was very evident and encouraged us to move forward with the software development and to improve the use of this kind of educational tool in biochemistry classes.

Topics: Biochemistry; Computer-Assisted Instruction; Diabetes Mellitus, Type 2; Education, Distance; Health Education; Humans; Insulin; Leptin; Multimedia; Obesity; Program Evaluation; Software; Teaching; Teaching Materials

One of the most exciting cell biology fields of study concerns the physiology and pathology of fat. The basic assumptions once held concerning the function of adipose tissue have been shown to be oversimplified or sometimes completely wrong. Fat does more than store excess energy; it is actually the largest endocrine organ in the body, and it may be one of the most active. Adipocytes release hormones and other molecules that act on nearby tissues and travel through the vasculature to distant sites, such as the brain, skeletal muscle, and liver. Under conditions of normal weight, those signals help the body to suppress hunger, utilize glucose, and decrease the risk of cardiovascular disease. However, under conditions of obesity, the hormones (or the proteins that bind the hormones) become abnormal and can result in states of chronic inflammation leading to diabetes and heart disease. In addition, excessive fat can lead to the accumulation of lipid droplets in nonfat cells, including skeletal and cardiac muscle. Although some lipid droplets are used as an immediate source of energy for cells, large numbers of stored droplets can cause cellular damage and cell death. The purposes of this article are to review the normal and deviant signals released by fat cells, to draw a link between those signals and chronic diseases such as diabetes, and to discuss the role of exercise in reversing some of the deviant signaling perpetrated by excess fat.

Topics: Adipokines; Adipose Tissue; Exercise; Humans; Inflammation; Leptin; Obesity

The incidence of obesity is rapidly increasing all over the world in epidemic proportions.The epidemia now affects young children and accumulative evidences suggest that the origin of the disease may occur during foetal development and early life. This has introduced the concept of "developmental programming" supported by experimental studies in animal models and numerous epidemiological data. This concept supports the idea that nutritional and hormonal status during pregnancy and early life could interfere irreversibly on the development of the organs involved in the control of food intake and metabolism and particularly the hypothalamic structures responsible of the establishment of the ingestive behaviour and regulation of energy expenditure. The mechanisms responsible of this developmental programming remain poorly documented. However, recent research indicate that the adipokine leptin plays a critical role in this programming.

Topics: Animals; Eating; Female; Fetal Growth Retardation; Genomic Imprinting; Humans; Leptin; Obesity; Pregnancy; Risk Factors

The integrated central actions of hormones secreted from pancreatic islets, the gut and adipocytes regulate both energy homeostasis and body weight. Dysregulation in these neurohormonal pathways probably contributes to pathogenesis of obesity and type 2 diabetes.. To examine hormone-based therapies targeting these interrelated pathways as potential treatments for obesity and diabetes.. Preclinical and clinical data on therapies based on hormones secreted from the pancreas (glucagon, insulin, amylin and pancreatic polypeptide), gut (glucagon-like peptide-1, glucose dependent insulinotropic polypeptide, cholecystokinin and peptide YY) and adipose tissue (leptin and adiponectin) as potential treatments for diabetes and obesity are reviewed.. In diabetes, hormone-based treatments have translated into new clinical platforms including insulin analogs, the GLP-1-like peptide receptor agonist exenatide and amylinomimetic pramlintide, which due to their complex interplay and the progressive nature of diabetes, can be utilized in different settings. Various peptide hormones and agonists/antagonists are currently under investigation as new approaches to treatment of obesity and diabetes.

Topics: Adipocytes; Adiponectin; Adipose Tissue; Amyloid; Animals; Body Weight; Diabetes Mellitus, Type 2; Energy Metabolism; Glucagon-Like Peptide 1; Homeostasis; Hormones; Humans; Intestinal Mucosa; Islet Amyloid Polypeptide; Leptin; Mice; Obesity; Pancreas

Several population-based studies have shown a significant association between TSH-level and BMI (body mass index). About 30% of the rest energy expenditure are regulated by thyroid hormones, which generated the hypothesis that thyroid hormone substitution with TSH-titration into the lower reference levels may prevent body weight gain. The opposite effect of thyroid hormones is appetite stimulation, which may be responsible for body weight gain in case of substitutive medication. The association between TSH and BMI has become a complex topic in the light of the endocrine activity of adipocytes. Adipocytes are not a silent fat mass, but increase the hormone level of leptin, which influences neurones in the hypothalamus, the thyreotropic axis and TSH secretion. BMI is positively correlated with serum leptin. Elevated leptin levels, endogenous in individuals with high BMI or exogenous after leptin injection for treatment of hypothalamic amenorrhoea, shift TSH in the upper reference level. Borderline elevated TSH levels are reversible in case of body weight reduction in obese persons. It remains unclear whether high TSH levels or high leptin level are responsible for obesity or represent secondary phenomenon. Recommendation for daily practice: Borderline elevated TSH-levels in obese patients will decrease in case of body weight reduction without hormone medication. After definitive treatment of hyperthyroidism patient's history for use of carbohydrates (increased during hyperthyroidism) should be noticed and substitution with thyroid hormones aims at TSH in the lower reference level. As body weight gain is observed in all TSH groups, a special concept for prevention and therapy of obesity (diet, daily exercise, behaviour training) should be initiated early and additionally to medication.

Topics: Adipose Tissue; Behavior Therapy; Body Mass Index; Diet, Reducing; Exercise; Humans; Leptin; Obesity; Reference Values; Thyroid Function Tests; Thyrotropin; Weight Gain

Leptin is an adipocyte-derived hormone and cytokine that regulates energy balance through a wide range of functions, including several that are important to cardiovascular health. Increased circulating leptin, a marker of leptin resistance, is common in obesity and independently associated with insulin resistance and cardiovascular disease (CVD) in humans. The mechanisms of leptin resistance include genetic mutation, leptin self-regulation, limited tissue access, and cellular or circulating molecular regulation. Evidence suggests that central leptin resistance causes obesity and that obesity-induced leptin resistance injures numerous peripheral tissues, including liver, pancreas, platelets, vasculature, and myocardium. This metabolic- and inflammatory-mediated injury may result from either resistance to leptin's action in selective tissues, or excess leptin action from adiposity-associated hyperleptinemia. In this sense, the term "leptin resistance" encompasses a complex pathophysiological phenomenon. The leptin axis has functional interactions with elements of metabolism, such as insulin, and inflammation, including mediators of innate immunity, such as interleukin-6. Leptin is even purported to physically interact with C-reactive protein, resulting in leptin resistance, which is particularly intriguing, given C-reactive protein's well-studied relationship to cardiovascular disease. Given that plasma levels of leptin and inflammatory markers are correlated and also predict cardiovascular risk, it is conceivable that part of this risk may be mediated through leptin resistance-related insulin resistance, chronic inflammation, type II diabetes, hypertension, atherothrombosis, and myocardial injury. Leptin resistance and its interactions with metabolic and inflammatory factors, therefore, represent potential novel diagnostic and therapeutic targets in obesity-related cardiovascular disease.

Topics: Animals; Cardiovascular Diseases; Humans; Inflammation; Leptin; Obesity

To review the concept of a possible link between asthma and obstructive sleep apnea syndrome (OSAS) and the impact on asthma symptoms of treatment of OSAS with continuous positive airway pressure (CPAP) in patients with both conditions.. The Ovid, MEDLINE, and PubMed databases from 1950 to the present were searched for relevant articles regarding a possible relationship between asthma and OSAS and the effectiveness of CPAP in treating OSAS.. Articles describing pathophysiologic conditions occurring in OSAS that may be linked to asthma pathogenesis were used for this review.. The data suggest that OSAS is an independent risk factor for asthma exacerbations. CPAP has been shown in prospective clinical studies to have a positive impact on asthma outcome in patients with concomitant OSAS. Ameliorative mechanisms of treatment with CPAP include mechanical and neuromechanical effects, gastroesophageal acid reflux suppression, local and systemic anti-inflammatory effects (including suppression of increased serum levels of inflammatory cytokines, chemokines, and vascular endothelial growth factor), cardiac function improvements, leptin level suppression, weight reduction, and sleep restoration.. Asthma and OSAS are increasingly troublesome public health issues. Mounting evidence implicates OSAS as a risk factor for asthma exacerbations, thereby linking these 2 major epidemics. We describe potential mechanisms whereby CPAP, the first line of therapy for OSAS, might modify airway smooth muscle function and asthma control in patients with both disorders. Despite the ever-increasing population of patients with both disorders, large, prospective, randomized controlled studies are necessary to more fully evaluate CPAP and asthma outcomes.

Topics: Asthma; Continuous Positive Airway Pressure; Gastroesophageal Reflux; Heart; Humans; Inflammation; Leptin; Obesity; Respiratory Mechanics; Risk Factors; Sleep; Sleep Apnea, Obstructive

Despite the early recognition of the strong association between obstructive sleep apnoea (OSA) and obesity, and OSA and cardiovascular problems, sleep apnoea has been treated as a "local abnormality" of the respiratory track rather than as a "systemic illness". In 1997, we first reported that the pro-inflammatory cytokines interleukin-6 (IL-6) and tumour necrosis factor-alpha (TNFalpha) were elevated in patients with disorders of excessive daytime sleepiness (EDS) and proposed that these cytokines were mediators of daytime sleepiness. In subsequent studies, it was shown that IL-6, TNFalpha, and insulin levels were elevated in sleep apnoea independently of obesity and that visceral fat was the primary parameter linked with sleep apnoea. Further studies showed that women with the polycystic ovary syndrome (PCOS) were much more likely than controls to have sleep-disordered breathing (SDB) and daytime sleepiness, suggesting a pathogenetic role of insulin resistance in OSA. Additional accumulated evidence that supports the role of obesity and the associated metabolic aberrations in the pathogenesis of sleep apnoea and related symptoms include: obesity without sleep apnoea is associated with daytime sleepiness; the protective role of gonadal hormones as suggested by the increased prevalence of sleep apnoea in post-menopausal women and the significantly reduced risk for OSA in women on hormonal therapy; partial effects of continuous positive airway pressure (CPAP) in obese patients with apnoea on hypercytokinemia, insulin resistance indices, and visceral fat; and that the prevalence of the metabolic syndrome in the U.S. population from the Third National Health and Nutrition Examination Survey (1988-1994) parallels the prevalence of symptomatic sleep apnoea in general random samples. Furthermore, the beneficial effect of a cytokine antagonist on EDS and apnoea in obese, male apnoeics and that of exercise and weight loss on SDB and EDS in general random or clinical samples, supports the hypothesis that cytokines and insulin resistance are mediators of EDS and sleep apnoea in humans. Finally, our recent finding that in obese, hypothalamic CRH neuron is hypoactive, provides additional evidence on the potential central neural mechanisms for depressed ventilation and consequent development of sleep apnoea in obese individuals. In conclusion, accumulating evidence provides support to our thesis that obesity via inflammation, insulin resistance, visceral adiposity, and

Topics: Adiposity; Female; Humans; Inflammation; Insulin Resistance; Intra-Abdominal Fat; Leptin; Male; Metabolic Syndrome; Models, Biological; Obesity; Polycystic Ovary Syndrome; Sleep Apnea Syndromes

The sympathetic nervous system is activated in human obesity and in the analogous experimental obesity produced by overfeeding. The causes remain uncertain and may be multiple. The consequences include hypertension, probably attributable to activation of the sympathetic outflow to the kidneys, and, more disputed, insulin resistance. The pattern of sympathetic activation in normal-weight and obesity-related hypertension differs in terms of the firing characteristics of individual sympathetic fibers (increased rate of nerve firing in normal-weight hypertensives, increased number of active fibers firing at a normal rate in obesity-hypertension) and the sympathetic outflows involved. The underlying mechanisms and the adverse consequences of the two modes of sympathetic activation may differ. Should antihypertensive drug therapy in obesity-hypertension specifically target the existing neural pathophysiology? Such an approach can be advocated on theoretical grounds. Perhaps more important is the requirement that chosen antihypertensives do not cause weight gain or insulin resistance.

Topics: Adrenergic beta-3 Receptor Agonists; Humans; Hyperinsulinism; Hypertension; Leptin; Obesity; Risk Factors; Sleep Apnea, Obstructive; Sympathetic Nervous System; Weight Loss

Nonalcoholic fatty liver disease (NAFLD) spans a spectrum from simple steatosis to nonalcoholic steatohepatitis (NASH) to cirrhosis. Simple steatosis is the substrate upon which the more serious entities in the spectrum develop; it is the first "hit" in the multistep pathogenesis of NASH, which is considered the hepatic manifestation of the metabolic syndrome. Demonstration of the existence of regulatable fatty acid transport mechanisms has contributed to clarifying the role of fatty acid disposition in obesity, the various components of NAFLD, and the metabolic syndrome. Hepatic steatosis is closely linked to obesity. This linkage is based on the fact that obesity results in marked enlargement of the intraabdominal visceral fat depots. The eventual development of insulin resistance leads to continuous lipolysis within these depots, releasing fatty acids into the portal circulation, where they are rapidly translocated to the liver and reassembled into triglycerides. Reactive oxygen species, generated in the liver from oxidation of fatty acids, are precipitating factors in the cascade of events leading from simple steatosis to NASH. Dysregulation of fatty acid disposition, with ectopic lipid accumulation in other tissues, is a major contributing factor to other components of the metabolic syndrome. Bariatric surgery is an effective treatment for severe obesity, but its role in the management of the various forms of fatty liver disease is unclear. Our review of the literature that includes both initial and follow-up liver biopsies suggests that most obese patients with simple steatosis and NASH who undergo bariatric surgery will achieve improvement in hepatic histology, but that occasional patients, especially those who lose weight very rapidly, may show worsening of either fibrosis or steatohepatitis.

Topics: Abdominal Fat; Adipocytes; Animals; Bariatric Surgery; Comorbidity; Diabetes Mellitus, Type 2; Fatty Acids; Fatty Liver; Gastrointestinal Hormones; Humans; Insulin Resistance; Leptin; Lipolysis; Liver; Metabolic Syndrome; Obesity; Obesity, Morbid

Leptin, a product of the obesity gene, is a molecule that has received much attention since its cloning in 1994. Initially, most work centered around the effects of leptin on satiety and energy balance. However, in recent years there has been an intense focus on leptin as it relates to the cardiovascular system. Plasma leptin concentration is markedly elevated in obesity and the metabolic syndrome, both of which are associated with increased incidence of cardiovascular pathologies. In many studies, hyperleptinemia has been linked to endothelial dysfunction (a known precursor to atherosclerotic cardiovascular disease) and activation of the sympathetic nervous system. Additionally, recent evidence suggests that leptin released from perivascular adipose tissue may also have deleterious effects on the underlying vasculature, including the coronary circulation. This report reviews pertinent literature on leptin-mediated endothelial dysfunction, leptin-mediated sympathetic activation, and leptin as a significant perivascular adipose-derived factor.

Topics: Animals; Autonomic Nervous System; Cardiovascular Diseases; Cohort Studies; Disease Models, Animal; Endothelium, Vascular; Female; Humans; Leptin; Male; Mice; Obesity; Receptors, Leptin; Risk Assessment; Sensitivity and Specificity

The metabolic syndrome represents a major public health burden because of its high prevalence in the general population and its association with cardiovascular disease and type 2 diabetes. Accumulated evidence based on biochemical, neurophysiologic, and indirect measurements of autonomic activity indicate that visceral obesity and the metabolic syndrome are associated with enhanced sympathetic neural drive and vagal impairment. The mechanisms linking metabolic syndrome with sympathetic activation are complex and not completely understood, and cause-effect relationships need further clarification from prospective trials. Components of the metabolic syndrome that may directly or indirectly enhance sympathetic drive include hyperinsulinemia, leptin, nonesterified fatty acids, proinflammatory cytokines, angiotensinogen, baroreflex impairment, and obstructive sleep apnea. beta-Adrenoceptor polymorphisms have also been associated with adrenoceptor desensitization, increased adiposity, insulin resistance, and enhanced sympathetic activity. Because chronic sympathetic activation contributes to hypertension and its target-organ damage, sympathoinhibition remains an important goal in the therapeutic management of the metabolic syndrome.

Topics: Adipokines; Cytokines; Diabetes Mellitus, Type 2; Female; Follow-Up Studies; Humans; Hyperinsulinism; Insulin Resistance; Leptin; Male; Metabolic Syndrome; Obesity; Risk Assessment; Sensitivity and Specificity; Sleep Apnea, Obstructive; Sympathetic Nervous System

Cardiovascular disease caused less than 10% of deaths worldwide at the beginning of the 20th century but accounted for nearly 50% toward its end. Obesity has seen a similarly sharp increase in prevalence and is a major contributing factor to the rise in cardiovascular disease incidence. Mechanisms of obesity-induced heart disease are multifaceted and remain largely unknown, but cardiomyocyte programmed cell death, or apoptosis, seems to play a critical role in their development and progression. The heart maintains a delicate balance between cell proliferation and cell death throughout its lifetime. Even a slight increase in the rate of myocyte apoptosis, as seen in various animal models, has devastating consequences for the heart. This article critically reviews studies conducted in animal models of obesity that have expanded our understanding of the mechanisms of cardiomyocyte apoptosis and their role in various obesity-associated cardiovascular diseases.

Topics: Animals; Apoptosis; Cardiovascular Diseases; Disease Models, Animal; Insulin Resistance; Leptin; Male; Myocytes, Cardiac; Obesity; Rats; Rats, Sprague-Dawley; Rats, Zucker; Risk Factors; Sensitivity and Specificity; Signal Transduction; Survival Rate

The prevalence of obesity, an established epidemiologic risk factor for many cancers, has risen steadily for the past several decades in the US. The increasing rates of obesity among children are especially alarming and suggest continuing increases in the rates of obesity-related cancers for many years to come. Unfortunately, the mechanisms underlying the association between obesity and cancer are not well understood. In particular, the effects on the carcinogenesis process and mechanistic targets of interventions that modulate energy balance, such as reduced-calorie diets and physical activity, have not been well characterized. The purpose of this review is to provide a strong foundation for the translation of mechanism-based research in this area by describing key animal and human studies of energy balance modulations involving diet or physical activity and by focusing on the interrelated pathways affected by alterations in energy balance. Particular attention is placed on signaling through the insulin and insulin-like growth factor-1 receptors, including components of the Akt and mammalian target of rapamycin (mTOR) signaling pathways downstream of these growth factor receptors. These pathways have emerged as potential targets for disrupting the obesity-cancer link. The ultimate goal of this work is to provide the missing mechanistic information necessary to identify targets for the prevention and control of cancers related to or caused by excess body weight.

Topics: Adiponectin; Animals; Energy Metabolism; Humans; Insulin; Insulin-Like Growth Factor I; Leptin; Neoplasms; Obesity; Oxidative Stress

Due to the public health problem represented by obesity, the study of adipose tissue, particularly of the adipocyte, is central to the understanding of metabolic abnormalities associated with the development of obesity. The concept of adipocyte as endocrine and functional cell is not totally understood and can be currently defined as the capacity of the adipocyte to sense, manage, and send signals to maintain energy equilibrium in the body. Adipocyte functionality is lost during obesity and has been related to adipocyte hypertrophy, disequilibrium between lipogenesis and lipolysis, impaired transcriptional regulation of the key factors that control adipogenesis, and lack of sensitivity to external signals, as well as a failure in the signal transduction process. Thus, dysfunctional adipocytes contribute to abnormal utilization of fatty acids causing lipotoxicity in non-adipose tissue such as liver, pancreas and heart, among others. To understand the metabolism of the adipocyte it is necessary to have an overview of the developmental process of new adipocytes, regulation of adipogenesis, lipogenesis and lipolysis, endocrine function of adipocytes and metabolic consequences of its dysfunction. Finally, the key role of adipose tissue is shown by studies in transgenic animals or in animal models of diet-induced obesity that indicate the contribution of adipose tissue during the development of metabolic syndrome. Thus, understanding of the molecular process that occurs in the adipocyte will provide new tools for the treatment of metabolic abnormalities during obesity.

Topics: Adipocytes; Adipogenesis; Adiponectin; Adipose Tissue, White; Animals; Apelin; Diet; Humans; Intercellular Signaling Peptides and Proteins; Leptin; Lipogenesis; Lipolysis; Nicotinamide Phosphoribosyltransferase; Obesity; Resistin; Retinol-Binding Proteins, Plasma; Sterol Regulatory Element Binding Proteins

Recently more and more evidences have emerged about the oncogenic effect of type 2 diabetes and metabolic syndrome. Among these evidences epidemiological data are in first line. There is a causal relationship according to gender, ethnicity and geographic situation between different tumors and type 2 diabetes/metabolic syndrome as well. Supposed pathomechanisms are obesity, cytokines, secreted excessively in adipose tissue, permanent and postprandial hyperglycemia, hyperinsulinism and insulin resistance, other growth factors, like proinsulin, insulin like growth factor-1, reactive oxygen species, angiogenesis, inflammation, and the multiple effects of inflammatory cytokines. It proved to be evident that both peroxisome-proliferator-activated receptors and the regulatory ubiquitin proteasome system have significant role in insulin sensitivity and in co-ordinating cell proliferation and angiogenesis. These mechanisms in metabolic syndrome are risk factors towards atherosclerosis and cancer diseases as well. This newly emerged knowledge may open new pathways in treating and preventing the above-mentioned pathologic processes.

Topics: Adiponectin; Adipose Tissue; Animals; Cell Proliferation; Cytokines; Diabetes Mellitus, Type 2; Humans; Hyperglycemia; Hyperinsulinism; Inflammation; Insulin Resistance; Insulin-Like Growth Factor I; Leptin; Metabolic Syndrome; Neoplasms; Neovascularization, Pathologic; Obesity; Peroxisome Proliferator-Activated Receptors; Reactive Oxygen Species; Risk Factors; Ubiquitins; Vascular Endothelial Growth Factor A

Recent work shows a high prevalence of low testosterone and inappropriately low LH and FSH concentrations in type 2 diabetes. This syndrome of hypogonadotrophic hypogonadism (HH) is associated with obesity, and other features of the metabolic syndrome (obesity and overweight, hypertension and hyperlipidemia) in patients with type 2 diabetes. However, the duration of diabetes or HbA1c were not related to HH. Furthermore, recent data show that HH is also observed frequently in patients with the metabolic syndrome without diabetes but is not associated with type 1 diabetes. Thus, HH appears be related to the two major conditions associated with insulin resistance: type 2 diabetes and the metabolic syndrome. CRP concentrations have been shown to be elevated in patients with HH and are inversely related to plasma testosterone concentrations. This inverse relationship between plasma free testosterone and CRP concentrations in patients with type 2 diabetes suggests that inflammation may play an important role in the pathogenesis of this syndrome. This is of interest since inflammatory mechanisms may have a cardinal role in the pathogenesis of insulin resistance. It is relevant that in the mouse, deletion of the insulin receptor in neurons leads to HH in addition to a state of systemic insulin resistance. It has also been shown that insulin facilitates the secretion of gonadotrophin releasing hormone (GnRH) from neuronal cell cultures. Thus, HH may be the result of insulin resistance at the level of the GnRH secreting neuron. Low testosterone concentrations in type 2 diabetic men have also been related to a significantly lower hematocrit and thus to an increased frequency of mild anemia. Low testosterone concentrations are also related to an increase in total and regional adiposity, and to lower bone density. This review discusses these issues and attempts to make the syndrome relevant as a clinical entity. Clinical trials are required to determine whether testosterone replacement alleviates symptoms related to sexual dysfunction, and features of the metabolic syndrome, insulin resistance and inflammation.

Topics: Animals; Atherosclerosis; Bone Density; Cross-Sectional Studies; Diabetes Complications; Diabetes Mellitus, Type 2; Hematocrit; Humans; Hypogonadism; Inflammation Mediators; Insulin Resistance; Leptin; Male; Metabolic Syndrome; Models, Biological; Obesity; Prostatic Neoplasms; Sexual Dysfunction, Physiological; Testosterone

Over the past 30 years, a sharp rise in the prevalence of overweight and obesity has been noted in both children and adults. Health consequences include biomechanical, biochemical and psychosocial factors, with broad implications toward central adiposity and a number of conditions with which it relates. Substantial new information has surfaced within the last decade that alters previous concepts regarding the role of adipose tissue in health and in disease. This literature review explores the role that white adipose tissue (WAT) plays within a cascade of endocrine interfaces that have significant health consequences. WAT is now known to be an active participant in regulating physiological and pathological processes, including immunity and inflammation and to play a primary role in the development of a triad of hormonal imbalance (leptin resistance, adrenaline resistance, insulin resistance). Particular focus is placed on leptin hormone and its potential influences on inflammation and a host of other metabolic disturbances.

Topics: Adipose Tissue, White; Adult; Child; Diet Therapy; Female; Hormones; Humans; Inflammation; Insulin Resistance; Leptin; Male; Obesity; Waist Circumference

The prevalence of obesity has considerably increased during the past thirty years. Possible consequences of obesity on respiratory physiology include a restrictive disorder, changes in ventilatory mechanics and an alteration of respiratory drive. Apart from the well established relation between obesity and obstructive sleep apnea-hypopnea syndrome, obesity is associated with two other respiratory disorders. On one hand, epidemiological and animal data suggest a causal relationship between obesity and asthma. On the other hand, morbid obesity is associated, through an alteration of the respiratory drive involving leptin, with a diurnal and nocturnal alveolar hypoventilation defining the obesity-hypoventilation syndrome. These data emphasize the necessity for the medical practitioner to investigate any respiratory symptomatology in obese patients.

Topics: Animals; Asthma; Body Mass Index; Humans; Leptin; Obesity; Obesity Hypoventilation Syndrome; Prevalence; Respiratory Tract Diseases; Sleep Apnea, Obstructive; Switzerland

In the spirit of celebration associated with the 20th anniversary of the Pennington Biomedical Research Center, we have seized the opportunity of taking a highly personal and not at all comprehensive 'whistle-stop tour' of a large body of evidence that, we feel, supports the following conclusions: (1) that body fat stores are regulated by biological control processes in humans as they are in lower animals; (2) that there are major inherited influences on the efficiency whereby such control processes operate in humans; (3) that the precise nature of those genetic and biological influences and how they interact with environmental factors are beginning to be understood; (4) that most of the genes discovered thus far have their principal impact on hunger, satiety and food intake; (5) that while there is understandable resistance to the notion that genes can influence a human behavior such as the habitual ingestion of food, the implications of these discoveries are essentially benign. Indeed, we hope that they may eventually lead to improved treatment for patients and, in addition, help to inculcate a more enlightened attitude to the obese with a reduction in their experience of social and economic discrimination.

Topics: Adiposity; Body Mass Index; Energy Metabolism; Feeding Behavior; Genetic Predisposition to Disease; Humans; Hunger; Leptin; Obesity; Satiety Response

Although variation in individual lifestyle and genotype are important factors in explaining individual variation in the risk of developing obesity in an obesogenic environment, there is growing evidence that developmentally plastic processes also contribute. These effects are mediated at least in part through epigenetic processes. These developmental pathways do not directly cause obesity but rather alter the risk of an individual developing obesity later in life. At least two classes of developmental pathway are involved. The mismatch pathway involves the evolved adaptive responses of the developing organism to anticipated future adverse environments, which have maladaptive consequences if the environment is mismatched to that predicted. This pathway can be cued by prenatal undernutrition or stresses that lead the organism to forecast an adverse future environment and change its developmental trajectory accordingly. As a result, individuals develop with central and peripheral changes that increase their sensitivity to an obesogenic environment. It provides a model for how obesity emerges in populations in rapid transition, but also operates in developed countries. There is growing experimental evidence that this pathway can be manipulated by, for example, postnatal leptin exposure. Secondly, maternal diabetes, maternal obesity and infant overfeeding are associated with a greater risk of later obesity. Early life offers a potential point for preventative intervention.

Topics: Adiposity; Animals; Epigenesis, Genetic; Fetal Development; Genetic Predisposition to Disease; Humans; Leptin; Obesity; Rats; Risk Factors

Owing to the increased incidence of obesity and its association with heart failure, there is now great interest in elucidating the underlying molecular mechanisms linking these pathologies. Since the discovery of adipose-derived hormones and cytokines, their important regulatory role in myocardial function has emerged. The events that these adipokines can regulate include alterations in myocardial metabolism, cardiomyocyte hypertrophy, cell death, and structure and composition of the extracellular matrix. Here, we focus on the last of these and review current research demonstrating an important role for adipokines, with particular emphasis on leptin and adiponectin, in regulating matrix metalloproteinases, tissue inhibitors of matrix metalloproteinases, and collagens. From this, it is clear that adipokines are capable of contributing to remodeling of the myocardial extracellular matrix, and the altered adipokine profiles observed in obese individuals may be important in the pathogenesis of heart failure. The feasibility of adipokine manipulation as a potential therapeutic treatment in preventing maladaptive cardiac remodeling is also discussed.

Topics: Adipokines; Adiponectin; Collagen; Cytokines; Extracellular Matrix; Heart Failure; Humans; Leptin; Matrix Metalloproteinases; Myocardium; Myocytes, Cardiac; Obesity; Ventricular Remodeling

It has been long known that the frequency of overweight and obese people is higher among depressed and bipolar patients than in the general population. The marked alteration of body weight (and appetite) is one of the most frequent of the 9 symptoms of major depressive episode, and these symptoms occur during recurrent episodes of depression with a remarkably high consequence. According to studies with representative adult population samples, in case of obesity (BMI over 30) unipolar or bipolar depression is significantly more frequently (20-45%) observable. Since in case of depressed patients appetite and body weight reduction is observable during the acute phase, the more frequent obesity in case of depressed patients is related (primarily) not only to depressive episodes, but rather to lifestyle factors, to diabetes mellitus also more frequently occurring in depressed patients, to comorbid bulimia, and probably to genetic-biological factors (as well as to pharmacotherapy in case of medicated patients). At the same time, according to certain studies, circadian symptoms of depression give rise to such metabolic processes in the body which eventually lead to obesity and insulin resistance. According to studies in unipolar and bipolar patients, 57-68% of patients is overweight or obese, and the rate of metabolic syndrome was found to be between 25-49% in bipolar patients. The rate of metabolic syndrome is further increased by pharmacotherapy. Low total and HDL cholesterol level increases the risk for depression and suicide and recent studies suggest that omega-3-fatty acids possess antidepressive efficacy. Certain lifestyle factors relevant to healthy metabolism (calorie reduction in food intake, regular exercise) may be protective factors related to depression as well. The depression- and possibly suicide-provoking effect of sibutramine and rimonabant used in the pharmacotherapy of obesity is one of the greatest recent challenges for professionals and patients alike.

Topics: Anti-Obesity Agents; Antidepressive Agents; Appetite Depressants; Appetite Regulation; Bipolar Disorder; Circadian Rhythm; Cyclobutanes; Depression; Depressive Disorder, Major; Dietary Carbohydrates; Energy Intake; Ghrelin; Humans; Hypothalamo-Hypophyseal System; Insulin Resistance; Leptin; Obesity; Piperidines; Pituitary-Adrenal System; Pyrazoles; Rimonabant; Seasonal Affective Disorder; Sleep Wake Disorders; Surveys and Questionnaires; Weight Gain; Weight Loss

Body weight is tightly regulated by a feedback mechanism involving peripheral adiposity signals and multiple central nervous system neurotransmitter pathways. Despite the tight regulation of body weight there is an increase in the prevalence of obesity and overweight in Western society. Obesity and overweight are conditions of excess body weight stored as fat. Syndecan-3, a member of the syndecan family of type I transmembrane heparan sulfate proteoglycans is a novel a regulator of feeding behavior and body weight. Syndecans are extracellular matrix molecules (ECMs) that modulate cell adhesion, cell-cell interactions and ligand-receptor interactions. The finding that syndecan-3 can regulate body weight is novel and provides a unique link between the extracellular matrix and body weight regulatory mechanisms. Uniquely, hormones such as leptin previously thought only to regulate body weight by modulating neuropeptide levels, have now been demonstrated to regulate neuronal plasticity in the hypothalamus. ECMs and syndecans have long been recognized as regulators of plasticity. Therefore, this review will focus on highlighting the role of syndecans and in particular syndecan-3 in neuronal development and synaptic organization and how these processes may integrate body weight regulation. As part of this review, we will highlight how syndecan-3 can mediate the activity of adiposity signals, such as leptin, and facilitate changes in neuronal plasticity.

Topics: Animals; Body Weight; Brain; Feedback, Physiological; Gene Expression Regulation, Developmental; Humans; Leptin; Mice; Mice, Knockout; Neural Pathways; Neuronal Plasticity; Obesity; Polymorphism, Genetic; Rats; Synaptic Transmission; Syndecans

It was previously believed that obesity and osteoporosis were two unrelated diseases, but recent studies have shown that both diseases share several common genetic and environmental factors. Body fat mass, a component of body weight, is one of the most important indices of obesity, and a substantial body of evidence indicates that fat mass may have beneficial effects on bone. Contrasting studies, however, suggest that excessive fat mass may not protect against osteoporosis or osteoporotic fracture. Differences in experimental design, sample structure, and even the selection of covariates may account for some of these inconsistent or contradictory results. Despite the lack of a clear consensus regarding the impact of effects of fat on bone, a number of mechanistic explanations have been proposed to support the observed epidemiologic and physiologic associations between fat and bone. The common precursor stem cell that leads to the differentiation of both adipocytes and osteoblasts, as well the secretion of adipocyte-derived hormones that affect bone development, may partially explain these associations. Based on our current state of knowledge, it is unclear whether fat has beneficial effects on bone. We anticipate that this will be an active and fruitful focus of research in the coming years.

Topics: 11-beta-Hydroxysteroid Dehydrogenases; Adipocytes; Adiponectin; Adipose Tissue; Amyloid; Aromatase; Bone Density; Cell Differentiation; Female; Humans; Insulin; Insulin-Like Growth Factor II; Interleukin-6; Islet Amyloid Polypeptide; Leptin; Male; Obesity; Osteoblasts; Osteoporosis; Peptide Fragments; PPAR gamma; Resistin; Transforming Growth Factor beta; Wnt Proteins

Loss of body weight is associated with bone loss, and body weight gain is associated with increased bone formation. The molecular mechanisms linking body weight, body composition, and bone density are now better understood. Lean mass is likely to have a significant, local effect on bone modeling and remodeling through mechanotransduction pathways. In contrast to the local regulation of bone formation and resorption by muscle-derived stimuli, peripheral body fat appears to influence bone mass via secretion of systemic, endocrine factors that link body weight to bone density even in non-weight bearing regions (e.g., the forearm). The cytokine-like hormone leptin, which is secreted by fat cells, is an important candidate molecule linking changes in body composition with bone formation and bone resorption. Increases in body fat increase leptin levels and stimulate periosteal bone formation through its direct anabolic effects on osteoblasts, and through central (CNS) effects including the stimulation of the GH-IGF-1 axis and suppression of neuropeptide Y, a powerful inhibitor of bone formation. Stimulation of beta2-adrenergic receptors through central (hypothalamic) leptin receptors does, however, increase remodeling of trabecular bone, resulting in a lower cancellous bone volume that may be better adapted to a concomitantly larger cortical bone compartment. These findings suggest that body weight and body fat can regulate bone mass and structure through molecular pathways that are independent of load-bearing. Furthermore, pharmacological manipulation of the signaling pathways activated by leptin may have significant potential for the treatment and prevention of bone loss.

Topics: Adipogenesis; Animals; Body Weight; Bone Density; Bone Development; Humans; Leptin; Mice; Obesity; Polymorphism, Genetic; Receptors, Leptin; Receptors, Neuropeptide Y

The adipose tissue-derived hormone leptin acts via its receptor (LRb) in the brain to regulate energy balance and neuroendocrine function. LRb signaling via STAT3 and a number of other pathways is required for the totality of leptin action. The failure of elevated leptin levels to suppress feeding and mediate weight loss in common forms of obesity defines a state of so-called leptin resistance. A number of mechanisms, including the leptin-stimulated phosphorylation of Tyr(985) on LRb and the suppressor of cytokine signaling 3, attenuate leptin signaling and promote a cellular leptin resistance in obesity. Several unique features of the arcuate nucleus of the hypothalamus may contribute to the severity of cellular leptin resistance in this region. Other mechanisms that govern feeding behavior and food reward may also underlie the inception of obesity.

Topics: Animals; Feedback, Physiological; Humans; Hypothalamus; Leptin; Obesity; Signal Transduction

Appetite suppressants have been available as weight-reducing aids for over 50 years. The first discovered was amphetamine, which was potent, but possessed undesirable side effects (it is a stimulant and elevates blood pressure). Subsequently, a variety of appetite drugs was developed, all structurally related to amphetamine, but mostly lacking unwanted side effects. Until recently, fenfluramine (FEN) was the most widely used; presently, sibutramine is the most commonly used appetite suppressant. While these appetite suppressants are effective at reducing hunger and food intake when given as a single dose or for short periods of time, their effectiveness diminishes when administered chronically. The biological mechanisms underlying this tolerance have not been carefully studied, but many possibilities have been identified, including the down-regulation in brain of neurotransmitter receptors that might mediate the action of these drugs and adaptive responses of the appetite control circuitry in brain. To date, however, few studies have examined these possibilities in any detail. This article focuses on the question of why appetite suppressants lose efficacy, when given chronically, because this issue is important to the development of the next generation of appetite suppressants. Chronic efficacy should be an issue studied relatively early in the drug development process. This issue is of particular relevance, since obesity treatment is now recognized as a long-term, not a short-term, process. If appetite suppressants are to become a more important tool in obesity treatment, agents that do not lose efficacy when administered for extended periods of time must be identified.

Topics: Animals; Appetite Depressants; Body Weight; Cyclobutanes; Drug Tolerance; Eating; Fenfluramine; Humans; Leptin; Obesity; Rats; Time Factors; Weight Loss

Recent evidences suggest that a number of chronic diseases seems to be associated with early prenatal and postnatal nutrition, even though the mechanisms underlying the link between early nutrition, health and well-being later in life have not been well understood. Considering that overweight and obesity derive from a condition of altered energy balance, one of the major interests of nutritional researchers is to provide breakthroughs in the understanding of hormonal patterns involved in energy balance regulation. Epidemiological surveys indicate that breastfeeding is protective against obesity in later life, even if the precise magnitude of this association remains not well defined. A lot of studies have shown the detection of hormones in breast milk, which have a role in energy balance regulation. In this review, we present a synopsis of previous and recent studies focusing on hormones in breast milk. It appears that promoting breastfeeding is an important factor in this process.

Topics: Adiponectin; Ghrelin; Humans; Infant; Infant Formula; Infant Nutritional Physiological Phenomena; Infant, Newborn; Leptin; Milk, Human; Obesity

Body weight impacts both bone turnover and bone density, making it, therefore, an important risk factor for vertebral and hip fractures and ranking it alongside age in importance. The effect of body weight is probably contributed to by both fat mass and lean mass, though in postmenopausal women, fat mass has been more consistently demonstrated to be important. A number of mechanisms for the fat-bone relationship exist and include the effect of soft tissue mass on skeletal loading, the association of fat mass with the secretion of bone active hormones from the pancreatic beta cell (including insulin, amylin, and preptin), and the secretion of bone active hormones (e.g., estrogens and leptin) from the adipocyte. These factors alone probably do not fully explain the observed clinical associations, and study of the actions on bone of novel hormones related to nutrition is an important area of further research. An understanding of this aspect of bone biology may open the way for new treatments of osteoporosis. More immediately, the role of weight maintenance in the prevention of osteoporosis is an important public health message that needs to be more widely appreciated.

Topics: Body Mass Index; Bone and Bones; Bone Density; Calcium; Female; Fractures, Bone; Humans; Insulin; Leptin; Male; Obesity; Osteoporosis; Risk Factors

Human beings are susceptible to sustained weight gain in the modern environment. Although both men and women can get fat, they get fat in different ways, and suffer different consequences. We review differences between men and women in the incidence of obesity, fat deposition patterns, fat metabolism, and the health consequences of obesity, and examine potential evolutionary explanations for these differences. Women generally have a larger proportion of body mass as fat, and are more likely to deposit fat subcutaneously and on their lower extremities; men are more likely to deposit fat in the abdominal region. Excess adipose tissue in the abdominal region, especially visceral fat, is associated with more health risks. Women have higher rates of reuptake of NEFA into adipose tissue; however, they also have higher rates of fat oxidation during prolonged exercise. Oestrogen appears to underlie many of these differences. Women bear higher nutrient costs during reproduction. Fat and fertility are linked in women, through leptin. Low leptin levels reduce fertility. Ovarian function of adult women is associated with their fatness at birth. In our evolutionary past food insecurity was a frequent occurrence. Women would have benefited from an increased ability to store fat in easily metabolisable depots. We suggest that the pattern of central obesity, more commonly seen in men, is not adaptive, but rather reflects the genetic drift hypothesis of human susceptibility to obesity. Female obesity, with excess adiposity in the lower extremities, reflects an exaggeration of an adaptation for female reproductive success.

Topics: Adipose Tissue; Adiposity; Biological Evolution; Female; Genetic Drift; Gonadal Steroid Hormones; Humans; Insulin; Leptin; Lipid Metabolism; Male; Obesity; Sex Characteristics

This review critically reappraises recent scientific evidence concerning central leptin insufficiency versus leptin resistance formulations to explain metabolic and neural disorders resulting from subnormal or defective leptin signaling in various sites in the brain. Research at various fronts to unravel the complexities of the neurobiology of leptin is surveyed to provide a comprehensive account of the neural and metabolic effects of environmentally imposed fluctuations in leptin availability at brain sites and the outcome of newer technology to restore leptin signaling in a site-specific manner. The cumulative new knowledge favors a unified central leptin insufficiency syndrome over the, in vogue, central resistance hypothesis to explain the global adverse impact of deficient leptin signaling in the brain. Furthermore, the leptin insufficiency syndrome delineates a novel role of leptin in the hypothalamus in restraining rhythmic pancreatic insulin secretion while concomitantly enhancing glucose metabolism and non-shivering thermogenic energy expenditure, sequelae that would otherwise promote fat accrual to store excess energy resulting from consumption of energy-enriched diets. A concerted effort should now focus on development of newer technologies for delivery of leptin or leptin mimetics to specifically target neural pathways for remediation of diverse ailments encompassing the central leptin insufficiency syndrome.

Topics: Animals; Humans; Leptin; Metabolic Diseases; Nervous System Diseases; Obesity; Syndrome

Appetite is regulated by a complex system of central and peripheral signals which interact in order to modulate the individual response to nutrient ingestion. Peripheral regulation includes satiety signals and adiposity signals, while central control is accomplished by several effectors, including the neuropeptidergic, monoaminergic and endocannabinoid systems. Satiety signals, including cholecystokinin (CCK), glucagon-like peptide-1 (GLP-1) and peptide YY (PYY), originate from the gastrointestinal (GI) tract during a meal and, through the vagus nerve, reach the nucleus tractus solitarius (NTS) in the caudal brainstem. From NTS afferents fibers project to the arcuate nucleus (ARC), where satiety signals are integrated with adiposity signals, namely leptin and insulin, and with several hypothalamic and supra-hypothalamic inputs, thus creating a complex network of neural circuits which finally elaborate the individual response to a meal. As for the neuropeptidergic system, ARC neurons secrete orexigenic substances, such as neuropeptide Y (NPY) and agouti-related peptide (AGRP), and anorexigenic peptides such as pro-opiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART). Other brain areas involved in the control of food intake are located downstream the ARC: among these, the paraventricular nucleus (PVN), which produces anorexigenic peptides such as thyrotropin releasing hormone (TRH), corticotrophin releasing hormone (CRH) and oxytocin, the lateral hypothalamus (LHA) and perifornical area (PFA), secreting the orexigenic substances orexin-A (OXA) and melanin concentrating hormone (MCH). A great interest in endocannabinoids, important players in the regulation of food intake, has recently developed. In conclusion, the present work reviews the most recent insights into the complex and redundant molecular mechanisms regulating food intake, focusing on the most encouraging perspectives for the treatment of obesity.

Topics: Adiposity; Animals; Anti-Obesity Agents; Appetite Regulation; Arcuate Nucleus of Hypothalamus; Biogenic Monoamines; Cannabinoid Receptor Modulators; Cholecystokinin; Feeding Behavior; Ghrelin; Glucagon-Like Peptide 1; Humans; Insulin; Leptin; Neuropeptides; Neurosecretory Systems; Obesity; Peptide YY; Pituitary Hormone-Releasing Hormones; Satiety Response; Signal Transduction

White adipose tissue was believed to be just an energy-storage organ, but it is now recognized to be an active participant in energy homoeostasis and physiological functions such as immunity and inflammation. Macrophages are components of adipose tissue and actively participate in its activities. Adipose tissue is known to express and secrete a variety of products known as 'adipokines', including leptin, adiponectin, resistin and visfatin, as well as cytokines and chemokines such as tumor necrosis factor-alpha, interleukin-6 and monocyte chemoattractant protein-1. The release of adipokines by either adipocytes or adipose tissue-infiltrated macrophages leads to a chronic subinflammatory state that could play a central role in the development of insulin resistance and type 2 diabetes, and the increased risk of cardiovascular disease associated with obesity.

Topics: Adipokines; Adiponectin; Endoplasmic Reticulum; Humans; Inflammation; Insulin Resistance; Interleukin-6; Leptin; Nicotinamide Phosphoribosyltransferase; Obesity; Plasminogen Activator Inhibitor 1; Resistin; Serum Amyloid A Protein; Tumor Necrosis Factor-alpha

It is becoming increasingly apparent that conditions experienced in early life play an important role in the long-term health of individuals. Alterations in development due to impaired, excessive or imbalanced growth, both in utero and during critical periods of relative plasticity beyond birth, can lead to the permanent programming of physiological systems. The regulation of energy balance is one area that is receiving particular attention, as rates of obesity and associated metabolic and cardiovascular disease continue to rise. Over recent decades, much progress has been made toward understanding the way in which metabolic tissues and physiological systems develop, and the impact of early life events and nutrition on these processes. It is apparent within human populations that some individuals are better able to maintain an appropriate body weight in the face of an obesogenic environment. Animal models have been widely used for the investigation of differential susceptibility to diet-induced obesity (DIO) and impaired energy balance regulation, and are shedding light on key pathways that may be involved. Alterations in pathways mediating energy homeostasis, outlined below, are likely candidates for programming effects following disturbed growth in early life.

Topics: Adipose Tissue; Animals; Diet; Disease Models, Animal; Energy Metabolism; Female; Glucocorticoids; Growth; Homeostasis; Humans; Leptin; Metabolic Diseases; Obesity; Overnutrition; Phenotype; Pregnancy

Many adverse effects of atypical antipsychotic treatment are associated with antagonism of monoamine receptors; however, data indicate that important metabolic effects, such as hypertriglyceridemia and impairment in glucose/insulin homeostasis, may not be related to these mechanisms, leading investigators to explore alternative hypotheses. Promising candidates include a possible impact of antipsychotics on peptide hormonal regulators of metabolic control such as leptin, ghrelin, and adiponectin. The purpose of this review is to summarize recent data on changes in these hormones during atypical antipsychotic treatment.. A Medline search was performed for papers published from January 1999 to January 2007 using key words antipsychotic, atypical antipsychotic, and individual atypical antipsychotic drug names cross-referenced with leptin, ghrelin, and adiponectin.. The bulk of the published work focused on changes in body weight and serum leptin, with far less data on ghrelin, and adiponectin, and nonweight metabolic changes. Leptin changes were directly related to a medication's weight gain liability, with no added antipsychotic effects on leptin signaling. Conflicting results emerged for the other markers, but all three long-term studies on ghrelin showed increased levels in patients on atypical antipsychotics with weight gain liabilities.. Leptin increases during antipsychotic treatment are a result of weight gain rather than a direct impact of atypical antipsychotics on leptin physiology. Preliminary long-term data show increased ghrelin levels, but this finding must be replicated. The association with antipsychotic effects on glucose and lipid metabolism and these hormones remains virtually unstudied. Future research should indicate whether ghrelin and other peptide hormones may be useful predictors of weight gain or metabolic changes in patients on antipsychotics.

Topics: Adiponectin; Adult; Animals; Antipsychotic Agents; Body Mass Index; Body Weight; Cross-Sectional Studies; Female; Ghrelin; Humans; In Vitro Techniques; Leptin; Male; Metabolic Syndrome; Obesity; Pharmacogenetics; Prospective Studies; Rats; Schizophrenia

Obesity and type 2 diabetes are the most prevalent metabolic diseases in the western world. Alarmingly, the cluster of pathologies characteristic of obesity-induced disease have started to emerge in children, a phenomenon that up until a decade ago was inconceivable. Hence, the development of new strategies to treat 'metabolic disease' is most warranted. Growing evidence suggests that during type 2 diabetes, a state of chronic low-grade inflammation exists in metabolically active tissues such as the liver, adipose tissue and skeletal muscle. This inflammation is often secondary to lipid accumulation in insulin-responsive tissues. Recent studies have focused on the therapeutic potential of ciliary neurotrophic factor (CNTF). CNTF is a pluripotent neurocytokine and, has shown promise as a potential anti-obesogenic therapy. CNTF acts both centrally and peripherally, mimics the biological actions of leptin while overcoming "leptin resistance", remains effective even after termination of therapy if administered centrally, and appears to reduce inflammatory signaling cascades associated with lipid accumulation in liver and skeletal muscle. The advantages and disadvantages of CNTF as a therapeutic strategy to alleviate obesity-associated diseases will be highlighted in this review.

Topics: Brain; Ciliary Neurotrophic Factor; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Humans; Leptin; Obesity; Receptor, Ciliary Neurotrophic Factor; Signal Transduction; Weight Loss

Decreases in both mass and secretory function of insulin-producing beta-cells contribute to the pathophysiology of type 2 diabetes. The histology of islets from patients with type 2 diabetes displays an inflammatory process characterized by the presence of cytokines, apoptotic cells, immune cell infiltration, amyloid deposits, and eventually fibrosis. This inflammatory process is probably the combined consequence of dyslipidemia, hyperglycemia, and increased circulating adipokines. Therefore, modulation of intra-islet inflammatory mediators, in particular interleukin-1 beta, appears as a promising therapeutic approach.

Topics: Cytokines; Diabetes Mellitus, Type 2; Dyslipidemias; Glucose; Humans; Hypoglycemic Agents; Inflammation; Insulin-Secreting Cells; Interleukin-1beta; Islets of Langerhans; Leptin; Obesity; Pancreatic Diseases

We and others have identified several single gene defects that disrupt the molecules in the leptinmelanocortin pathway causing severe obesity in humans. In this review, we consider these human monogenic obesity syndromes and discuss how far the characterisation of these patients has informed our understanding of the physiological role of leptin and the melanocortins in the regulation of human body weight and neuroendocrine function.

Topics: Body Weight; Child; Child, Preschool; Humans; Leptin; Mutation; Obesity; Phenotype; Pro-Opiomelanocortin; Proprotein Convertase 1; Receptor, Melanocortin, Type 4; Receptor, trkB; Receptors, Leptin; Recombinant Proteins

Most laboratory-based research on obesity is carried out in rodents, but there are a number of other interesting models in the animal kingdom that are instructive. This includes domesticated animal species such as pigs and sheep, as well as wild, migrating and hibernating species. Larger animals allow particular experimental manipulations that are not possible in smaller animals and especially useful models have been developed to address issues such as manipulation of fetal development. Although some of the most well-studied models are ruminants, with metabolic control that differs from monogastrics, the general principles of metabolic regulation still pertain. It is possible to obtain much more accurate endocrine profiles in larger animals and this has provided important data in relation to leptin and ghrelin physiology. Genetic models have been created in domesticated animals through selection and these complement those of the laboratory rodent. This short review highlights particular areas of research in domesticated and wild species that expand our knowledge of systems that are important for our understanding of obesity and metabolism.

Topics: Animal Migration; Animals; Birds; Cattle; Disease Models, Animal; Epigenesis, Genetic; Female; Ghrelin; Insulin Resistance; Leptin; Neuropeptide Y; Obesity; Pregnancy; Pregnancy, Animal; Seasons; Sheep; Sus scrofa

Adipose tissue is the source of soluble mediators (adipokines), secreted mainly by adipocytes. Leptin acts on the brain and peripheral organs to regulate energy homeostasis and the neuroendocrine axis. Adiponectin regulates glucose and lipid metabolism by targeting the liver and skeletal muscle. Adiposederived proinflammatory cytokines, vasoactive peptides, coagulation and complement factors, visfatin, vaspin and retinol-binding protein signal through paracrine and hormonal mechanisms. Understanding the biology of adipose tissue and the rapidly growing list of adipokines provides new insights into normal physiological regulation, as well as the pathogenesis and treatment of obesity, diabetes and disorders of lipid metabolism and cardiovascular system.

Topics: Adipokines; Adiponectin; Animals; Energy Metabolism; Female; Glucose; Humans; Leptin; Lipid Metabolism; Male; Nicotinamide Phosphoribosyltransferase; Obesity; Resistin; Retinol-Binding Proteins, Plasma

Obesity is associated with several endocrine diseases, including common ones such as hypothyroidism and polycystic ovarian syndrome to rare ones such as Cushing's syndrome, central hypothyroidism and hypothalamic disorders. The mechanisms for the development of obesity vary in according to the endocrine condition. Hypothyroidism is associated with accumulation of hyaluronic acid within various tissues, additional fluid retention due to reduced cardiac output and reduced thermogenesis. The pathophysiology of obesity associated with polycystic ovarian syndrome remains complex as obesity itself may simultaneously be the cause and the effect of the syndrome. Net excess of androgen appears to be pivotal in the development of central obesity. In Cushing's syndrome, an interaction with thyroid and growth hormones plays an important role in addition to an increased adipocyte differentiation and adipogenesis. This review also describes remaining rare cases: hypothalamic obesity due to central hypothyroidism and combined hormone deficiencies.

Topics: Catecholamines; Cushing Syndrome; Endocrine System Diseases; Female; Glucocorticoids; Humans; Hypothalamic Diseases; Hypothyroidism; Leptin; Male; Obesity; Polycystic Ovary Syndrome; Thyroid Function Tests; Triiodothyronine

The relentless rise in the prevalence of obesity predicts an exponential increase in the incidence of obesity-related complications. Medical and surgical treatments are necessary to prevent and treat obese co-morbidities, thereby avoiding disability and premature death. Interventions for obesity should be evaluated not by weight loss alone but against the new incidence in obesity-related co-morbidities, their remission or improvement. In combination with lifestyle measures, currently available pharmacological therapies -- rimonabant, orlistat and sibutramine -- achieve 5-10% weight loss, although a return to baseline is the norm after cessation of medication. All these agents demonstrate approximately 0.5% reduction in HbA1c in diabetic subjects; orlistat also reduces the new incidence of type 2 diabetes. Modest improvement in lipid profiles and reduced calculated cardiovascular risk is observed, but data on improvement of other co-morbidities are sparse. In contrast, surgical procedures that restrict food ingestion and/or curtail the absorptive surface area of the gut consistently achieve substantial weight loss, typically 20-35%, effect resolution of co-morbid conditions and improve quality of life. Although mortality is low, complications and hospitalisation are not uncommon after bariatric surgery. Intriguingly, surgical patients experience a reduction in appetite and report changes in food preference. Accentuation of the normal gastrointestinal hormonal response to food intake and possible changes in vagal afferent signalling are proposed to induce satiety. Increased understanding of body weight homeostasis and appetite regulation has provided an impressive list of potential targets for drug development, with the promise that single or combination therapy may ultimately challenge the supremacy of bariatric surgery.

Topics: Adipose Tissue; Amyloid; Anticonvulsants; Antidepressive Agents; Anxiety; Appetite Regulation; Bariatric Surgery; Body Mass Index; Bupropion; Cholecystokinin; Ciliary Neurotrophic Factor; Clinical Trials as Topic; Cyclobutanes; Depression; Diabetes Mellitus, Type 2; Female; Fluoxetine; Fructose; Ghrelin; Humans; Intra-Abdominal Fat; Islet Amyloid Polypeptide; Isoxazoles; Lactones; Leptin; Metabolic Syndrome; Metformin; Obesity; Obesity, Morbid; Orlistat; Oxyntomodulin; Peptide YY; Piperidines; Polycystic Ovary Syndrome; Pyrazoles; Rimonabant; Sertraline; Sleep Apnea, Obstructive; Surgical Procedures, Operative; Topiramate; Zonisamide

Catch-up growth early in life (after fetal, neonatal or infantile growth retardation) is a major risk factor for later obesity, type-2 diabetes and cardiovascular diseases. These risks are generally interpreted alongside teleological arguments that environmental exposures which hinder growth early in life lead to programming of 'thrifty mechanisms' that are adaptive during the period of limited nutrient supply (or growth constraint), but which increase risks for diseases during improved nutrition and catch-up growth later in life. This paper addresses this notion of 'thrifty mechanisms' in the light of evidence that catch-up growth is characterized by a disproportionately higher rate of fat gain relative to lean tissue gain, and that such preferential catch-up fat is in part driven by energy conservation mechanisms operating via suppressed thermogenesis. It provides a molecular-physiological framework which integrates emerging insights into mechanisms by which this thrifty 'catch-up fat' phenotype cross-links with insulin and leptin resistance.

Topics: Adipose Tissue; Animals; Body Fat Distribution; Glucose; Humans; Infant; Infant, Low Birth Weight; Infant, Newborn; Infant, Small for Gestational Age; Insulin Resistance; Leptin; Metabolic Diseases; Muscle, Skeletal; Obesity; Signal Transduction; Thermogenesis

Obesity results from an abnormal accumulation of fat in the white adipose tissue. Recent research utilizing genetic models of obesity in rodents has implicated a major role of leptin as a controller of obesity. Leptin is a 167-amino acid peptide hormone encoded by the obesity gene (ob), which is secreted by adipocytes and plays an important role in regulating food intake, energy expenditure and adiposity. Leptin receptors (OB-R) are expressed in the central nervous system mainly in afferent satiety centres of hypothalamus and in peripheral organs such as adipose tissues, skeletal muscles, pancreatic beta-cells and liver, thus indicating the autocrine and paracrine role of leptin in energy regulation. In human beings, a highly organized circadian pattern of leptin secretion is observed with peak levels in the midnight probably resulting from cumulative hyperinsulinemia of entire day. Leptin has a dual role in weight maintenance. Leptin reflects total body adipose tissue mass whereas in conditions of negative and positive energy balance, the dynamic changes in plasma leptin concentration function as a sensor of energy balance and influence the efferent energy regulation pathways. Many effects of leptin on metabolism are mediated by interaction with Insulin and also by synergistic action with cholecystokinin. Besides physiological roles, leptin may influence pathological conditions like obesity-associated atherosclerosis, oxidative stress and cancers. The purpose of the present review is to summarize the important aspects of the biology, actions, and regulation of leptin and to serve as an update of new information.

Topics: Adipose Tissue, White; Animals; Circadian Rhythm; Energy Metabolism; Humans; Hypothalamus; Insulin; Leptin; Obesity; Receptors, Leptin; Signal Transduction

Obesity, characterized by enhanced food intake (hyperphagia) and reduced energy expenditure that results in the accumulation of body fat, is a major risk factor for various diseases, including diabetes, cardiovascular disease, and cancer. In the United States, more than half of adults are overweight, and this number continues to increase. The adipocyte-secreted hormone leptin and its downstream signaling mediators play crucial roles in the regulation of energy balance. Leptin decreases feeding while increasing energy expenditure and permitting energy-intensive neuroendocrine processes, such as reproduction. Thus, leptin also modulates the neuroendocrine reproductive axis. The gonadal steroid hormone estrogen plays a central role in the regulation of reproduction and also contributes to the regulation of energy balance. Estrogen deficiency promotes feeding and weight gain, and estrogen facilitates, and to some extent mimics, some actions of leptin. In this review, we examine the functions of estrogen and leptin in the brain, with a focus on mechanisms by which leptin and estrogen cooperate in the regulation of energy homeostasis.

Topics: Animals; Energy Metabolism; Estrogens; Humans; Hypothalamus; Infertility; Leptin; Melanocortins; Obesity; Receptor Cross-Talk; Receptors, Estrogen; Signal Transduction; STAT3 Transcription Factor

The pathogenesis of idiopathic intracranial hypertension (IIH) is poorly understood. Several mechanisms have been suggested, but no one mechanism has been able to account for all manifestations of the disease. Although IIH predominantly affects obese, premenopausal women, little is known about whether or how the obesity contributes to the IIH. Obesity is a heterogeneous condition, consisting of different phenotypes that are influenced by the regional distribution of adipose tissue. This review explores the literature to integrate current knowledge on the relationships between obesity and IIH. The review evaluates the hypotheses that dysregulation of insulin, glucose metabolism, sex hormones, adipokines, glucocorticoids, lipids and free fatty acids in obesity could predispose to IIH. One potential common pathway linking metabolic disorders to the pathogenesis of IHH is a thrombotic tendency due to dysregulation of haemostatic risk factors. This could cause either occult cerebral sinus thrombosis or partial thrombosis of the parasagittal venous lacunae, with subsequent impaired resorption of cerebrospinal fluid and venous hypertension. Investigations that evaluate obesity, fat metabolism, endocrinological dysregulation and thrombotic tendency in patients with IIH are required so that pathogenic mechanisms can be clarified and management strategies in IIH can be improved.

Topics: Adipose Tissue; Blood Glucose; Cerebrospinal Fluid Pressure; Female; Humans; Leptin; Male; Obesity; Phenotype; Pseudotumor Cerebri; Risk Factors; Sex Factors

Bones of the skeleton are constantly remodeled through bone resorption by cells called osteoclasts and bone formation by cells called osteoblasts. Both cell types are under multi-hormone control. New research findings demonstrate that bone formation by osteoblasts is negatively regulated by the hormone leptin, which is secreted by adipocytes and acts through the leptin receptor in the central nervous system and ultimately through the sympathetic nervous system. Leptin deficiency leads to increased osteoblast activity and increased bone mass. Reciprocally, expression of the Esp gene, exclusive to osteoblasts, regulates glucose homeostasis and adiposity through controlling the osteoblastic secretion of the hormone-like substance osteocalcin. An undercarboxylated form of osteocalcin acts as a regulator of insulin in the pancreas and adiponectin in the adipocyte to modulate energy metabolism. Osteocalcin deficiency in knockout mice leads to decreased insulin and adiponectin secretion, insulin resistance, higher serum glucose levels and increased adiposity.

Topics: Bone and Bones; Bone Development; Bone Resorption; Energy Metabolism; Humans; Leptin; Obesity; Osteoblasts; Osteocalcin; Osteoclasts; Osteogenesis

Studies described in the recent literature support the idea that gene therapy can lead to genuine clinical benefits when mediated by plasmid delivery in conjunction with electroporation. Plasmid-mediated muscle-targeted gene transfer offers the potential of a cost-effective pharmaceutical-grade therapy delivered by simple intramuscular injection. This approach is particularly appropriate for modulating muscle and fat mass and their intrinsic properties, from treatment of conditions such as cachexia associated with chronic diseases, autoimmune diseases, e.g., myasthenia gravis, to stimulation or suppression of appetite, and further to in vivo manipulation of glucose metabolism and fat deposition in patients with diabetes, or to basic studies of muscle-specific transcription factors and their impact in development. Recent innovations, including in situ electroporation, enabling sustained systemic protein delivery within the therapeutic range, are reviewed. Translation of these advances to human clinical trials will enable muscle- and fat-targeted gene therapy to become a viable therapeutic alternative.

Topics: Adipose Tissue; Animals; Animals, Domestic; Appetite; Body Composition; Cachexia; Electrochemotherapy; Genetic Therapy; Humans; Leptin; Muscles; Myasthenia Gravis; Obesity; Plasmids; Transcription Factors

Adiponectin, a protein hormone produced by adipocytes, is also found in breast milk, which in turn is implicated in childhood obesity prevention. Although a biological role for adiponectin has not been firmly established, clinical and experimental research indicates that it regulates lipid and glucose metabolism, affects foetal development, and exerts anti-inflammatory and antiatherogenic effects.. This review demonstrates an emerging interest of paediatric research on adiponectin. A better understanding of adiponectin's bioactivity might clarify whether breast milk indeed prevents childhood obesity.

Topics: Adipocytes; Adiponectin; Breast Feeding; Child; Child Welfare; Child, Preschool; Humans; Infant; Infant, Newborn; Leptin; Milk, Human; Obesity; Pediatrics

With the growing prevalence of obesity, scientific interest in the biology of adipose tissue has been extended to the secretory products of adipocytes, since they have been shown increasingly to affect several aspects of the pathogenesis of obesity-related diseases. Until relatively recently, the role of adipose tissue itself in the development of obesity and its consequences was considered to be a passive one. It is now clear that, in addition to storing energy in the form of triglycerides, adipocytes also secrete a large variety of proteins, including cytokines, chemokines and hormone-like factors. This production of proatherogenic chemokines by adipose tissue is of particular interest, since their local secretion, for example by perivascular adipose depots, may provide a novel mechanistic link between obesity and associated vascular complications.

Topics: Acute-Phase Proteins; Adipocytes; Adipokines; Adiponectin; Adipose Tissue; Cardiovascular Diseases; Humans; Inflammation; Inflammation Mediators; Leptin; Obesity; Resistin

The various hormones, proteins and other compounds related to developing obesity, insulin resistance and type 2 diabetes are analyzed in the paper. 1) Leptin, ciliary neurutrophic factor, adiponectin, glucagon-like peptide 1, peptide YY, neuromedin S, as well as the protein receptors of these hormones decrease the food consumption, increase the energy turnover, and prevent obesity, insulin resistance, and type 2 diabetes development. The mediators of these hormone and receptor actions are melanocyte stimulating hormone (MSH), corticotropin-releasing hormone (CRH), and the others. 2) Ghrelin, endogenose cannabinoides, galanin-like peptide and the mediators of their actions: neuropeptide Y (NPY) and Agouti gene related protein (AGRP) increase the appetite and food consumption. Peroxisome proliferation-activated receptor (PPAR) performs the similar action on food intake. The activation of the first group compound functioning decreases the obesity, increases the energy turnover, facilitates the insulin action and prevents the insulin resistance and type 2 diabetes. Increasing the activities of the second group, as well as, decreasing the actions of the first one of substances induce the opposite effects and facilitate obesity, insulin resistance, and type 2 diabetes developments. The interconnections of the molecular mechanisms of so many hormone actions make the very complicated tusk to study the various endocrine disorders including diabetes mellitus as well.

Topics: Adiponectin; Ciliary Neurotrophic Factor Receptor alpha Subunit; Diabetes Mellitus; Hormones; Humans; Hypothalamus; Insulin Resistance; Leptin; Obesity; Transcription Factors

An activation of the endocannabinoid system (ECS) in obesity with increased concentrations of endocannabinoids in several tissues and in the circulation is described in this review. This increased availability of endocannabinoids might stimulate cannabinoid receptors in a pathophysiological manner. The successful use of the cannabinoid receptor CB(1) inverse agonists rimonabant and taranabant for weight loss and the treatment of obesity-associated metabolic disorders might well be through blocking this overstimulation of cannabinoid receptors. At present, no single mechanism has been identified that explains the increased bioavailability of endocannabinoids in obesity. Both increased synthesis and decreased degradation appear to operate in a species- and tissue-dependent manner, but many pieces of the puzzle still need to be collected. For example, most data show decreased fatty acid amide hydrolase (FAAH) expression and/or activity as a result of obesity or high-fat intake, but the endocannabinoid predominantly increased in tissues is 2-arachidonoylglycerol (2-AG), which is not degraded by FAAH in vivo. Furthermore, the influence of dietary fatty acids on the synthesis of endocannabinoids needs to be studied in much more detail. Although weight loss does not seem to influence activation of the endocannabinoid system (ECS) in human obesity, suggesting an underlying mechanisms independent of body weight, no such mechanism at the genetic level has yet been identified either. Thus, activation of the ECS is a hallmark of abdominal obesity, and explains the success of pharmacological CB(1) blockade, but serious attempts have to be made to clarify the underlying mechanisms of this activation.

Topics: Adipose Tissue; Animals; Brain; Cannabinoid Receptor Modulators; Diet; Dietary Fats, Unsaturated; Disease Models, Animal; Endocannabinoids; Humans; Leptin; Liver; Obesity; Pancreas; Receptors, Cannabinoid; Weight Loss

The M(3) muscarinic acetylcholine (ACh) receptor (M(3) mAChR) is expressed in many central and peripheral tissues. It is a prototypic member of the superfamily of G protein-coupled receptors and preferentially activates G proteins of the G(q) family. Recent studies involving the use of newly generated mAChR mutant mice have revealed that the M(3) mAChR plays a key role in regulating many important metabolic functions. Phenotypic analyses of mutant mice that either selectively lacked or overexpressed M(3) receptors in pancreatic beta -cells indicated that beta -cell M(3) mAChRs are essential for maintaining proper insulin release and glucose homeostasis. The experimental data also suggested that strategies aimed at enhancing signaling through beta -cell M(3) mAChRs might be beneficial for the treatment of type 2 diabetes. Recent studies with whole body M(3) mAChR knockout mice showed that the absence of M(3) receptors protected mice against various forms of experimentally or genetically induced obesity and obesity-associated metabolic deficits. Under all experimental conditions tested, M(3) receptor-deficient mice showed greatly ameliorated impairments in glucose homeostasis and insulin sensitivity, reduced food intake, and a significant elevation in basal and total energy expenditure, most likely due to increased central sympathetic outflow and increased rate of fatty acid oxidation. These findings are of potential interest for the development of novel therapeutic approaches for the treatment of obesity and associated metabolic disorders.

Topics: Animals; Gastrointestinal Tract; Gene Expression; Insulin; Insulin Secretion; Insulin-Secreting Cells; Leptin; Mice; Mice, Knockout; Mice, Mutant Strains; Mice, Transgenic; Obesity; Phenotype; Receptor, Muscarinic M3; Sympathetic Nervous System

Obesity is a growing worldwide problem and is associated with a wide range of adverse effects on the female reproductive system. The endocrinological changes in obesity that may cause these adverse effects are complex and include changes in circulating adipokines and sex steroids as well as insulin resistance. Considerable evidence suggests an adverse effect of obesity on the risk of miscarriage and other maternal and fetal complications. Obese patients are also more prone to infertility. The most important single method to improve reproductive performance in obese women is weight loss that can be achieved with lifestyle changes and diet. Antiobesity drugs may also be used and, in severe cases, bariatric surgery.

Topics: Abortion, Spontaneous; Adiponectin; Anti-Obesity Agents; Bariatric Surgery; Endocrinology; Female; Fertilization in Vitro; Ghrelin; Humans; Infertility, Female; Leptin; Obesity; Pregnancy; Resistin; Risk

Obesity regulates bone metabolism not only by increasing weight loading but by modulating cytokines or hormones which are known to affect bone remodeling. As a result, it has been generally believed that obesity leads to an increase in bone mass. However, recent observations revealed that excessive fat mass may not protect against osteoporotic fractures.

Topics: Adipocytes; Body Weight; Bone and Bones; Bone Remodeling; Cell Differentiation; Diet, Reducing; Fractures, Bone; Humans; Leptin; Obesity; Osteoblasts; Osteoporosis; Risk

In this brief review, we introduce some major themes in the regulation of energy, lipid, and glucose metabolism by the central nervous system (CNS). Rather than comprehensively discussing the field, we instead will discuss some of the key findings made regarding the interaction of the hormones ghrelin and leptin with the CNS.

Topics: Aged; Appetite; Arcuate Nucleus of Hypothalamus; Body Weight; Central Nervous System; Diabetes Mellitus; Energy Metabolism; Ghrelin; Glucose; Homeostasis; Humans; Hypothalamus; Leptin; Obesity

The incidence and prevalence of obesity and the metabolic syndrome have risen markedly in the past decade, representing a serious cardiovascular health hazard with significant morbidity and mortality. The etiology of the metabolic syndrome and its various pathogenic mechanisms are incompletely defined and under intense investigation. Contemporary research suggests that the adipocyte-derived hormone leptin may be an important factor linking obesity, the metabolic syndrome, and cardiovascular disorders. Although recent evidence indicates that under normal conditions leptin may be an important factor in regulating pressure and volume, during situations of chronic hyperleptinemia and leptin resistance, this hormone may function pathophysiologically for the development of hypertension and cardiac and renal diseases. Future research will determine if reduction of circulating leptin and/or blockade of its peripheral actions can confer cardiovascular and renal protection in hyperleptinemic patients with obesity and the metabolic syndrome.

Topics: Appetite Regulation; Blood Pressure; Cardiovascular Diseases; Heart; Humans; Hypertension; Insulin Resistance; Kidney; Leptin; Metabolic Syndrome; Obesity; Receptors, Leptin; Risk Factors; Sympathetic Nervous System

The clustering of cardiovascular risk factors associated with abdominal obesity is well established. Although currently lacking a universal definition, the metabolic syndrome describes a constellation of metabolic abnormalities, including abdominal obesity, and was originally introduced to characterize a population at high cardiovascular risk. Adipose tissue is a dynamic endocrine organ that secretes several inflammatory and immune mediators known as adipokines. Dysregulation of adipokine secretion, free fatty acid toxicity, and the site-specific differences in abdominal (visceral) versus subcutaneous fat support abdominal obesity as a causal factor mediating the insulin resistance, increased risk of diabetes, and cardiovascular disease in the metabolic syndrome.

Topics: Adipokines; Adiponectin; Adiposity; Cardiovascular Diseases; Fatty Acids, Nonesterified; Humans; Insulin Resistance; Intra-Abdominal Fat; Leptin; Metabolic Syndrome; Obesity; Renin-Angiotensin System; Risk Factors; Subcutaneous Fat, Abdominal

Obesity is now regarded as a global epidemic affecting both adults and children, and is associated with significant morbidity and mortality. Thus the effective management of obesity has become an important clinical focus. Therefore, an understanding of the pathways controlling appetite, satiety and food intake is critical for gaining an insight into the pathogenesis of obesity and also for the development of diagnostic tests and therapeutic agents for use in the clinical management of this condition. Over the last decade or more research using both mouse and human genetic models has elucidated the critical role of the leptin-melanocortin pathway in the hypothalamus, in regulating mammalian energy balance. In tandem with this, a clearer understanding of the regulation of gut-derived hormones and their interaction with the central nervous system has further illuminated the complex interplay between central and peripheral aspects of energy regulation. The obesity epidemic and the expanded knowledge base relating to its aetiopathogenesis have specific implications for clinical biochemistry. In particular, an increase in workload may be expected due to biochemical investigation of obesity and its co-morbidities. Moreover, advice on the in-depth investigation of complex cases of obesity may be sought, including information on newer diagnostic tests, such as serum leptin or molecular genetic analysis. There may also be a substantive role for chemical pathologists in establishing and running clinical obesity services. Finally, clinical biochemistry has a role in research pertaining to obesity and cardiometabolic risk.

Topics: Appetite; Energy Intake; Energy Metabolism; Homeostasis; Humans; Hypothalamus; Insulin; Leptin; Melanocortins; Models, Biological; Obesity; Satiation

CART (cocaine- and amphetamine-regulated transcript) peptides are neuromodulators that are involved in feeding, drug reward, stress, cardiovascular function, and bone remodeling. CART peptides are abundant but discretely distributed in the brain, pituitary and adrenal glands, pancreas, and gut. High expression of CART in discrete hypothalamic nuclei associated with feeding has led to behavioral and pharmacological studies that strongly support an anorectic action of CART in feeding. Subsequent studies on humans and transgenic animals provide additional evidence that CART is important in the regulation of appetite as mutations in the CART gene are linked to eating disorders, including obesity and anorexia. The expression of CART in the mesolimbic dopamine circuit has lead to functional studies demonstrating CART's psychostimulant-like effects on locomotor activity and conditioned place preference in rats. These and other findings demonstrated that CART modulates mesolimbic dopamine systems and affects psychostimulant-induced reward and reinforcing behaviors. The link between CART and psychostimulants was substantiated by demonstrating alterations of the CART system in human cocaine addicts. CART seems to regulate the mesolimbic dopamine system, which serves as a common mechanism of action for both feeding and addiction. Indeed, recent studies that demonstrated CART projections from specific hypothalamic areas associated with feeding to specific mesolimbic areas linked to reward/motivation behaviors provide evidence that CART may be an important connection between food- and drug-related rewards. Given the enormous public health burden of both obesity and drug addiction, future studies exploring the pharmacotherapies targeting CART peptide represent an exciting and challenging research area.

Topics: Animals; Appetite; Central Nervous System Stimulants; Eating; Glucocorticoids; Humans; Leptin; Nerve Tissue Proteins; Obesity; RNA, Messenger; Substance-Related Disorders

Topics: Animals; Disease Models, Animal; Drug Resistance; Humans; Leptin; Models, Biological; Obesity

Current explanations for obesity center around a predisposition in genotype and phenotype, possibly triggered by an inflammatory process or event, and exacerbated by environmental and psychological factors. It is likely that a variety of physiologic factors may act in combination to produce clinical obesity. Leptin resistance may be an important neurochemical cause of obesity; elevated leptin levels have been correlated with weight gain over extended time periods. Genetic studies support the postulate that a gene originating with our cave-dwelling ancestors, critical to survival when food was scare, has evolved into a trigger for obesity and related diseases. A variety of biochemical markers are prevalent in obesity and obesity-linked disease states. C-reactive protein, interleukin-6, and others are elevated in obesity, supporting the hypothesis that inflammation plays a role in the condition. Tumor necrosis factor-alpha is overexpressed in obesity and diabetes, suggesting that it may be part of the link between the 2 conditions.

Topics: Appetite; Biomarkers; C-Reactive Protein; Cardiovascular Diseases; Causality; Cost of Illness; Diabetes Mellitus, Type 2; Dietary Fats; Genetic Predisposition to Disease; Genotype; Humans; Inflammation; Interleukin-6; Leptin; Life Style; Neoplasms; Obesity; Phenotype; Tumor Necrosis Factor-alpha; United States

To describe the pathophysiological mechanisms by which obesity increases the propensity to thrombosis, the leading cause of death in the Western World, with particular emphasis on the role of inflammation, oxidative stress, dyslipidaemia, insulin resistance and the coagulation cascade.. Review article.. Medline (1966-2005) and Cochrane library review of literature examining the relationship between obesity and thrombosis. Search terms included obesity, overweight, body mass index, thrombosis, cardiovascular disease, venous thromboembolism, peripheral arterial disease, and coronary heart disease.. Obesity is an important and growing public health issue that is estimated to affect more than half of the UK adult population. Obesity, in particular central (visceral) obesity, is associated with significant, and largely preventable, morbidity and mortality including an increased incidence and prevalence of arterial and venous thrombotic events. The various mechanisms by which obesity may cause thrombosis include: the actions of so-called adipocytokines from adipose tissue, e.g. leptin and adiponectin; increased activity of the coagulation cascade and decreased activity of the fibrinolytic cascade; increased inflammation; increased oxidative stress and endothelial dysfunction; and disturbances of lipids and glucose tolerance in association with the metabolic syndrome.. Obesity appears to be associated with thrombosis via several mechanisms. These pro-thrombotic factors are all improved by weight loss.

Topics: Adiponectin; Global Health; Humans; Leptin; Morbidity; Obesity; Risk Factors; Thrombosis

Examination of individuals with 'extreme phenotypes' has revealed some rare monogenic disorders that were previously unknown. This identification can shed light on physiological pathways that are also important in normal physiology and how their impairment leads to more common, milder, multigenic forms of the disease. Ultimately, this is a potential route to treatment of both disease types. This approach is discussed in relation to Type 2 diabetes, arising from both insufficient insulin production and insulin resistance.

Topics: Diabetes Mellitus, Type 2; Genetic Predisposition to Disease; Humans; Insulin; Insulin Resistance; Leptin; Metabolic Diseases; Models, Biological; Obesity; Phenotype; PPAR gamma; Receptor, Melanocortin, Type 4

Leptin and ghrelin are two hormones that have been recognized to have a major influence on energy balance. Leptin is a mediator of long-term regulation of energy balance, suppressing food intake and thereby inducing weight loss. Ghrelin on the other hand is a fast-acting hormone, seemingly playing a role in meal initiation. As a growing number of people suffer from obesity, understanding the mechanisms by which various hormones and neurotransmitters have influence on energy balance has been a subject of intensive research. In obese subjects the circulating level of the anorexigenic hormone leptin is increased, whereas surprisingly, the level of the orexigenic hormone ghrelin is decreased. It is now established that obese patients are leptin-resistant. However, the manner in which both the leptin and ghrelin systems contribute to the development or maintenance of obesity is as yet not clear. The purpose of this review is to provide background information on the leptin and ghrelin hormones, their role in food intake and body weight in humans, and their mechanism of action. Possible abnormalities in the leptin and ghrelin systems that may contribute to the development of obesity will be mentioned. In addition, the potentials of leptin and ghrelin as drug targets will be discussed. Finally, the influence of the diet on leptin and ghrelin secretion and functioning will be described.

Topics: Body Weight; Energy Intake; Energy Metabolism; Ghrelin; Humans; Leptin; Obesity; Peptide Hormones

Topics: Cytokines; Diabetes Mellitus; Humans; Inflammation; Insulin; Insulin Resistance; Leptin; Obesity; Signal Transduction; Suppressor of Cytokine Signaling Proteins

Considerable evidence has suggested that excessive weight gain is the most common cause of arterial hypertension. This association has been observed in several populations, in different regions of the world. Obesity-hypertension, a term that underscores the link between these two deleterious conditions, is an important public health challenge, because of its high frequency and concomitant risk of cardiovascular and kidney diseases. The obesity-hypertension pandemic imposes a considerable economic burden on societies, directly reflecting on healthcare system costs. Increased renal sodium reabsorption and blood volume expansion are central features in the development of obesity-hypertension. Overweight is also associated with increased sympathetic activity. Leptin, a protein expressed in and secreted by adipocytes, is the main factor linking obesity, increased sympathetic nervous system activity and hypertension. The renin-angiotensin-aldosterone system has also been causally implicated in obesity-hypertension, because angiotensinogen is expressed in and secreted by adipose tissue. Hypoadiponectinemia, high circulating levels of free fatty acids and increased vascular production of endothelin-1 (ET-1) have been reported as potential mechanisms for obesity-hypertension. Lifestyle changes are effective in obesity-hypertension control, though pharmacological treatment is frequently necessary. Despite the consistency of the mechanistic approach in explaining the causal relation between hypertension and obesity, there is yet no evidence that one class of drug is superior to the others in controlling obesity-hypertension. In this review, we present the current knowledge and research in obesity-hypertension, exploring the epidemiologic evidence of the association, its probable pathophysiological mechanisms and treatment issues.

Topics: Adolescent; Adult; Antihypertensive Agents; Child; Exercise; Female; Humans; Hypertension; Leptin; Life Style; Male; Obesity

Leptin, a peptide secreted by the white adipose tissue, circulates to the central nervous system and signals the status of body energy stores, regulating feeding behavior and energy balance. As human obesity is characterized by hyperleptinemia and leptin resistance, increasing leptin sensitivity is an attractive target for obesity treatment.

Topics: Humans; Leptin; Lipid Metabolism; Obesity; Recombinant Proteins; Signal Transduction

Scientific interest in the endocannabinoid (EC) system developed as a result of the known effects of tetrahydrocannabinol, including an increased desire to consume food. Further investigation has led to the belief that the EC system plays a role in accumulation of intra-abdominal fat and worsening of cardiovascular disease (CVD) risk factors. The EC system has been identified as a neuromodulatory system that is normally inactive but can be overstimulated to cause and exacerbate numerous metabolic pathologies. EC agonists and receptors have been identified in the brain, liver, and peripheral adipose tissue, and the EC system is known to affect metabolism in these areas and others through neuromodulatory signals. Meal size, body weight, and numerous metabolic factors such as triglyceride and cholesterol levels, insulin resistance, and glucose intolerance can be affected via the EC system. Further research into the EC system is warranted to elucidate its role in metabolic homeostasis.

Topics: Adipocytes; Adipose Tissue; Cannabinoid Receptor Modulators; Endocannabinoids; Homeostasis; Humans; Hypothalamus; Insulin; Leptin; Liver; Obesity; Receptors, Cannabinoid; Satiety Response

Obesity is associated with significant morbidity and mortality and is increasing in prevalence worldwide. Associated conditions include insulin resistance (IR), diabetes, hypertension and dyslipidaemia; a clustering of these has recently been termed as metabolic syndrome. Weight gain is a major predictor of the metabolic syndrome with waist circumference being a more sensitive indicator than body mass index as it reflects both abdominal subcutaneous adipose tissue and visceral adipose tissue (VAT). VAT has more metabolic activity and secretes a number of hormones and pro-inflammatory cytokines which are linked with the metabolic abnormalities listed above. Central obesity also increases the risk of obstructive sleep apnoea syndrome (OSAS), where the sleep disordered breathing may also independently lead to/or exacerbate IR, diabetes and cardiovascular risk. The contribution of OSAS to the metabolic syndrome has been under-recognized. The putative mechanisms by which OSAS causes or exacerbates these other abnormalities are discussed. We propose that activation of nuclear factor kappa B by stress hypoxia and/or by increased adipokines and free fatty acids released by excess adipose tissue is the final common inflammatory pathway linking obesity, OSAS and the metabolic syndrome both individually and, in many cases, synergistically.

Topics: Adiponectin; Diabetes Mellitus, Type 2; Humans; Inflammation; Insulin Resistance; Leptin; Metabolic Syndrome; NF-kappa B; Obesity; Risk Factors; Sleep Apnea Syndromes

The prevalence of obesity, especially among the young, is dramatically increasing in the United States. Obesity is associated with accelerated atherosclerosis and increased rates of cardiovascular death. There are many plausible mechanisms by which an increase in adipose tissue could adversely affect the vessel wall. These include the changes in blood pressure, glucose level, lipid/lipoprotein metabolism, and systemic inflammation. In addition, factors secreted by adipose tissue may directly influence vessel wall homeostasis by influencing the function of endothelial cells, arterial smooth muscle cells, and macrophages in the vessel wall. There is general agreement that central, as opposed to peripheral, adipose tissue confers the most cardio-metabolic risk. Although the basis of this differential risk has not been not established, the pattern of gene expression and secretory products in visceral fat would be predicted to be more atherogenic compared with that in subcutaneous peripheral fat. Numerous studies have shown the beneficial effects of weight loss on markers of cardiovascular risk but fewer have demonstrated improvement in direct measures of large vessel disease. The unfolding role of adipose tissue as an important metabolic and secretory organ provides new opportunities for developing more effective approaches for preventing obesity and its atherosclerotic complications.

Topics: Adiponectin; Adipose Tissue; Atherosclerosis; Endothelium, Vascular; Humans; Insulin Resistance; Leptin; Obesity; Prevalence; Prognosis; Risk Factors; United States

Topics: Adipocytes, White; Adiponectin; Adipose Tissue; Biomedical Research; Humans; Inflammation; Leptin; Obesity

Topics: Animals; Body Mass Index; Body Weight; Female; Gastritis; Gerbillinae; Helicobacter Infections; Helicobacter pylori; Humans; Leptin; Male; Mice; Obesity; Pepsinogens; Rats

To describe data on changes in body composition in childhood cancer survivors. Underlying mechanisms in development of obesity are addressed, in order to discuss intervention strategies.. A systematic literature search was undertaken with a number of search terms.. Female survivors of ALL and brain tumours, especially if treated with cranial irradiation, showed a higher prevalence of obesity compared with the general population, while survivors of other malignancies had a higher prevalence of underweight. Influences of corticosteroid treatment and cytostatics on body composition are uncertain. Diminished physical activity, early adiposity rebound (<5 years of age) and/or hypothalamic involvement of tumour or treatment, and subsequent growth hormone deficiency, may play a role in the development of obesity in childhood cancer survivors.. Longitudinal prospective studies in more extensive cohorts are necessary to estimate actual prevalence and facilitate the unravelling of the underlying mechanisms in change of body composition.

Topics: Body Composition; Body Mass Index; Brain Neoplasms; Child; Child, Preschool; Cohort Studies; Cranial Irradiation; Growth Hormone; Health Status; Humans; Leptin; Longitudinal Studies; Obesity; Polymorphism, Genetic; Prevalence

The prevalences of both obesity and asthma have clearly increased in recent decades, giving rise to speculation that they may be related. Studies have found that obesity precedes and predicts the onset of asthma (time effect), that increased obesity leads to more severe asthma (dose-response effect), that weight reduction (by diet or gastric bypass) improves asthmatic symptoms, and that obesity co-occurs with intermediate asthma phenotypes (obese young girls undergoing early menarche). In the light of that evidence, we can finally suggest a causal relationship between obesity and asthma. Various biological mechanisms (immunologic and inflammatory, hormonal, genetic, nutritional, mechanical, and others related to physical activity) have been put forth to explain the relationship. However, this relation is complex, involving not only the interaction of genetic and environmental factors in triggering both diseases but also the likely participation of several mechanisms at once.

Topics: Adolescent; Adult; Airway Resistance; Asthma; Child; Chromosome Mapping; Cytokines; Diet; Disease Susceptibility; Female; Hormones; Humans; Inflammation; Leptin; Male; Menarche; Motor Activity; Obesity; Pregnancy; Prenatal Exposure Delayed Effects; Respiratory Mechanics; Sex Factors; Weight Loss

The brain hypothalamus coordinates extra-hypothalamic regions to maintain energy homeostasis through the regulation of food intake and energy expenditure. A number of anorexigenic and orexigenic molecules in the hypothalamic nuclei participate in the control of energy homeostasis. Leptin and pro-opiomelanocortin (POMC)-derived alpha-melanocyte-stimulating hormone are key anorectic molecules, and the leptin receptor and POMC gene are both expressed in the hypothalamic arcuate nucleus. Although it has been considered that melanocortin signaling is localized downstream to leptin signaling, data have accumulated to support the concept of a leptin-independent melanocortin signaling system. We focus on and review the melanocortin signaling system that functions dependently or independently of leptin signaling in the regulation of energy homeostasis.

Topics: Animals; Appetite Regulation; Arcuate Nucleus of Hypothalamus; Energy Metabolism; Homeostasis; Humans; Leptin; Melanocortins; Obesity; Pro-Opiomelanocortin; Receptors, Cell Surface; Receptors, Leptin; Receptors, Melanocortin; Signal Transduction

Within the last decade an intensive research led to an identification of several genes which are involved in a regulation of energy balance. In most cases, carriers of these gene mutations do not exhibit further characteristic phenotypic features except for a severe obesity. Obesity based on mutation of one gene product is called monogenic obesity. Mutations in genes for leptin, leptin receptor, proopiomelanocortin, prohormone convertase 1, melanocortin 4 and 3 receptor disrupt the physiological humoral signalization between peripheral signals and the hypothalamic centres of satiety and hunger. Defects of all above mentioned genes lead to phenotype of abnormal eating behaviour followed by a development of severe early-onset obesity. Mutations of melanocortin 4 receptor gene represent the most common cause of monogenic obesity because they are detected in almost 6 % children with early-onset severe obesity. Mutations of the other genes involved in energy homeostasis are very rare. Although these mutations are sporadic we assume that further research of monogenic forms of obesity might lead to our understanding of physiology and pathophysiology of regulation of the energy homeostasis and eating behaviour. Additionally, they may open new approach to the management of eating behaviour and to the treatment of obesity.

Topics: Energy Metabolism; Humans; Leptin; Mutation; Obesity; Pro-Opiomelanocortin; Proprotein Convertase 1; Receptors, Cell Surface; Receptors, Leptin; Receptors, Melanocortin

The aim of this manuscript was to review the knowledge about leptin, detailing its relationship with energetic intake and physical activity. Leptin is an adipocyte hormone, recognized mainly for its putative role in control of energy expenditure, food intake, body weight and reproductive function. Leptin has still important peripheral actions, including its role on the ovarian tissue. The intracellular signaling mechanisms are recognized in hypothalamus, but in peripheral tissue are not fully understood. The exercise, when practiced by women, if not appropriately planned according to food intake, can modify the leptin release. When energy imbalances induced by exercise and/or deficient food ingestion occurs, low leptin levels are observed, leading to a reduction in GnRH (gonadotropin-release hormone), in LH (luteinizing hormone) and FSH (follicle-stimulating hormone) in pituitary, and consequently a minor release of ovarian estrogens. This process is named hypothalamic amenorrhea, and has repercussions in the woman's health. In this perspective, it is important to emphasize the need to evaluate the energy expenditure from exercise and to formulate adequate alimentary plans to these individuals.

Topics: Adipose Tissue; Adolescent; Adult; Age Factors; Amenorrhea; Biomarkers; Body Mass Index; Caloric Restriction; Child; Diet; Energy Metabolism; Exercise; Female; Humans; Hypothalamus; Leptin; Obesity; Sports

Obesity is a major public health problem in the Western world resulting in serious social, physical and psychological damages. The genesis of obesity is complex involving a variety of factors such as genetic, psychological, metabolic and environmental factors. Progress in endocrinology and metabolism show that adipocyte is considered now as an endocrine tissue producing several substance including adiponectin, tumor necrosis factor-alpha, interleukin-6 and leptin. Specifically, leptin is the main peptide produced by the adipocyte and its serum concentration represents an important peripheral signal in the regulation of food intake and energy expenditure in mammals. In addition to leptin, a new peptide was discovered recently named ghrelin. Ghrelin, a peptide hormone identified in the stomach, is directly involved with the regulation of energy balance and obesity. Physical exercise has been used as a non-pharmacological tool in management of body weight and the effect of physical activity on weight control is an important issue for clinical studies in endocrinology field. Thus, this review will attempt to update the knowledge of leptin and ghrelin on the body weight regulation and the effect of exercise training on these peptide concentrations. It can be concluded that the relationship between physical exercise and the plasma concentration of these peptides is not clear. The reasons for that could be related to the differences in duration, intensity and frequency of the training program employed in each study. Indeed, most of the studies have not analyzed the intensity of training program by either plasma lactate concentration or maximum oxygen consumption. On the other hand, genetic basis could also explain the discrepancies found in some studies, since it has been shown that polymorphism for a variety of genes might be an important factor to determine the differences of cellular response to physical training.

Topics: Animals; Energy Intake; Energy Metabolism; Exercise; Ghrelin; Humans; Leptin; Mice; Obesity; Physical Fitness

Several endocrine changes have been described in the obesity state. The corticotropic axis is hyperresponsive and there is enhancement of hormonal clearance, but cortisol levels are within the normal range. It is important to characterize a pseudo-Cushing in obesity. Leptin seems to be a permissive hormone for the beginning of puberty. In adults, gonadotropines are normal, and hyperandrogenism and hyperestrogenism are found. In women, insulin resistance has a central role in polycystic ovarian syndrome (POS), which is associated to ovarian hyperandrogenemia. In obese subjects, growth hormone (GH) is generally low and IGF1 is normal. Thyroid function is commonly normal in obese subjects.

Topics: Adrenocorticotropic Hormone; Endocrine Glands; Gonadotropins, Pituitary; Growth Hormone; Hormones; Humans; Hypothalamo-Hypophyseal System; Insulin Resistance; Leptin; Obesity; Thyrotropin

An understanding of the mechanisms that regulate energy homeostasis is essential for understanding novel obesity therapies. The status of energy reserves is communicated to the brain by adiposity and satiety signals. These signals modify either anabolic or catabolic pathways and, consequently, alter food intake in line with signaled energy requirements. New antiobesity therapies are in development that target anabolic or catabolic regulatory networks to reduce food intake and/or increase energy expenditure to promote weight loss.

Topics: Adiposity; Animals; Anti-Obesity Agents; Body Weight; Cannabinoid Receptor Modulators; Cholecystokinin; Energy Metabolism; Glucagon-Like Peptide 1; Humans; Leptin; Melanocyte-Stimulating Hormones; Neuropeptide Y; Obesity; Pro-Opiomelanocortin; Receptor, Cannabinoid, CB1; Serotonin; Serotonin Receptor Agonists; Thyroid Hormones

The unparalleled global rates of obesity and type 2 diabetes, together with the associated cardiovascular morbidity and mortality, are referred to as the "diabesity pandemic". Changes in lifestyle occurring worldwide, including the increased consumption of high-caloric foods and reduced exercise, are regarded as the main causal factors. Central obesity and insulin resistance have emerged as important linking components. Understanding the aetiology of the cluster of pathologies that leads to the increased risk is instrumental in the development of preventive and therapeutic strategies. Historically, skeletal muscle, adipose tissue and liver were regarded as key insulin target organs involved in insulin-mediated regulation of peripheral carbohydrate, lipid and protein metabolism. The consequences of impaired insulin action in these organs were deemed to explain the functional and structural abnormalities associated with insulin resistance. The discovery of insulin receptors in the central nervous system, the detection of insulin in the cerebrospinal fluid after peripheral insulin administration and the well-documented effects of intracerebroventricularly injected insulin on energy homeostasis, have identified the brain as an important target for insulin action. In addition to its critical role as a peripheral signal integrating the complex network of hypothalamic neuropeptides and neurotransmitters that influence parameters of energy balance, central nervous insulin signalling is also implicated in the regulation of peripheral glucose metabolism. This review summarizes the evidence of insulin action in the brain as part of the multifaceted circuit involved in the central regulation of energy and glucose homeostasis, and discuss the role of impaired central nervous insulin signalling as a pathogenic factor in the obesity and type 2 diabetes epidemic.

Topics: Animals; Brain; Diabetes Mellitus, Type 2; Disease Outbreaks; Energy Intake; Energy Metabolism; Glucose; Humans; Insulin; Insulin Resistance; Leptin; Life Style; Obesity; Physical Exertion; Receptor, Insulin; Signal Transduction

The increasing prevalence of the metabolic syndrome in numerous populations throughout the world is currently of major concern, and presents a huge global health problem. The link between low birth weight and the subsequent development of obesity, disrupted glucose homeostasis and hypertension is now well established, and there is extensive evidence supporting these associations in both epidemiological and experimental studies. Alterations in the secretion of, and responses to, the circulating hormones insulin and leptin are likely candidates in terms of disease development. The aim of current research is to define how the central and peripheral pathways in which these signals exert their effects may be disrupted following poor early growth, and how this disruption contributes to the development of metabolic disease. The present review aims to outline the existing evidence whereby alterations in early growth may programme an individual to be at increased risk of the metabolic syndrome. The development of central appetite and expenditure circuits and of peripheral metabolic tissues, are likely to play a key role in the long-term regulation of energy balance.

Topics: Animals; Appetite Regulation; Birth Weight; Disease Models, Animal; Energy Intake; Energy Metabolism; Genetic Predisposition to Disease; Humans; Leptin; Metabolic Syndrome; Nutritional Physiological Phenomena; Obesity; Risk Factors

Topics: Animals; Comorbidity; Diabetes Mellitus; Global Health; HIV Infections; Humans; Infections; Leptin; Malaria; Malnutrition; Measles; Obesity; Protein-Energy Malnutrition; Risk Factors; T-Lymphocytes; Tuberculosis

Topics: Adiponectin; Adiposity; Atherosclerosis; Diabetes Mellitus, Type 2; Dyslipidemias; Humans; Leptin; Lipid Metabolism; Lipid Metabolism Disorders; Obesity; Peptide Hormones; Resistin

The incidence of obesity is increasing in the United States and around the world, and it is likely that obese patients will present for orthodontic therapy in greater numbers in the future. The implications of obesity for psychosocial well-being, bone metabolism, craniofacial growth, and pubertal growth must be assessed in treating obese orthodontic patients. This review article focuses on the relevant issues concerning obesity in regard to orthodontic therapy.

Topics: Adolescent; Animals; Body Mass Index; Cephalometry; Facial Bones; Female; Humans; Leptin; Male; Mice; Obesity; Orthodontics, Corrective; Puberty; Risk Factors; Sex Factors; Time Factors

Leptin is an adipocyte-derived, satiety-regulating hormone that acts within the hypothalamus and other brain sites. Obese humans and animals are largely resistant to central actions of leptin. Rising leptin levels associated with progressing obesity are generally regarded as simply a consequence rather than a causative factor in the leptin resistance and obesity. Several lines of evidence suggest otherwise. Chronic overexpression of central leptin induces a leptin resistance that mimics many of the characteristics associated with diet-induced or adult-onset obesity including reduced leptin receptors, diminished signaling, and impaired responsiveness to exogenous leptin. Moreover, these animals have increased susceptibility to diet-induced obesity. New data with a leptin antagonist demonstrate that blockade of leptin receptors also exaggerates diet-induced obesity. These findings suggest an important role for elevated leptin in the development of leptin resistance and obesity, especially in today's society with an overabundance of readily available high caloric food. Once leptin resistance takes hold, each subsequent exposure to high-density food faces diminished counter-regulatory responses, leading to exacerbated weight gain.

Topics: Adult; Diet; Drug Resistance; Humans; Leptin; Obesity; Signal Transduction

The increasing national prevalence of obesity is a major public health concern and a substantial burden on the health care resources of Canada. In addition to the direct health impact of obesity, this condition is a well-established risk factor for the development of various prevalent comorbidities including type 2 diabetes, hypertension, and cardiovascular disease. Historically, adipose tissue has been regarded primarily as an organ for energy storage. However, the discovery of leptin in the mid 1990's revolutionized our understanding of this tissue and has focused attention on the endocrine function of adipose tissue as a source of secreted bioactive peptides. These compounds, collectively termed adipokines, regulate a number of biological functions including appetite and energy balance, insulin sensitivity, lipid metabolism, blood pressure, and inflammation. The physiological importance of adipokines has led to the hypothesis that changes in the synthesis and secretion of these compounds in the obese are a causative factor contributing to the development of obesity and obesity-related diseases in these individuals. Following from this it has been proposed that pharmacologic manipulation of adipokine levels may provide novel effective therapeutic strategies to treat and prevent obesity, type 2 diabetes, and cardiovascular disease.

Topics: Adiponectin; Adipose Tissue; Angiotensin II; Animals; Cardiovascular Diseases; Complement Activation; Complement C3a; Complement Factor D; Cytokines; Diabetes Mellitus, Type 2; Fibrinolysis; Humans; Inflammation; Insulin Resistance; Interleukin-6; Leptin; Nicotinamide Phosphoribosyltransferase; Obesity; Plasminogen Activator Inhibitor 1; Renin-Angiotensin System; Resistin; Retinol-Binding Proteins; Retinol-Binding Proteins, Plasma; Risk Factors; Tumor Necrosis Factor-alpha

Obesity is responsible for the mounting incidence of metabolic disease in adult and pediatric populations. Understanding of the pathogenesis and maintenance of the obese state has advanced rapidly over the past 10 years. Bodily energy reserves are managed actively by complex systems that regulate food intake, substrate partitioning, and energy expenditure. An underlying assumption that circulating factors released from storage organs were able to signal bodily energy reserves was confirmed with the discovery of the leptin system. This proof of concept has spurred on the discovery of a multitude of other adipocyte-generated factors. These circulating factors signal to the brain and other organs of metabolic importance, including adipose tissue, liver, muscle, and the immune system. Adipose-derived factors have numerous implications for the basic biology of obesity and provide prospective targets for the amelioration of obesity and its adverse metabolic consequences. In this review we detail the current understanding of leptin as a prototypical adipose tissue-derived hormone related to appetite and obesity. We also describe other important adipose-derived factors in relation to their metabolic effect.

Topics: Adipocytes; Animals; Eating; Energy Metabolism; Humans; Leptin; Obesity; Signal Transduction

While obesity has been historically considered a criteria to establish the diagnosis of hypothyroidism, the association between them is seldom encountered in patients. Nowadays the main metabolic criteria is the gain of weight in the presence of other symptoms of hypothyroidism. The large differences between the thermogenesis of hypothyroid and hyperthyroid patients underline the complex relationship of thyroid hormones and metabolic pathways. The treatment of a subclinical hypothyroidism has almost no influence on the body weight, whereas in more severe dysfunctions a weight loss is expected, usually less than 10% of body weight. Thereafter severe obesity may not be secondary to a thyroid failure.

Topics: Body Mass Index; Body Weight; Humans; Hypothyroidism; Leptin; Obesity; Thyrotropin; Thyroxine

Research in the last 10-15 years has shown that fat cells (adipocytes) produce and release proteins with specific biologic activities. These proteins, termed adipokines, include the hormones leptin, adiponectin, and resistin. Adipose tissue is now recognized as an active endocrine organ. With the obesity pandemic swelling in the Western world, ongoing research is aimed at determining the biologic links between obesity and cardiovascular disease. This review presents basic historical background information on the major adipokines, introduces findings from clinical studies associating adipokines with cardiovascular disease, and summarizes results from recent basic science research studies of mechanisms of adipokine-induced cardiovascular dysfunction. Particular emphasis is placed on the action of adipokines in the coronary circulation-especially effects of adipokines on endothelial function, as endothelial damage is likely a critical event initiating atherosclerotic coronary artery disease.

Topics: Adiponectin; Animals; Cardiovascular Diseases; Humans; Leptin; Obesity; Resistin

This review deals with the question whether resistance to obesity affects resistance to atherosclerosis.. Resistance to diet-induced obesity in inbred mouse strains involves an adequate response to Leptin, the main regulator of the energy balance cycle. Leptin, an adipokine with both central and peripheral targets, regulates food intake and energy expenditure. Adequate response to leptin involves repression of stearoyl-CoA desaturase, activation of Amp-activated protein-kinase and uncoupling proteins, resulting in fatty acid oxidation and energy expenditure. Most of the obesity-resistant strains are also resistant to atherosclerosis, but so far no information concerning the response to the leptin cycle is available in these strains when bred onto a LDLR(-/-) or apoE(-/-) background. Recent studies in mouse strains on an atherosclerosis permissive background have identified genetic links between obesity and atherosclerosis. Moreover, information derived from studies on mice was applied in order to learn about the metabolic effectors in humans and is included in this review.. The data presented in this review provide recent information concerning metabolic pathways that play an important role in the regulation of energy balance, a prerequisite for resistance to obesity. Hopefully they will provide a background for future genetic studies involved in resistance to atherosclerosis.

Topics: Animals; Atherosclerosis; Disease Models, Animal; Energy Metabolism; Genetic Predisposition to Disease; Humans; Leptin; Mice; Mice, Inbred Strains; Mice, Obese; Obesity

The recent rapid increase in the prevalence of obesity across the world is undoubtedly due to changes in diet and lifestyle. However, it is also indisputable that different people react differently to this change in environment and this variation in response is likely to be genetically determined. While for the majority of people this effect is presumed to be polygenic in origin, there is now strong evidence for a small number of genes having a large effect in some families with severe obesity. Studies of these families, coupled with parallel studies in murine models, have provided novel insights into the molecules involved in the regulation of appetite, energy expenditure and nutrient partitioning. We review here the lessons we have learnt from mouse models of obesity, both naturally occurring and artificially generated through targeted gene deletions, and more importantly from human monogenic syndromes of obesity. These have illuminated the critical role in which the central leptin melanocortin pathway plays in the control of mammalian food intake and body weight.

Topics: Animals; Appetite Regulation; Body Weight; Disease Models, Animal; Energy Metabolism; Humans; Leptin; Melanocortins; Mice; Obesity

Growing evidence suggests that food intake, energy expenditure and endogenous glucose production are regulated by hypothalamic areas that respond to a variety of peripheral signals. Therefore, in response to a reduction in energy stores or circulating nutrients, the brain initiates responses in order to promote positive energy balance to restore and maintain energy and glucose homeostasis. In contrast, in times of nutrient abundance and excess energy storage, key hypothalamic areas activate responses to promote negative energy balance (i.e. reduced food intake and increased energy expenditure) and decreased nutrient availability (reduced endogenous glucose production). Accordingly, impaired responses or 'resistance' to afferent input from these hormonal or nutrient-related signals would be predicted to favour weight gain and insulin resistance and may contribute to the development of obesity and type 2 diabetes.

Topics: Animals; Diabetes Mellitus, Type 2; Eating; Energy Metabolism; Feedback, Physiological; Glucose; Homeostasis; Humans; Hypothalamus; Insulin Resistance; Leptin; Liver; Obesity; Signal Transduction; Weight Gain

Recent evidence demonstrated that posttranslational processing of neuropeptides is critical in the pathogenesis of obesity. Leptin or other physiological changes affects the biosynthesis and processing of many peptides hormones as well as the regulation of the family of prohormone convertases responsible for the maturation of these hormones. Regulation of energy balance by leptin involves regulation of several proneuropeptides such as proTRH and proopiomelanocortin. These proneuropeptide precursors require for their maturation proteolytic cleavage by the prohormone convertases 1 and 2 (PC1/3 and PC2). Because biosynthesis of mature peptides in response to leptin requires prohormone processing, it is hypothesized that leptin might regulate hypothalamic PC1/3 and PC2 expression, ultimately leading to coordinated processing of prohormones into mature peptides. Leptin has been shown to increase PC1/3 and PC2 promoter activities, and starvation of rats, leading to low serum leptin levels, resulted in a decrease in PC1/3 and PC2 gene and protein expression in the paraventricular and arcuate nucleus of the hypothalamus. Changes in nutritional status also changes proopiomelanocortin processing in the nucleus of the solitary tract, but this is not reversed by leptin. The PCs are also physiologically regulated by states of hyperthyroidism, hyperglycemia, inflammation, and suckling, and a recently discovered nescient helix-loop-helix-2 transcription factor is the first one to show an ability to regulate the transcription of PC1/3 and PC2. Therefore, the coupled regulation of proneuropeptide/processing enzymes may be a common process, by which cells generate more effective processing of prohormones into mature peptides.

Topics: Animals; Helix-Loop-Helix Motifs; Hypothalamo-Hypophyseal System; Hypothalamus; Leptin; Neurons; Obesity; Pro-Opiomelanocortin; Proprotein Convertases; Thyroid Gland; Thyrotropin-Releasing Hormone

This review summarizes key aspects of what has been learned about the physiology of leptin deficiency as it can be observed in obese-hyperglycemic ob/ob mice. These mice lack functional leptin. They are grossly overweight and hyperphagic, particularly at young ages, and develop severe insulin resistance. They have been used as a model for obesity and as a rich source of pancreatic islets with high insulin release capacity. The leptin deficiency manifests also with regard to immune function, the cardiovascular system including angiogenesis, supportive tissue function, malignancies, and reproductive function. ob/ob Mice are well suited for studies on the interaction between leptin and insulin, and for studies on initial aspects of metabolic disturbances leading to type-2 diabetes.

Topics: Animals; Disease Models, Animal; Humans; Hyperglycemia; Insulin; Islets of Langerhans; Leptin; Mice; Mice, Obese; Obesity

The incidence and prevalence of obesity has risen markedly in the last decade, and this epidemic represents a serious health hazard with significant morbidity and mortality. Although hypertension is recognized as one of the most serious consequences of obesity, its pathophysiology remains incompletely understood. Contemporary research suggests that the recently discovered hormone leptin may represent a common link between these 2 pathologic conditions. Leptin is primarily synthesized and secreted by adipocytes. One of the major functions of this hormone is the control of energy balance. By binding to receptors in the hypothalamus, it reduces food intake and promotes elevation in temperature and energy expenditure. In addition, increasing evidence suggests that leptin, through both direct and indirect actions, may play an important role in cardiovascular and renal functions. Although the relevance of endogenous leptin needs further clarification for the control of renal sodium excretion and vascular tone, it appears to be a potential pressure and volume-regulating factor in normal situations. However, in conditions of chronic hyperleptinemia, such as obesity, leptin may function pathophysiologically for the development of hypertension as well as cardiac and renal disease. Thus, in addition to weight control, reduction of circulating leptin may confer cardiovascular and renal protective effects in patients with obesity-hypertension.

Topics: Blood Pressure; Heart Diseases; Humans; Hypertension; Kidney Diseases; Leptin; Obesity; Sympathetic Nervous System

Topics: Adiponectin; Adipose Tissue; Animals; Complement C3; Fatty Acids, Nonesterified; Humans; Inflammation; Intercellular Signaling Peptides and Proteins; Leptin; Obesity

The satiety factor leptin has received extensive attention especially in terms of its potential role in appetite suppression and regulation of energy expenditure. Once considered to be solely derived from adipose tissue, which accounts for the greatly increased levels observed in obese subjects, it is now apparent that leptin can be produced by a multiplicity of tissues, including the heart, where it appears to function in an autocrine and paracrine manner. Plasma leptin concentrations are also elevated in patients with heart disease including those with congestive heart failure. Leptin exerts its biological effects via a family of receptors termed Ob-R. In cardiac cells, one of leptin's primary actions is to produce cardiomyocyte hypertrophy through multifaceted cell signaling mechanisms including stimulation of mitogen-activated protein kinase and activation of the RhoA/Rho kinase (ROCK) pathway. The hypertrophic effect of leptin suggests that it may contribute to myocardial remodeling after cardiac injury and offers the potential targeting of the leptin system as a novel cardiac therapy.

Topics: Adipose Tissue; Cardiomyopathy, Hypertrophic; Humans; Leptin; Mitogen-Activated Protein Kinases; Myocardium; Myocytes, Cardiac; Obesity; Risk Factors; Signal Transduction

Genetic and environmental factors interact to regulate body weight. Overall, the heritability of obesity is estimated at 40% to 70%. More than 244 genes have been found to strongly affect adiposity when overexpressed or deleted in mice. These genes can be considered in four broad categories: regulation of food intake by molecular signalling in the hypothalamus and hindbrain by signals originating in adipose tissue, gut and other organs; regulation of adipocyte differentiation and fat storage; regulation of spontaneous exercise activity; and effect on basal and postprandial thermogenesis. Rare variants in the coding sequences of major candidate genes account for an obese phenotype in 5% to 10% of individuals.

Topics: Adipose Tissue; Animals; Energy Metabolism; Genetic Predisposition to Disease; Humans; Hypothalamus; Leptin; Mice; Obesity; Sensitivity and Specificity

The purpose of this review is to provide updated information on the role of ghrelin in food intake and energy homeostasis, and on its mechanism of action. Moreover, the potential of ghrelin as a target for drugs to treat cachexia and obesity will be discussed.. Whereas the effects of ghrelin in the regulation of appetite, food intake and energy homeostasis have been fairly well documented, the pathways responsible for the effects of ghrelin are now increasingly being understood. As a consequence, clinical applications of ghrelin are now being developed.. Ghrelin is an endogenous orexigenic peptide recently discovered in the stomach. Ghrelin is involved in short-term regulation of food intake since its plasma levels increase before meals and decrease strongly postprandially. Ghrelin is also involved in long-term body-weight regulation by inducing adiposity. Ghrelin might be useful for cachexia and obesity treatment.

Topics: Anorexia; Appetite; Body Weight; Energy Intake; Energy Metabolism; Ghrelin; Humans; Leptin; Obesity

Upper body obesity and the related metabolic disorder type 2 diabetes have been identified as risk factors for breast cancer, and associated with late-stage disease and a poor prognosis. Components of the metabolic syndrome, including visceral adiposity, insulin resistance, hyperglycemia and hyperinsulinemia, with or without clinically manifest diabetes mellitus, low serum high-density lipoprotein cholesterol and hypertension have all been related to increased breast cancer risk. The biochemical mechanisms include extraglandular oestrogen production, reduced sex hormone-binding globulin with consequent elevation of the bioactive plasma free oestradiol and increased insulin biosynthesis, all of which exert mitogenic effects on both untransformed and neoplastic breast epithelial cells. Obesity, type 2 diabetes and the metabolic syndrome also have in common an increased production of leptin and a decreased production of adiponectin by adipose tissue, with consequent elevations and reductions, respectively, in the circulating levels of these two adipokines. These changes in plasma leptin and adiponectin, acting through endocrine and paracrine mechanisms, have been associated in several studies with an increase in breast cancer risk and, perhaps, to more aggressive tumours; studies in vitro showed that leptin stimulates, and adiponectin inhibits, tumour cell proliferation and the microvessel angiogenesis which is essential for breast cancer development and progression.

Topics: Adiponectin; Body Composition; Breast Neoplasms; Diabetes Mellitus, Type 2; Female; Humans; Intercellular Signaling Peptides and Proteins; Leptin; Metabolic Syndrome; Obesity; Risk Factors

Endogenous endocannabinoids (ECs) (anandamide and 2-arachidonoyl glycerol) are part of the leptin-regulated neural circuitry involved in appetite regulation. One of the sites of the orexigenic action of ECs involves activation of cannabinoid-1 (CB1) receptors in the lateral hypothalamus, from which neurons involved in mediating food reward project into the limbic system. In animal models of obesity, pharmacologic blockade or genetic ablation of CB1 receptors causes a transient reduction in food intake accompanied by sustained weight loss, reduced adiposity, and reversal of hormonal/metabolic changes, such as elevated levels of plasma leptin, insulin, glucose, and triglyceride, and reduced levels of plasma adiponectin (Acrp30). However, the beneficial effects of CB1 blockade on weight and metabolism cannot be explained by appetite suppression alone. Animal studies suggest that CB1 blockade exerts a direct peripheral as well as a central effect on fat metabolism. CB1 receptor blockade with rimonabant has been shown to not only reduce weight and adiposity but also to directly modulate fat metabolism at peripheral sites in skeletal muscle, adipose tissue, and the liver. Preclinical animal studies suggest that CB1 blockade acts on adipocytes to increase Acrp30 expression, on hepatocytes to decrease de novo lipogenesis and increase fatty acid oxidation, and on skeletal muscle to reduce blood glucose and insulin levels. Extrapolating from animal studies to the clinic, CB1 receptor blockade offers a promising strategy not only for reducing weight and abdominal adiposity but also for preventing and reversing its metabolic consequences.

Topics: Adipose Tissue; Animals; Appetite Regulation; Cannabinoid Receptor Modulators; Endocannabinoids; Energy Metabolism; Homeostasis; Humans; Leptin; Liver; Metabolic Diseases; Mice; Mice, Knockout; Models, Animal; Obesity; Receptor, Cannabinoid, CB1

Obesity has become a global epidemic and carries a considerable negative impact in regard to quality of life and life expectancy. A primary problem is that obese individuals are at increased risk of suffering from cardiovascular disease complications such as myocardial infarction and stroke. Because fat accumulation is a consistent aspect of obesity, mechanisms that may link adipose tissue to cardiovascular disease complications should be considered. Proteins expressed from adipose tissue, known as adipokines, are hypothesized to have important effects on the progression and incidence of cardiovascular disease complications. This review examines the evidence that adipokines play a direct role in vascular thrombosis, an important event in cardiovascular disease complications.

Topics: Adiponectin; Adipose Tissue; Animals; Hemostasis; Leptin; Mice; Obesity; Plasminogen Activator Inhibitor 1; Thrombosis; Tumor Necrosis Factor-alpha

Leptin, among the best known hormone markers for obesity, exerts pleiotropic actions on multiple organ systems. In this review, we summarize major leptin signaling pathways, namely Janus-activated kinase/signal transducers and activators of transcription and mitogen-activated protein kinase, including possible mechanisms of leptin resistance in obesity. The effects of leptin on the cardiovascular system are discussed in detail, including its contributions to hypertension, atherosclerosis, depressed myocardial contractile function, fatty acid metabolism, hypertrophic remodeling, and reduction of ischemic/reperfusion injury. The overall goal is to summarize current understanding of how altered leptin signaling in obesity contributes to obesity-related cardiovascular disease.

Topics: Animals; Cardiovascular Diseases; Cardiovascular System; Central Nervous System; Hormone Antagonists; Humans; Leptin; Obesity; Risk Factors; Signal Transduction

Obesity is a highly prevalent disease with multiple implications for cardiovascular morbidity and mortality. The traditional view of obesity is that excessive adipose tissue represents a passive storage depot of excess energy. However, obesity has been demonstrated to be a highly active endocrine organ with multiple metabolic pathways that interact with classic cardiac risk factors. The role of inflammation in atherosclerosis has been clarified by the ready availability of a variety of markers, including C-reactive protein, adiponectin, tumor necrosis factor-alpha, hemostatic markers, resistin, and a variety of emerging markers such as interleukins and adhesion molecules. Adipose tissue has been demonstrated to be the site of synthesis of a variety of proteins that are intimately involved in the regulation of inflammation. The concept that obesity represents an inflammatory state has gained credence over the past decade and has provided insights into the mechanisms of atherosclerosis and risk factor interaction.

Topics: Acute-Phase Proteins; Adiponectin; Atherosclerosis; Cardiovascular Diseases; Humans; Inflammation; Inflammation Mediators; Leptin; Obesity; Resistin; Risk Factors; Tumor Necrosis Factor-alpha

The fact that fat issue is an endocrine gland secreting several hormones participating in the pathogenesis of type 2 diabetes mellitus (DM2) is universally recognized. Fat issue secretes leptin, tumor necrosis factor alpha, resistin, adiponectin, interleukin-6, free fatty acids, visfatin, omentin, perilipin, and other substances that influence the condition of insulinoresistance, one of the main factors responsible for DM2. Subcutaneous fat and visceral depot fat tissue differ in the spectrum of hormones they produce; the list of these hormones is presented in the article. The presence of abdominal or visceral obesity is combined with significant insulinoresistance, which, in its turn, increases the risk of vascular complications of diabetes. The article also cover the participation of other mechanisms - insulin secretion defect, oxidation stress, low secretion of glucagon-like peptide 1, apoptosis, an increased quantity of amyloid and the fl-cell pull in the pancreatic island--in DM2 pathogenesis. The authors present data on the secretion of leptin, resistin, adiponectin, and tumor necrosis factor a, as well as the condition of the functional activity of beta-cells and the degree of insulinoresistance in 30 DM2 patients receiving dietotherapy.

Topics: Adipocytes; Adiponectin; Adipose Tissue; Diabetes Mellitus, Type 2; Disease Progression; Humans; Insulin Resistance; Interleukin-6; Leptin; Obesity; Tumor Necrosis Factor-alpha

Body mass--strictly speaking: the adipose tissue mass--is regulated in a feed-back system by the hypothalamus and brainstem, where adiposity signals (leptin, insulin, amylin) and intestinal peptides (ghrelin, PYY, PP, GLP-1, OXM, CCK) and the vagal nerve provide afferent information to the central controller on the size of white adipose tissue and the actual nutritional state, respectively. Two distinct groups of neurons in the arcuate nucleus accept and process the afferent information provided by leptin produced by white adipocytes in proportion to their mass. Leptin binding to the leptin-receptors on the surface of these neurons initiates intracellular signal transduction and activation of target genes, resulting in the synthesis and release of neuropeptides (POMC, CART) with anorectic effects. Secondary centers in the brain are also activated, and finally integrated effector mechanisms are generated in order to regulate the balance between energy intake and expenditure. The regulation of body weight is carried out by the central nervous system in a complex and redundant way, characterized by interconnections and overlaps with other neuroendocrine functions, such as growth, thyroid and adrenal function, memory, addictive and reward mechanisms. Targeting one or another component of this complicated system with drugs might result in interference with other systems and functions, so the occurrence of adverse events is probable. The worldwide epidemic of obesity--resulting mostly from the abundance of energy-dense foods and sedentary lifestyle coupled with a regulatory system unable to cope with this environment--has resulted in a continuous increase of research activities in both academic and industrial centers to develop new drugs and treatment strategies beyond lifestyle changes (diet, physical activity and behavioral therapy) to fight obesity more effectively.

Topics: Adipose Tissue, White; Amyloid; Animals; Anti-Obesity Agents; Appetite; Appetite Regulation; Body Composition; Body Mass Index; Body Weight; Brain; Brain Stem; Eating; Energy Intake; Energy Metabolism; Gastrointestinal Hormones; Ghrelin; Global Health; Humans; Hypothalamus; Insulin; Islet Amyloid Polypeptide; Leptin; Nerve Tissue Proteins; Neurosecretory Systems; Obesity; Peptide Hormones; Pro-Opiomelanocortin; Satiety Response; Signal Transduction

A cluster of risk factors associated with obesity defines the metabolic syndrome and identifies cardiometabolic risk. Accumulation of fat in the visceral depot is a more reliable predictor of cardiovascular disease than is total body mass or body mass index. The recent discovery of the endocannabinoid-CB1 receptor system and its impact on the regulation of energy metabolism represents a significant advance that will help target visceral fat and its metabolic implications. As a highly active endocrine organ, visceral fat secretes many bioactive molecules, known as adipokines. Dysregulation of these adipokines contributes to the pathogenesis of the obesity-associated metabolic syndrome, resulting in insulin resistance, type 2 diabetes, hypertension, hyperlipidemia, and vascular disease. Even modest weight reduction leads to reduced cardiometabolic risk by affecting the individual components comprising the metabolic syndrome.

Topics: Adiponectin; Anti-Obesity Agents; Blood Coagulation; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Diet; Dyslipidemias; Exercise; Fatty Acids; Humans; Hypertension; Inflammation Mediators; Insulin Resistance; Intra-Abdominal Fat; Leptin; Life Style; Metabolic Syndrome; Obesity; Practice Guidelines as Topic; Risk Factors; Weight Loss

A minute-to-minute crosstalk between the hypothalamic neuropeptide Y (NPY) network and the hormone leptin is essential for energy homeostasis. Leptin insufficiency i.e. lack of leptin restraint due to genetic and environmental factors on the hypothalamic NPY system confers obesity, a cluster of metabolic afflictions and shorter lifespan. A state-of-the-art gene transfer technology using recombinant adeno-associated viral vector to overcome hypothalamic leptin insufficiency was employed in rodent models of obesity, metabolic syndrome and shorter lifespan. Our findings show that life-long tonic repression of NPY system with a stable increase in leptin availability in the hypothalamus prevented the age-related and high fat-diet-induced obesity, hyperinsulinemia and diabetes and extended lifespan. Additional health benefits include increased energy expenditure and normalization of neuroendocrine control on reproduction, and promotion of brain and bone growth. We propose that central leptin gene therapy or novel long-acting leptin mimetics should be tested clinically to decelerate the worldwide epidemic of obesity, diabetes and shortened lifespan.

Topics: Animals; Genetic Therapy; Humans; Hypothalamus; Insurance Benefits; Leptin; Life Expectancy; Neuropeptide Y; Obesity

Leptin, a key hormone in energy homeostasis and neuroendocrine function, has a permissive role in initiating puberty and is crucial in the pathogenesis of reproductive dysfunction in several disease states of energy imbalance. KiSS1 neurons have recently been suggested to mediate leptin's effect on the reproductive system. New insights from recent animal studies and clinical trials are discussed.. Alterations in the expression profile of the KiSS1 gene and the kisspeptin receptor have been linked to reproductive dysfunction in leptin-deficient states. Neuroendocrine, including reproductive, dysfunction can be restored in humans and animals by leptin-replacement therapy. These insights have significantly advanced our understanding of hormonal systems needed to maintain normal reproduction. These data, if confirmed, also suggest a role for leptin as a novel therapeutic approach in several disease states.. Recent proof-of-concept studies involving leptin administration to humans underline the critical role of leptin not only in regulating energy homeostasis, but also in maintaining normal reproductive function. Leptin-replacement therapy is currently under intensive investigation as a potential novel therapeutic option for several conditions associated with reproductive dysfunction due to hypoleptinemia.

Topics: Amenorrhea; Animals; Anorexia Nervosa; Energy Metabolism; Female; Gonads; Humans; Hypothalamo-Hypophyseal System; Infertility; Kisspeptins; Leptin; Male; Menarche; Obesity; Polycystic Ovary Syndrome; Puberty; Reproduction; Sex Characteristics; Tumor Suppressor Proteins

Interest in the biology of white adipose tissue has increased dramatically since the discovery of leptin in 1994. The identification of the product of the gene obese (ob) threw light on the role of adipose tissue in the physiopathology of obesity-related diseases and spurred the identification of numerous other adipokines, many of a proinflammatory nature. It has become increasingly evident that white adipose tissue-derived cytokines mediate between obesity-related exogenous factors (nutrition and lifestyle) and the molecular events that lead to metabolic syndrome, inflammation, and cardiovascular diseases. Here we review recent adipokine research, with particular attention to the roles of adiponectin, leptin, resistin, visfatin, apelin, omentin, and chemerin in such conditions.

Topics: Adipokines; Cardiovascular Diseases; Cardiovascular System; Chemokines; Cytokines; Humans; Leptin; Nicotinamide Phosphoribosyltransferase; Obesity; Resistin

The adipose-derived hormone leptin is well known for its function in the control of energy homeostasis. Recent studies suggest a novel role for this adipokine in the regulation of mood and emotion. Low levels of leptin have been found to be associated with depressive behaviors in rodents and humans. Pharmacological studies indicate that leptin has antidepressant-like efficacy. Both leptin insufficiency and leptin resistance may contribute to alterations of affective status. Identifying the key brain regions that mediate leptin's antidepressant activity and dissecting its intracellular signal transduction pathways may provide new insights into the pathogenesis of depression and facilitate the development of novel therapeutic strategies for the treatment of this illness.

Topics: Animals; Biogenic Monoamines; Depression; Humans; Hypothalamo-Hypophyseal System; Leptin; Mood Disorders; Nerve Growth Factors; Obesity; Pituitary-Adrenal System; Receptors, Leptin

The prevalence of obesity is rising dramatically in developed and developing countries. Obesity contributes to increased mortality from numerous causes, but the most important of these is cardiovascular death. The relationship between obesity and atherogenesis is multifactorial, including alterations in the composition and level of lipoproteins, changes in blood pressure, and changes in circulating coagulation and inflammatory factors. Mouse models can be useful for dissecting selected aspects of this complex relationship. One area in which these models can be of particular value is in investigating the effect of secretory products of adipose tissue on the vessel wall. Adipocytes and adipose tissue secrete numerous factors and their level of expression is altered in obese states. Adipose tissue and adipocytes produce adiponectin, resistin, leptin, and apolipoproteins (serum amyloid A and apoE); all of which can directly impact vessel wall homeostasis. Mouse models utilizing deletion or overexpression of many of these factors have demonstrated an important impact of these on vessel wall homeostasis. Subsequent to the development of obesity, factors secreted from adipose tissue have also been shown to have direct effect on liver production of systemic inflammatory factors. Mouse models have validated the importance of angiotensin II, TNFalpha, and MCP-1 for impacting vessel wall health in obese states. In summary, excess adipose tissue produces myriad changes in organismal homeostasis with potential impact on the vessel wall. The power of mouse genetics permits targeted mechanistic investigation for understanding how obesity accelerates atherosclerosis in a complex in vivo milieu.

Topics: Adipose Tissue; Animals; Blood Vessels; Endothelium, Vascular; Humans; Leptin; Mice; Obesity

The global epidemic of obesity and type-2 diabetes mellitus (T2DM) has highlighted the need for new therapeutic approaches. The association of insulin resistance with these disorders and the knowledge that insulin receptor signaling is mediated by tyrosine (Tyr) phosphorylation have generated great interest in the regulation of the balance between Tyr phosphorylation and dephosphorylation. Several protein Tyr phosphatases (PTPs) have been implicated in the regulation of insulin action, with the most convincing data for PTP1B. Murine models targeting PTP1B, PTP1B(-/-)mice, demonstrate enhanced insulin sensitivity without the weight gain seen with other insulin sensitizers such as peroxisome proliferator-activated receptor gamma (PPARgamma) agonists, probably due to a second action of PTP1B as a negative regulator of leptin signaling. Despite intensive efforts and recent progress, a safe, selective and efficacious PTP1B inhibitor has yet to be identified.

Topics: Animals; Diabetes Mellitus, Type 2; Drug Design; Humans; Insulin; Insulin Resistance; Leptin; Obesity; Protein Tyrosine Phosphatase, Non-Receptor Type 1; Protein Tyrosine Phosphatase, Non-Receptor Type 11; Protein Tyrosine Phosphatase, Non-Receptor Type 2; Receptor-Like Protein Tyrosine Phosphatases, Class 2; Receptor, Insulin; Signal Transduction; Structure-Activity Relationship; Substrate Specificity

Unique genetic traits appear to play a role in the increased rates of hypertension (HTN), glucose dysregulation/diabetes (T2DM), and obesity in persons of African descent. Indeed, with increasing rates of westernization/urbanization and concomitant increases in obesity and T2DM, a similar predisposition to the cardiometabolic syndrome and cardiovascular disease (CVD) can be seen in Africans compared with persons of African descent, with CVD reaching epidemic proportions in many areas of Africa. In addition, the complex relationships of metabolic abnormalities that are unique to individuals of African descent have also been demonstrated in Africans. These include: (1) a dissociation of HTN to insulin resistance; (2) relative favorable lipid profile in the setting of increasing rates of CVD; (3) low levels of visceral adiposity in the setting of obesity and insulin resistance; and (4) a dissociation of insulin sensitivity and adiponectin when compared with Caucasians. Although not well understood, these unique relationships suggest that conventional parameters for CVD do not apply to Africans of persons of African descent.

Topics: Adiponectin; Africa; Diabetes Mellitus, Type 2; Dyslipidemias; Genetic Predisposition to Disease; Humans; Hypertension; Insulin Resistance; Leptin; Life Style; Metabolic Syndrome; Obesity; Risk Factors

Reduction in sleep time has become an endemic condition in modern society and current literature has found important epidemiological associations between damage in the habitual standard of sleep and obesity. On this basis, the present revision analyzed the role of sleep and its alteration in the promotion of obesity. Diverse studies indicate that subjects that sleep less have greater possibility of becoming obese, and the shortening of sleep increases the leptin/ghrelin reason, generating increase of the appetite and hunger. This can be associated to the biggest caloric intake and promotion of obesity. An adequate standard of sleep becomes basic for the regulation of body mass and must be stimulated by health professionals.

Topics: Appetite; Body Mass Index; Feeding Behavior; Ghrelin; Humans; Hunger; Leptin; Obesity; Sleep; Time Factors

The metabolic syndrome refers to the clustering of upper body obesity, atherogenic dyslipidemia, insulin resistance and elevated blood pressure. Both, obesity and metabolic syndrome, have the potential to influence on the incidence and severity of cardiovascular disease with serious implications for worldwide health care systems. Obesity plays a central role in the development of insulin resistance and dyslipidemia through the mediation of a pro-inflammatory and pro-thrombotic state. Adipose tissue has been shown to exert important endocrine and immune functions. Pathogenesis of obesity associated metabolic syndrome is mediated by disturbed production and release of biologically active molecules by fat cells and other cells infiltrating fat tissue. In obese subjects synthesis of several bioactive compounds--adipokines and cytokines/chemokines by adipose tissue cells is dysregulated. Those bioactive molecules participate in regulation of apetite and energy homeostasis, lipid metabolism (tumour necrosis factor alpha--TNF-alpha), insulin sensitivity (TNF-alpha, adiponectin, resistin, visfatin) immunity (monocyte chemoattractant protein-1--MCP-1, TNF-alpha, IL-6), angiogenesis, blood pressure and hemostasis (plasminogen activator inhibitor--PAI-1). The effects of major pro-/anti-inflammatory and pro-thrombotic adipokines on several physiological processes will be discussed in this review. Also, an evidence-based approach to the laboratory diagnosis and treatment of metabolic syndrome will be presented.

Topics: Adiponectin; Cardiovascular Diseases; Complement Factor D; Humans; Inflammation; Interleukin-6; Leptin; Metabolic Syndrome; Models, Biological; Nicotinamide Phosphoribosyltransferase; Obesity; Plasminogen Activator Inhibitor 1; Resistin; Risk; Thrombosis; Tumor Necrosis Factor-alpha

Obesity is an independent risk factor for cardiovascular diseases. As the first obese gene product identified, leptin participates in many physiological processes. Besides its well known effects on food intake and energy metabolism, leptin has been shown to regulate cardiovascular function, glucose and lipid metabolism. Although the precise role of leptin on cardiac health is still at large, the peptide may initiate both hypertrophic and anti-hypertrophic effects on hearts. Circulating leptin levels are believed to correlate closely with body mass index (BMI) and total amount of body fat, and predict change of heart morphology and function. This is evidenced by that fact that compromised cardiac function is present in both hyperleptinemic (db/db) and hypoleptinemic (ob/ob) mouse models. Leptin replenishment may reconcile depressed cardiac contractile function in ob/ob mice, indicating the permissive effect of leptin on cardiac function. Multiple signal pathways including NO, Jak/STAT, p38 MAP kinase, ET-1 and NADPH oxidase have been implicated to participate in the cardiac regulatory response of leptin. In addition, elevated plasma leptin levels are speculated to be an independent risk factor for cardiovascular diseases such as hypertension and myocardial infarction. The current dogma indicates that physiological range of leptin may be essential for normal cardiomyocyte structure and function whereas disrupted leptin signaling due to too much or too little leptin may trigger functional and morphological alterations leading to cardiac dysfunction.

Topics: Animals; Appetite Regulation; Energy Metabolism; Heart; Heart Diseases; Humans; Insulin; Leptin; Models, Biological; Myocardial Contraction; Obesity; Physical Fitness; Receptors, Leptin; Signal Transduction

Obesity is considered one of the risk factors for metabolic disorders such as diabetes mellitus. There is increasing evidence that obesity and diabetes are under the control of numerous cytokines and hormones, such as adiponectin and leptin. In addition, a number of studies have revealed that the brain functions play a role in the development of obesity and diabetes mellitus. Histamine and its receptors are classical inflammatory mediators in peripheral tissues and also function in the brain. The results of physiological and pharmacological studies revealed that brain histamine and its receptors are involved in the regulation of obesity and diabetes mellitus. Leptin has been shown to regulate obesity and diabetes partially via brain histamine and its receptors. In this review, we focused on the roles of brain histamine and its receptors in regulating obesity and diabetes mellitus.

Topics: Animals; Brain; Diabetes Mellitus; Glucose; Histamine; Homeostasis; Humans; Leptin; Models, Biological; Neurons; Obesity; Receptors, Histamine

Obesity is an increasing health problem not only in the industrialized western countries but, also in the developing countries like India. The adipose tissue specific obese (ob) gene and its peptide product leptin were discovered in 1994. Leptin binding to specific receptors in the hypothalamus results in altered expression of orexigenic and anorexigenic neuropeptides that regulate neuroendocrine functions and energy homeostasis. Recent patents and experimental evidence suggest that leptin plays an important role in the pathogenesis of obesity and eating disorders. Central leptin action also includes regulation of blood pressure, bone mass, and immune function. Peripherally also, leptin plays an important role in direct regulation of immune cells, pancreatic beta cells, adipocytes and muscle cells. Leptin receptors are present on human endothelial cells, and it has been shown to induce angiogenesis both in vitro and in vivo. Further, leptin appears to be a potential pressure and volume regulating factor and may function pathophysiologically as a common link to obesity and hypertension. Obesity is also a risk factor for several other cardiovascular diseases like myocardial hypertrophy, myocardial infarction, coronary atherosclerosis and increased cardiovascular morbidity and mortality. Recent progress in understanding central and peripheral leptin receptor signaling pathways may provide potential new targets to combat obesity, hypertension etc.

Topics: Amino Acid Sequence; Cardiovascular System; Humans; Leptin; Models, Biological; Obesity

Although obesity has been consistently linked to an increased risk of several malignancies, including cancers of the colon, gallbladder, kidney, and pancreas, its role in prostate cancer etiology remains elusive. Data on the association between obesity and prostate cancer incidence are inconsistent, and in some studies obesity is associated with an increase in risk of high-grade prostate cancer but with a decrease in risk of low-grade tumors. In contrast, obesity has been consistently associated with an increased risk of prostate cancer aggressiveness and mortality. The differential effects of obesity on subtypes of prostate cancer suggest etiologic heterogeneity in these tumors and complex interactions between androgen metabolism and several putative risk factors, including insulin resistance, diabetes, inflammation, and genetic susceptibility, on prostate cancer risk. Data on the role of abdominal obesity, insulin resistance, and metabolic syndrome in prostate cancer etiology are limited. Obesity has been shown to be associated with a state of low-grade chronic inflammation, and insulin resistance and the metabolic syndrome are associated with adverse metabolic profiles and with higher circulating concentrations of inflammation-related markers, including leptin, interleukin-6, and tumor necrosis factor-, many of which have been shown to enhance tumor growth. Thus, whether obesity and metabolic syndrome modulate the risk of prostate cancer through chronic inflammation needs to be investigated further. Given that the prevalence of obesity and metabolic syndrome is increasing worldwide and that the world population is aging, the roles of obesity and metabolic syndrome in prostate carcinogenesis warrant further clarification.

Topics: Abdominal Fat; Body Mass Index; Humans; Inflammation; Leptin; Male; Metabolic Syndrome; Obesity; Prostatic Neoplasms; Risk Factors; Somatomedins

The growing population of overweight humans threatens both industrialized and developing countries and has been accompanied by obesity-related disorders, including type II diabetes, hypertension, cardiovascular pathology and nonalcoholic fatty liver disease. Recent researches have demonstrated that intestinal microbiota may be associated with the host's obesity. There were researches on the interaction between Bacteroides thetaiotaomicron and the energy metabolism of the host. Methanobrevibacer smithii had been improved to impact the host's energy metabolism through modulating the gene transcription of B. thetaiotaomicron. The microbiota can direct the host to increase hepatic production of triglycerides, promote storage of triglycerides in adipocytes through suppression of intestinal expression of a circulating LPL inhibitor, and have an effect on the host's energy deposition through the interaction with host's hormones (eg. Leptin) . Some metabolic products of the microbiota like SCFAs, other organic acids, alcohols and gases can be used by the host directly. Researches mentioned above are just started. According to the results above, some key points remain unknown. For example, the underlying mechanism of the interaction between microbiota or some unique microbes and the host, the procedure of dietary polysaccharides degradation of the microbes, and the relationship between the microbiota and the host's hormones. In this paper, the corresponding research results of author' s lab has also been reviewed and the future research prospect s have been summarized.

Topics: Angiopoietin-Like Protein 4; Angiopoietins; Animals; Bacteria; Energy Metabolism; Humans; Intestines; Leptin; Methane; Obesity; Triglycerides

Leptin a cytokine protein secreted by adipose tissue raises considerable interest as a potential mediator of the protective effects of fat mass on bone tissue. After menopause heavier women conserve bone mass better than those with lower body weight. The protective effect of obesity on bone mass has been ascribed to a high body fat content. As Leptin levels reflect the body fat content it has emerged as a possible mediator of these protective effects.. A search of the available literature focused on the role of leptin on bone tissue.. Both peripheral and central action of leptin on bone metabolism have been proposed. In vitro and in vivo evidence supports the hypothesis that leptin can act directly or indirectly on bone remodelling by modulating both osteoblast and osteoclast activities. However, studies in humans have not yet been able to confirm these actions possibly because of the shifting balance between stimulatory direct action and suppressive indirect action of leptin on bones via the hypothalamus. The effects of oestrogen decline and deficiency during natural or artificially induced menopause and administration of hormone replacement therapy has on leptin production remains controversial. Various studies have shown differences in leptin values in pre- and postmenopausal women. The existing clinical data on this issue are discordant.. Larger clinical studies are necessary to clarify leptin's role in vivo and to assess the contribution of the central and peripheral role of leptin in the overall maintenance of bone turnover in human beings.

Topics: Bone and Bones; Female; Humans; Leptin; Obesity; Osteoporosis, Postmenopausal; Postmenopause

Obesity is a chronic metabolic disorder that affects one third of American adults. Modest weight losses of just 5% to 10% of body weight, which are achievable with lifestyle modification and pharmacotherapy, can lead to remarkable improvements in many obesity-associated co-morbidities, including dyslipidemia, hypertension, and type 2 diabetes. In this review, the indications for pharmacotherapy and the goals of treatment are discussed, and current and future pharmacologic approaches to the treatment of obesity are examined. Current pharmacologic therapies for obesity are limited, but recent advances in our understanding of the complex and overlapping endocrine pathways that regulate body weight have led to new opportunities for antiobesity drug development. Important drug targets that are highlighted in this review include adipocyte-derived hormones, hypothalamic neuropeptides, and gastrointestinal hormones.

Topics: Amyloid; Anti-Obesity Agents; Appetite Depressants; Body Weight; Chronic Disease; Comorbidity; Cyclobutanes; Exenatide; Gastrointestinal Hormones; Humans; Islet Amyloid Polypeptide; Lactones; Leptin; Metformin; Obesity; Orlistat; Peptides; Piperidines; Pyrazoles; Randomized Controlled Trials as Topic; Rimonabant; Venoms

Topics: Ghrelin; Helicobacter Infections; Helicobacter pylori; Humans; Leptin; Obesity; Risk Factors

Millions of people worldwide suffer from type 2 diabetes mellitus. There are two major factors that play a role in its pathogenesis: insulin resistance and impaired secretion of insulin by beta-cells. Impaired insulin action is closely linked to the phenomenon of obesity. The adipose tissue releases free fatty acids but also hormones and cytokines such as leptin, adiponectin, resistin, TNF-alpha and others. All those particles modify insulin action. This review article summarizes contemporary opinions on the role of obesity in the generation of resistance to insulin and subsequently impaired glucose tolerance as well as overt type 2 diabetes mellitus.

Topics: Adiponectin; Adipose Tissue; Blood Glucose; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Insulin; Insulin Resistance; Leptin; Metabolic Syndrome; Obesity; Resistin; Tumor Necrosis Factor-alpha

The prevalence of obesity has markedly increased over the past two decades, especially in the industrialized countries. While the impact of excess body weight on the development of cardiac disease and diabetes has been well documented, the link between obesity and carcinogenesis is just being recognized. This review will focus on the link between leptin, a cytokine that is elevated in obese individuals, and cancer development. First, we briefly discuss the biological functions of leptin and its signaling pathways. Then, we summarize the effects of leptin on different cancer types in experimental cellular and animal models. Next, we analyze epidemiological data on the relationship between obesity and the presence of cancer or cancer risk in patients. Finally, leptin as a target for cancer treatment and prevention will be discussed.

Topics: Animals; Cell Proliferation; Humans; Leptin; Metabolism; Neoplasms; Obesity; Risk Factors; Signal Transduction

Obesity is a risk factor for many diseases. Thirty per cent of Americans are viewed as super obese; therefore, we need to find a solution. We already know about the diseases associated with obesity such as high blood pressure, diabetes, sleep apnoea, etc. Lately, there has been an increased interest in understanding if cancer is related to obesity. In this paper, we review the incidence of colon cancer and obesity. Insulin is the best established biochemical mediator between obesity and colon cancer. Hyperinsulinaemia, such as occurs in type II diabetes, is important in the pathogenesis of colon cancer. All adipose tissue is not equal. Visceral abdominal fat has been identified as the essential fat depot for pathogenetic theories that relate obesity and colon cancer. The genders differ as regards to how the relationship between obesity and colon cancer has been evaluated. Obesity imposes a greater risk of colon cancer for men of all ages and for premenopausal women than it does for postmenopausal women. Regular exercise reduces the risk of developing colon cancer and the risk of death from colon cancer should it develop. We believe that a combination of waist circumference (WC) and body mass index (BMI) measurements is recommended to assess the obesity related risk of developing colon cancer. Radiographic assessments of visceral abdominal fat may eventually prove to be the best means of assessing a patient's obesity related risk of developing colon cancer. Although WC is better established as a measure of obesity than BMI, the evidence for colon cancer risk is not secure on this point; combining BMI and WC measurements would appear, at present, to be the wisest approach for colon cancer risk assessment. Doctors who wish to decrease their patients' risk of dying of colon cancer should advise weight loss and exercise. Conversely, physicians and public health authorities should consider both exercise and obesity when designing colon cancer screening protocols. Morphometric cut offs should be adjusted, if possible, for age, sex, ethnicity, and height.

Topics: Adipose Tissue; Colonic Neoplasms; Exercise; Female; Humans; Insulin; Leptin; Male; Menopause; Obesity; Risk Factors; Sex Factors

This paper sets out to review the implication of the melanocortin system in regulating feeding behavior and energy balance during short- and long-term food deprivation. It is discussed in relation to: (1) body fat exhaustion and the known enhanced drive for refeeding in late fasting and (2) peripheral hormonal status with emphasis on the effect of leptin administration on melanocortin gene expression according to fat store mobilization.

Topics: Animals; Energy Metabolism; Fasting; Leptin; Melanocyte-Stimulating Hormones; Obesity; Rats; Signal Transduction

This paper reviews aspects of our research, focusing on the role of the melanocortin system in the central regulation of feeding and energy balance, which was begun in 1997. It describes data from successive physiological studies, concerning the identity of the appetite-regulating melanocortin receptor, melanocortin-4 receptor (MC4R) regulation with altered nutritional status, the role of MC4R in dietary obesity and the identity of the endogenous MC4R ligand.

Topics: Animals; beta-MSH; Hypothalamus; Leptin; Obesity; Rats; Receptor, Melanocortin, Type 4; Satiety Response; Signal Transduction

Hypothalamic neuronal histamine and its H(1) receptor (H(1)-R) form part of the leptin signaling pathway in the brain, and regulate body weight and adiposity by affecting food intake and energy expenditure. The pro-opiomelanocortin (POMC)-melanocortin 4 receptor (MC4-R) is also important for leptin signaling. We investigated whether and how these two neuronal pathways interact in regulating energy metabolism. From studies of agouti yellow (A(y)/a) obese mice, a model of a defect in POMC-MC4-R signaling, we concluded that the histamine H(1)-R signaling pathway is independent of the POMC-MC4-R complex in regulating food intake, energy metabolism, and adiposity.

Topics: Animals; Appetite Regulation; Energy Metabolism; Feeding Behavior; Histamine; Leptin; Melanocyte-Stimulating Hormones; Mice; Neurons; Obesity; Pro-Opiomelanocortin; Rats; Receptor, Melanocortin, Type 4; Receptors, Histamine H1

Obesity-associated prostate cancer (PCa) remains controversial, although most studies rely on body mass index evaluation, which is an indirect measure of fatness. Studies using body fat measurement and disease stratification according to PCa stage found stronger associations between obesity and PCa. Leptin is a pleiotrophic hormone mainly synthesized by adipocytes that acts in peripheral organs such as the prostate. This article reviews obesity-associated leptin's pathophysiological role in PCa progression. PCa development results from some known risk factors. Currently, there is enough evidence suggesting that leptin is an additional factor involved in advanced PCa occurrence, and obesity association with high-grade disease. Life-long exposure to genetic and/or environmental susceptibility factors that predispose to obesity and higher leptin levels may increase the risk for advanced PCa.

Topics: Chemoprevention; Humans; Leptin; Male; Obesity; Prostatic Neoplasms; Signal Transduction

An interactive network comprised of neuropeptide Y (NPY) and cohorts is obligatory in the hypothalamic integration of appetite and energy expenditure on a minute-to-minute basis. High or low abundance of NPY and cognate receptors dysregulates the homeostatic milieu engendering hyperphagia, decreased energy expenditure, obesity and attendant metabolic syndrome cluster of dyslipidemia, glucose intolerance, insulin resistance and hyperinsulinemia, risk factors for type II diabetes and cardiovascular diseases. Increasing the supply of the endogenous repressor hormone leptin locally in the hypothalamus with the aid of leptin gene therapy, blocked age-related and dietary obesities, and the sequential development of dyslipidemia, hyperglycemia, and insulin resistance. Thus, sustained repression of NPY signaling with increased leptin selectively in the hypothalamus can avert environmental obesity and the risks of metabolic diseases.

Topics: Animals; Dyslipidemias; Genetic Therapy; Humans; Hypothalamus; Insulin Resistance; Leptin; Metabolic Syndrome; Neuropeptide Y; Obesity

Leptin is a recently isolated circulating peptide hormone that is primarily synthesized and secreted by adipocytes. One of the major functions of this hormone is the control of energy balance by binding to receptors in the hypothalamus, leading to reduction in food intake, elevation in temperature and energy expenditure. In addition, increasing evidence suggests that leptin, through both direct and indirect actions, may play an important role in cardiovascular and renal functions. While the relevance of endogenous leptin needs further clarification, it appears to be a potential pressure- and volume-regulating factor, and may function pathophysiologically as a common link to obesity and hypertension.

Topics: Animals; Hemodynamics; Humans; Hypertension; Kidney; Leptin; Obesity; Receptors, Cell Surface; Receptors, Leptin; Sympathetic Nervous System

Interactions between our conserved 'thrifty genotype' and current trends toward reduced physical activity and increased food intake are posited as the root cause of the rising prevalence of obesity in the modern era. The past decade has seen tremendous advances in our understanding of the physiological regulation of energy balance and adiposity, and important insights into the pathogenesis of obesity. We have gained a more comprehensive view of the energy homeostasis system from the discovery of the adiposity hormone leptin, the subsequent identification of hypothalamic and other brain neuropeptide systems controlling energy balance, and the progress in understanding the molecular mechanisms by which cells can sense and respond to changes in metabolic state. Numerous targets have been identified for potential pharmacological and genetic approaches to obesity management. Some of the most recent developments are prototypic compounds that manipulate fat metabolism, both in peripheral tissues and in the brain, to reduce body fat synthesis and storage and to increase fat oxidation, to reduce food intake, and to increase energy expenditure.

Topics: Adipose Tissue; Animals; Energy Intake; Feeding Behavior; Homeostasis; Humans; Hypothalamus; Leptin; Lipid Peroxidation; Mice; Motor Activity; Neurons; Obesity; Signal Transduction

Excess adiposity over the pre- and postmenopausal years is linked to risk of postmenopausal breast cancer. Weight loss could potentially reduce risk amongst those with excess weight via beneficial effects on the hormonal (decreased circulating levels of oestradiol, testosterone, insulin) and secretory profiles of adipocytes (decreased production of leptin, tumour necrosis factor-alpha, interleukin 6 and increased production of adiponectin). Only modest reductions in adipose tissue are achieved and sustained with current weight loss programmes, which makes strategies to mitigate the adverse metabolic effect of adiposity a priority for cancer prevention. The adverse hormonal and secretory effects of adipose tissue are influenced substantially by acute changes in energy balance prior to changes in adiposity. Human and animal studies have shown dietary energy restriction to bring about favourable changes in circulating levels of insulin, leptin, sex hormone binding globulin, insulin-like growth factor-1, oestradiol, testosterone, reactive oxygen species, and the production and secretion of locally acting adipokines and inflammatory cytokines, that is, increased adiponectin and decreased interleukin-6. Achieving and sustaining energy restriction remains a difficult challenge. Intermittent energy restriction is a potential strategy for promoting periods of energy restriction on a long-term basis. Animal and human data suggest that intermittent energy restriction may have cancer preventative effects beyond that of chronic energy restriction and weight loss. Intermittent energy restriction may be a potential strategy for the primary prevention of breast cancer.

Topics: Adiponectin; Adipose Tissue; Androgens; Animals; Breast Neoplasms; Cytokines; Energy Intake; Energy Metabolism; Female; Gonadal Steroid Hormones; Humans; Insulin; Insulin-Like Growth Factor I; Leptin; Obesity; Oxidation-Reduction; Reactive Oxygen Species; Sex Hormone-Binding Globulin

Most obese subjects exhibit leptin resistance, thus restricting the value of direct leptin administration for treatment of obesity. Understanding the leptin signalling mechanism has become crucial for design of novel therapeutic strategies for leptin-resistant/obese patients. The SH2-containing cytoplasmic tyrosine phosphatase Shp2 has recently been shown to play a critical role in leptin signalling and functions in hypothalamic control of energy balance and metabolism. Shp2 appears to downregulate the LepRb-STAT3 pathway while promoting extracellular-regulated kinase activation by leptin. Overall, Shp2 is a leptin signal enhancer, as evidenced by the obese and hyperleptinemic phenotype of mutant mice with Shp2 deleted in postmitotic forebrain neurons. Pharmaceutical enhancement of Shp2 activity may be a new approach worthy of consideration in clinical treatment of leptin resistance and obesity. This article discusses the significance of recent experimental data on Shp2 and also the prospects for using Shp2 as a therapeutic target for obese patients.

Topics: Animals; Anti-Obesity Agents; Drug Delivery Systems; Drug Resistance; Humans; Intracellular Signaling Peptides and Proteins; Leptin; Obesity; Protein Tyrosine Phosphatase, Non-Receptor Type 11; Protein Tyrosine Phosphatases

Prostate cancer, the third most common cancer in men worldwide, varies substantially according to geographic region and race/ethnicity. Obesity and associated endocrine variation are foremost among the risk factors that may underlie these regional and ethnic differences. The association between obesity and prostate cancer incidence is complex and has yielded inconsistent results. Studies that have linked obesity with prostate cancer mortality, advanced stage disease, and higher grade Gleason score, however, have produced more consistent findings, indicating that obesity may not necessarily increase the risk of prostate cancer, but may promote it once established. Additionally, metabolic syndrome, which includes disturbed glucose metabolism and insulin bioactivity, may also be associated with prostate carcinogenesis. Adipokines, defined as biologically active polypeptides produced by adipose tissue, have been linked with a number of carcinogenic mechanisms, including angiogenesis, cell proliferation, metastasis, and alterations in sex-steroid hormone levels. A number of emerging studies have implicated the role of adipokines in prostate carcinogenesis. This review explores the specific roles of several adipokines as putative mediating factors between obesity and prostate cancer with particular attention to leptin, interleukin-6 (IL-6), heparin-binding epidermal growth factor-like growth factor (HB-EGF), vascular endothelial growth factor (VEGF) and adiponectin.

Topics: Adipose Tissue; Epidermal Growth Factor; Heparin-binding EGF-like Growth Factor; Humans; Intercellular Signaling Peptides and Proteins; Interleukin-6; Leptin; Male; Obesity; Prostatic Neoplasms; Risk Factors; Vascular Endothelial Growth Factor A

Recent discoveries, notably of the hormones leptin and adiponectin, have revised the notion that adipocytes are simply a storage depot for body energy. Instead, adipocytes are also endocrine organs, with multiple metabolic roles in regulating whole-body physiology. Small adipocytes in lean individuals promote metabolic homeostasis; the enlarged adipocytes of obese individuals recruit macrophages and promote inflammation and the release of a range of factors that predispose toward insulin resistance. Exercise activates the AMP-activated protein kinase (AMPK) in muscle and other tissues, a pathway that increases fat oxidation and glucose transport. Importantly, the adipocyte hormones leptin and adiponectin also activate AMPK; remarkably, the same pathway is activated by certain antidiabetic agents such as thiazolidinediones. Increasingly, our understanding of the adipocyte as an endocrine organ is leading to new insights into obesity and health.

Topics: Adipocytes; Adiponectin; Adipose Tissue; Animals; Energy Metabolism; Humans; Inflammation; Leptin; Obesity

Obesity and its related metabolic diseases, including type 2 diabetes, are associated with alterations in the circulating levels of various peptides. These include the adipocytokines (peptides released by adipocytes which circulate, such as leptin, adiponectin and resistin), and other peptides whose levels are altered in association with obesity (such as ghrelin, neuropeptide Y, interleukin-1 beta and tumour necrosis factor-alpha). While the primary action of these peptides is linked with the regulation and maintenance of energy balance and metabolism, many of them have also been shown to possess vasoactive, inflammatory and other properties that influence vascular biology, vascular physiology and atherogenesis. As such, they may form an important mechanistic link between obesity and cardiovascular disease. In this review, we will outline the vasoactive properties of adipocytokines and other obesity-related peptides. In particular, as pharmacotherapies suggested to achieve weight loss will alter the pathways associated with these peptides, such treatments might have either beneficial or deleterious effects on the incidence and progression of cardiovascular disease.

Topics: Adiponectin; Adipose Tissue; Atherosclerosis; Diabetes Mellitus, Type 2; Ghrelin; Humans; Leptin; Muscle, Smooth, Vascular; Obesity; Peptide Hormones

Several adipose-derived cytokines (adipokines) have been suggested to act as a link between accumulated fat mass and altered insulin sensitivity. Resistin and tumour necrosis factor-alpha (TNF-alpha) have been implicated in impairing insulin sensitivity in rodents; conversely, two other adipokines, leptin and adiponectin, increase insulin sensitivity in lean and obese rodents. Currently, there is considerable focus on the concept that lipid accumulation in skeletal muscle leads to the development of insulin resistance. Adiponectin and leptin have each been demonstrated to increase rates of fatty acid (FA) oxidation and decrease muscle lipid content, which may in part be the underlying mechanism to their insulin sensitizing effect. These effects on FA metabolism appear to be mediated in part through the activation of AMP-activated protein kinase. Evidence derived from animal and human studies suggests that the ability of leptin and adiponectin to stimulate FA oxidation in muscle is impaired in the obese condition. Thus, leptin and adiponectin resistance may be an initiating factor in the accumulation of intramuscular lipids, such as diacylglycerol and ceramide, and the ensuing development of insulin resistance. Lifestyle factors such as diet and exercise are able to restore the sensitivity of muscle to leptin. The actual physiological roles of resistin and TNF-alpha in altering muscle lipid metabolism are more controversial, but each has been shown to directly impair insulin signalling and consequently, insulin stimulated glucose uptake in muscle. However, the possibility that resistin and TNF-alpha reduces insulin sensitivity in muscle by directly impairing FA metabolism in this tissue leading to lipid accumulation, has been virtually unexamined. Thus, the contribution of various adipokines to the development of insulin resistance is complex and not fully understood. Finally, the effects of these adipokines on metabolism and insulin sensitivity are generally studied in isolation, making it difficult to predict the interactive effects and the net impact on insulin sensitivity.

Topics: Adiponectin; Animals; Fatty Acids; Glucose; Humans; Insulin; Insulin Resistance; Leptin; Muscle, Skeletal; Obesity; Oxidation-Reduction; Peptide Hormones; Rats; Receptors, Cell Surface; Resistin; Tumor Necrosis Factor-alpha

Topics: Animals; Fatty Liver; Humans; Leptin; Mice; Obesity

Topics: Animals; Brain; Cytokines; Hypothalamo-Hypophyseal System; Interleukin-1; Leptin; Mice; Obesity; Pituitary-Adrenal System; Receptors, Cell Surface; Receptors, Leptin

A series of epidemiological, clinical and experimental studies have shown that there are associations between the fetal and neonatal nutritional environment and the amount and distribution of adipose tissue in adult life. This review considers the evidence for these relationships and discusses the potential impact of the prenatal nutritional experience on the development of the endocrine and neuroendocrine systems that regulate energy balance, with a particular emphasis on the role of the adipocyte-derived hormone, leptin. In the rodent, leptin derived from the mother may exert an important influence on the development of the appetite regulatory neural network and on the subsequent regulation of leptin synthesis and the risk for obesity in the offspring. In species such as the human and sheep, there is also recent evidence that the synthesis and secretion of adipocyte-derived hormones, such as leptin, are regulated in fetal life. Furthermore, the hypothalamic neuropeptides that regulate energy intake and expenditure in adult life are also present within the fetal brain and may be regulated by the prevailing level of maternal and hence fetal nutrient and hormonal signals, including leptin. This work is important in determining those initiating mechanisms within the 'fat-brain' axis in early life that precede the development of adult obesity.

Topics: Adipocytes; Adult; Animals; Appetite Regulation; Female; Fetus; Humans; Infant Nutritional Physiological Phenomena; Infant, Newborn; Leptin; Maternal Nutritional Physiological Phenomena; Obesity; Pregnancy; Prenatal Exposure Delayed Effects

Obesity is a major health problem. It increases the risk of cardiovascular diseases, 2-type diabetes mellitus, cancers, and premature mortality. Apart from some monogenic forms, it's a polygenic disorder, the result of interaction of genes and environmental factors. Genetic variants of proteins taking part in the regulation of food intake or thermogenesis and tissue mediators produced by the adipose tissue are responsible the genetic components of obesity. Identification of the genetic background of the obesity will help to understand the exact molecular mechanism of the pathogenesis, make possible the prevention, as well as individual therapeutic interventions.

Topics: Animals; Carrier Proteins; Disease Models, Animal; Humans; Ion Channels; Leptin; Membrane Proteins; Mitochondrial Proteins; Obesity; PPAR gamma; Pro-Opiomelanocortin; Proprotein Convertase 1; Receptor, Melanocortin, Type 4; Receptors, Adrenergic, beta-3; Receptors, Cell Surface; Receptors, Leptin; Risk Factors; Uncoupling Protein 1

Epidemiological data indicate that obesity is a risk factor for incident asthma, and that obesity is also associated with increased asthma severity. Importantly, obesity antedates asthma. The observations that weight loss improves asthma and that obese mice have innate airway hyperresponsiveness and increased responses to asthma triggers also support a relationship between obesity and asthma. The basis for this relationship is unknown, but might be the result of common etiologies, comorbidities, effects of obesity on lung volume or adipokines. Understanding the mechanistic basis for the relationship between obesity and asthma could lead to new therapeutic strategies for treatment of this susceptible population.

Topics: Adiponectin; Adipose Tissue; Animals; Asthma; Body Weight; Comorbidity; Humans; Leptin; Mice; Mice, Obese; Obesity; Respiratory Function Tests; Risk Factors; Tumor Necrosis Factor-alpha

The endocannabinoid system has recently emerged as an important regulator of energy homeostasis, involved in the control of both appetite and peripheral fat metabolism. We briefly review current understanding of the possible sites of action and cellular mechanisms involved in the central appetitive and peripheral metabolic effects of endocannabinoids. Studies in our laboratory, using leptin-deficient obese rodents and CB1 cannabinoid receptor (CB1)-deficient mice, have indicated that endocannabinoids acting via CB1 are involved in the hunger-induced increase in food intake and are negatively regulated by leptin in brain areas involved in appetite control, including the hypothalamus, limbic forebrain and amygdala. CB1-/- mice are lean and are resistant to diet-induced obesity (DIO) despite similar energy intake to wild-type mice with DIO, suggesting that CB1 regulation of body weight involves additional peripheral targets. Such targets appear to include both adipose tissue and the liver. CB1 expressed in adipocytes has been implicated in the control of adiponectin secretion and lipoprotein lipase activity. Recent findings indicate that both endocannabinoids and CB1 are present in the liver and are upregulated in DIO. CB1 stimulation increases de novo hepatic lipogenesis through activation of the fatty acid biosynthetic pathway. Components of this pathway are also expressed in the hypothalamus where they have been implicated in the regulation of appetite. The fatty acid biosynthetic pathway may thus represent a common molecular target for the central appetitive and peripheral metabolic effects of endocannabinoids.

Topics: Animals; Appetite Regulation; Brain; Cannabinoid Receptor Modulators; Endocannabinoids; Energy Metabolism; Fatty Acids; Homeostasis; Humans; Leptin; Liver; Obesity; Receptor, Cannabinoid, CB1

Leptin, a 167-amino acid peptide hormone produced by white adipose tissue, is primarily involved in the regulation of food intake and energy expenditure. Leptin receptors are expressed in many tissues including the cardiovascular system. Plasma leptin concentration is proportional to body adiposity and is markedly increased in obese individuals. Recent studies suggest that hyperleptinemia may play an important role in obesity-associated cardiovascular diseases including atherosclerosis. Leptin exerts many potentially atherogenic effects such as induction of endothelial dysfunction, stimulation of inflammatory reaction, oxidative stress, decrease in paraoxonase activity, platelet aggregation, migration, hypertrophy and proliferation of vascular smooth muscle cells. Leptin-deficient and leptin receptor-deficient mice are protected from arterial thrombosis and neointimal hyperplasia in response to arterial wall injury. Several clinical studies have demonstrated that high leptin level predicts acute cardiovascular events, restenosis after coronary angioplasty, and cerebral stroke independently of traditional risk factors. In addition, plasma leptin correlates with markers of subclinical atherosclerosis such as carotid artery intima-media thickness and coronary artery calcifications. Inhibition of leptin signaling may be a promising strategy to slow the progression of atherosclerosis in hyperleptinemic obese subjects.

Topics: Adipose Tissue; Animals; Atherosclerosis; Humans; Leptin; Obesity; Oxidative Stress; Risk Factors

Histamine-containing neurons and histamine H1 receptors are distributed within the brain and peripheral tissues. The results of physiological and pharmacological studies have revealed that brain histamine and H1 receptors are involved in the regulation of feeding and obesity in rodents. The adipocytokine leptin regulates feeding and obesity, partially through brain histamine. Furthermore, recent studies have provided evidence that regulation of the diurnal rhythm of feeding through H1 receptors is a crucial factor in the development of obesity. Thus, the regulation of H1 receptors is important for the control of energy metabolism, feeding rhythms and obesity in rodents.

Topics: Animals; Brain; Circadian Rhythm; Feeding Behavior; Histamine; Histamine H1 Antagonists; Humans; Hypothalamus; Leptin; Obesity; Receptors, Histamine H1

Topics: Adipose Tissue; Adult; Body Mass Index; Exercise Therapy; Humans; Hypertension; Kidney Diseases; Leptin; Obesity; Racial Groups; Risk Factors; Treatment Outcome

Recent epidemiology demonstrates higher rate of obesity and metabolic syndrome in offspring with undernutrition in utero. IUGR babies with intrauterine undernutrition grow rapidly to catch up with normal growth course. Leptin is an adipocyte derived satiety factor that regulates food intake and energy expenditure. We demonstrated in mice model with maternal food restriction during pregnancy that premature leptin surge during neonatal catch up growth of the offspring lead them to impaired leptin sensitivity and obesity in adulthood.

Topics: Animals; Disease Models, Animal; Eating; Energy Intake; Female; Fetal Growth Retardation; Humans; Leptin; Malnutrition; Metabolic Syndrome; Obesity; Pregnancy; Pregnancy Complications

It now appears that, in most obese patients, obesity is associated with a low-grade inflammation of white adipose tissue (WAT) resulting from chronic activation of the innate immune system and which can subsequently lead to insulin resistance, impaired glucose tolerance and even diabetes. WAT is the physiological site of energy storage as lipids. In addition, it has been more recently recognized as an active participant in numerous physiological and pathophysiological processes. In obesity, WAT is characterized by an increased production and secretion of a wide range of inflammatory molecules including TNF-alpha and interleukin-6 (IL-6), which may have local effects on WAT physiology but also systemic effects on other organs. Recent data indicate that obese WAT is infiltrated by macrophages, which may be a major source of locally-produced pro-inflammatory cytokines. Interestingly, weight loss is associated with a reduction in the macrophage infiltration of WAT and an improvement of the inflammatory profile of gene expression. Several factors derived not only from adipocytes but also from infiltrated macrophages probably contribute to the pathogenesis of insulin resistance. Most of them are overproduced during obesity, including leptin, TNF-alpha, IL-6 and resistin. Conversely, expression and plasma levels of adiponectin, an insulin-sensitising effector, are down-regulated during obesity. Leptin could modulate TNF-alpha production and macrophage activation. TNF-alpha is overproduced in adipose tissue of several rodent models of obesity and has an important role in the pathogenesis of insulin resistance in these species. However, its actual involvement in glucose metabolism disorders in humans remains controversial. IL-6 production by human adipose tissue increases during obesity. It may induce hepatic CRP synthesis and may promote the onset of cardiovascular complications. Both TNF-alpha and IL-6 can alter insulin sensitivity by triggering different key steps in the insulin signalling pathway. In rodents, resistin can induce insulin resistance, while its implication in the control of insulin sensitivity is still a matter of debate in humans. Adiponectin is highly expressed in WAT, and circulating adiponectin levels are decreased in subjects with obesity-related insulin resistance, type 2 diabetes and coronary heart disease. Adiponectin inhibits liver neoglucogenesis and promotes fatty acid oxidation in skeletal muscle. In addition, adiponectin counteracts

Topics: Adiponectin; Adipose Tissue; Diabetes Mellitus, Type 2; Humans; Inflammation; Insulin Resistance; Interleukin-6; Leptin; Lipid Metabolism; Macrophages; Obesity; Resistin; Signal Transduction; Tumor Necrosis Factor-alpha

Adipose tissue is responsive to both central and peripheral metabolic signals and is itself capable of secreting a number of proteins. These adipocyte-specific or enriched proteins, termed adipokines, have been shown to have a variety of local, peripheral, and central effects. These secreted proteins, which include tumor necrosis factor (TNF)-alpha, resistin, IL-6, IL-8, acylation-stimulating protein (ASP), angiotensinogen, plasminogen activator inhibitor-1 (PAI-1) ("bad" adipokines) and leptin, adiponectin ("good" adipokines) seem to play important regulatory roles in a variety of complex processes, including fat metabolism, feeding behavior, hemostasis, vascular tone, energy balance, and insulin sensitivity, but none is without controversy regarding its respective mechanism and scope of action. The present review is focused on the effects of free fatty acids and a restricted number of adipokines, which have been implicated in vascular (angiotensinogen, PAI-1) and energy and glucose homeostasis (ASP, TNFalpha, IL-6, resistin, leptin, adiponectin).

Topics: Adipocytes; Adiponectin; Adipose Tissue; Anti-Obesity Agents; Cardiovascular Physiological Phenomena; Cytokines; Energy Metabolism; Fatty Acids, Nonesterified; Glucose; Homeostasis; Humans; Intercellular Signaling Peptides and Proteins; Leptin; Obesity; Peptide Hormones; Resistin

Asthma and obesity are prevalent disorders, each with a significant public health impact, and a large and growing body of literature suggests an association between the two. The systemic inflammatory milieu in obesity leads to metabolic and cardiovascular complications, but whether this environment alters asthma risk or phenotype is not yet known. Animal experiments have evaluated the effects of leptin and obesity on airway inflammation in response to both allergic and nonallergic exposures and suggest that airway inflammatory response is enhanced by both endogenous and exogenous leptin. Cross-sectional and prospective cohort studies of humans have shown a modest overall increase in asthma incidence and prevalence in the obese, although body mass index does not appear be a significant modifier of asthma severity. Studying the obesity-asthma relationship in large cohorts, in which self-reports are frequently used to ascertain the diagnosis of asthma, has been complicated by alterations in pulmonary physiology caused by obesity, which may lead to dyspnea or other respiratory symptoms but do not fulfill accepted physiologic criteria for asthma. Recent investigations toward elucidating a shared genetic basis for these two disorders have identified polymorphisms in specific regions of chromosomes 5q, 6p, 11q13, and 12q, each of which contains one or more genes encoding receptors relevant to asthma, inflammation, and metabolic disorders, including the beta(2)-adrenergic receptor gene ADRB2 and the glucocorticoid receptor gene NR3C1. Further research is warranted to synthesize these disparate observations into a cohesive understanding of the relationship between obesity and asthma.

Topics: Adipocytes; Animals; Asthma; Body Mass Index; Comorbidity; Compliance; Cytokines; Gonadal Steroid Hormones; Humans; Inflammation; Leptin; Obesity; Polymorphism, Genetic; Respiratory Hypersensitivity; Sex Factors

There is a growing worldwide epidemic of obesity. Obese people have a higher incidence of type 2 diabetes and cardiovascular disease, and hence present increasing social, financial and health burdens. Weight loss is always difficult to achieve through lifestyle changes alone, and currently licensed anti-obesity drug treatments, such as orlistat and sibutramine, if tolerated, only achieve modest weight loss. Therefore, there is a need to identify more potent pharmacological targets. In the last 10 years, discoveries of new hormones such as leptin and ghrelin, together with greater understanding of previously described hormones such as cholecystokinin (CCK), pancreatic polypeptide (PP), peptide YY (PYY) and glucagon-like peptide 1 (GLP-1), have led to a rapid increase in our knowledge of the regulation of energy balance. Among the most important factors, controlling appetite and satiety are peptide hormones released from the gut. In this paper, we provide a full up-to-date overview of the current state of knowledge of this field, together with the potential of these peptides as drugs, or as other therapeutic targets, in the treatment of obesity. Finally, we propose an integrated model to describe the complex interplay of these hormones in the broader physiology of energy balance.

Topics: Appetite Regulation; Cholecystokinin; Energy Metabolism; Gastrointestinal Hormones; Ghrelin; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Humans; Leptin; Obesity; Oxyntomodulin; Peptide Hormones; Peptide YY; Satiation

Topics: Adipose Tissue; Child; Child, Preschool; Disease Outbreaks; Energy Intake; Energy Metabolism; Environment; Exercise; Genetic Predisposition to Disease; Humans; Infant; Infant, Newborn; Leptin; Obesity; Primary Prevention

Topics: Adipocytes; Adiponectin; Animals; Diet, Atherogenic; Energy Metabolism; Exercise; Humans; Insulin Resistance; Leptin; Life Style; Metabolic Syndrome; Obesity; Tumor Necrosis Factor-alpha

Leptin is an adipocyte-secreted hormone which plays a key role in energy homeostasis. Recent advances in leptin physiology have revealed that the main role of this hormone in humans is to signal energy availability in energy-deficient states. Interventional studies in leptin deficient children and observational studies in normal girls and boys support a role for leptin as a permissive factor for the initiation of puberty in children. Moreover, recent "proof of concept" studies involving leptin administration to humans further support its critical role in regulating energy homeostasis, neuroendocrine and immune function as well as insulin resistance in states of energy/caloric deprivation. Leptin's potential role in the therapy of several disease states, including hypothalamic amenorrhea, anorexia nervosa and syndromes of insulin resistance is under intensive investigation.

Topics: Adolescent; Child; Energy Metabolism; Female; Homeostasis; Humans; Immunity; Infant, Newborn; Insulin Resistance; Leptin; Male; Mutation; Neurosecretory Systems; Obesity; Puberty

The obesity epidemic has focused attention on the endocrine function of adipose tissue. Adipose tissue secretes leptin, cytokines, complement factors, and components of the coagulation cascade, most of which are increased in obesity. In contrast, a strong negative correlation exists between adiponectin and adiposity, insulin sensitivity, diabetes, vascular inflammation, and atherosclerosis. Adiponectin treatment in rodents increases insulin sensitivity and reduces lipids and atherogenesis. Chronic and central adiponectin treatment reduces weight, glucose, and lipids. The insulin-sensitizing action of thiazolidinediones is mediated, in part, through adiponectin. A causal role of adiponectin in diabetes, dyslipidemia, and atherosclerosis has been established in knockout mice. Therefore, adiponectin seems to be a marker of obesity-related diseases and a potential therapeutic target.

Topics: Adipocytes; Adiponectin; Animals; Disease Models, Animal; Energy Metabolism; Homeostasis; Humans; Leptin; Mice; Mice, Knockout; Obesity

Histamine H3 receptors (H3Rs) are autoreceptors that negatively regulate the release of histamine and other neurotransmitters such as norepinephrine, dopamine, and acetylcholine in the central nervous system (CNS). Consistent with the wide-spread projection of histaminergic neurons from the lateral hypothalamus, H3Rs are widely distributed in the CNS and are believed to play a variety of physiological roles, including regulation of feeding, arousal, cognition, pain, and endocrine systems. To further understand the physiological roles of H3Rs in vivo, we produced H3R knockout (H3R-/-) mice and found that H3R-/- mice displayed hyperphagia and late-onset obesity associated with hyperinsulinemia and leptinemia, the fundamental marks of metabolic syndromes. A series of non-imidazole H3R antagonists/inverse agonists with improved selectivity and potency have been developed and were found to regulate feeding and body weight gain in laboratory animals. Taken together, these observations suggest that H3Rs are involved in the regulation of feeding behavior and body weight. Several H3R inverse agonists targeting cognitive disorders and dementia have entered clinical trials. These trials will give critical information about the physiological functions of H3Rs in humans.

Topics: Animals; Feeding Behavior; Histamine Antagonists; Hyperinsulinism; Hyperphagia; Leptin; Mice; Mice, Knockout; Obesity; Receptors, Histamine H3

Four mechanisms were reviewed to explain the possible association between sweetened beverages and increased overweight or obesity: excess caloric intake, glycemic index and glycemic load, lack of effect of liquid calories on satiety, and displacement of milk. The findings were inconsistent across studies. The strongest support was for the excess caloric intake hypothesis, but the findings were not conclusive. Assigning possible links between sweetened beverage consumption and adiposity requires research that compares and contrasts specific mechanisms, especially in populations at risk for obesity, while controlling for likely confounding variables.

Topics: Adiposity; Beverages; Dietary Sucrose; Energy Intake; Genetic Predisposition to Disease; Glycemic Index; Humans; Insulin; Insulin Secretion; Leptin; Obesity; Risk Factors; Satiety Response; Sweetening Agents

Obesity and diabetes are major public health threats worldwide. Insulin resistance appears to be a significant factor in this global epidemic. In this present review, we have focused on a human model of insulin resistance which embodies many of the metabolic abnormalities that are associated with the morbidity of diabetes and obesity. Lipodystrophy in rodents and humans is a severe model of insulin resistance, and we use a novel therapeutic approach with the administration of the newly discovered leptin to ameliorate many of these metabolic abnormalities. The ability to study the administration of leptin in this setting of severe insulin resistance allows us perform a coveted look into a human condition where metabolic dysfunction can be reversed or controlled.

Topics: Adiponectin; Animals; Diabetes Mellitus; Humans; Insulin Resistance; Leptin; Lipodystrophy; Obesity; Treatment Outcome

Onset expression of Type 2 (NIDDM) diabetes and obesity metabolic syndromes (DOS) are characterized by premature, progressive cytoatrophy and organo-involution induced by dysregulated cellular gluco- and lipo-metabolic cascades. The consequential systemic, interstitial and intracellular hyperlipidemia disrupts normal cytointegrity and metabolic responsivity to the established hypercaloric pericellular environments. The sequential cytostructural, metabolic and endocrine disturbances associated with the development of progressive DOS-associated hypercytolipidemia compromises cellular metabolic response cascades and promotes cytochemical disturbances which culminate with nuclear lipoapoptosis and cytoatrophy. The dramatic alterations in interstitial glucose and lipid (free fatty acids/triglycerides) concentrations are recognized to influence interstitial and cytoplasmic microchemical environments, which markedly alter cellular nutrient diffusion and active trans-membrane flux rates. The progressive exacerbation of interstitial and cytoplasmic lipid imbibition has been demonstrated to be associated with DNA fragmentation by lipo-infiltration into the chromatin matrix, inducing structural disruption and physical dissolution, indexed as nuclear lipoapoptosis. Therapeutic reduction of the severity of hypercytolipidemia-induced structural and cytochemical compromise promotes the restoration of homeostatic metabolic support for normalized cytostructural indices and supportive cellular gluco- and lipo-metabolic cascades. The re-establishment of a homeostatic interstitial microenvironment moderates the severity of cytolipidemic compromise within affected cell types, reduces nuclear lipo-infiltration and DNA lipo-dissolution, resulting in the preservation of cytostructural integrity. Through the therapeutic restoration of extra- and intra-cellular microchemical environments in genetically dysregulated metabolic syndrome models, the coincident cytochemical, endocrine and metabolic disturbances associated with progressive hypercytolipidemia, resulting from the expressed systemic hypercaloric environmental and hepato-pancreatic endometabolic disturbances which characterize Type 2 (NIDDM) diabetes-obesity and metabolic (X) syndromes, may be ameliorated.

Topics: Animals; Apoptosis; Apoptosis Regulatory Proteins; Diabetes Mellitus, Type 2; Disease Models, Animal; Humans; Hyperlipidemias; Leptin; Mutation; Obesity; Receptors, Cell Surface; Receptors, Leptin; Syndrome

The worldwide increase in the prevalence of obesity is becoming one of the most important clinical-epidemiological phenomena of the present days. Environmental factors such as changes in life-style and feeding behavior associated with poorly characterized genetic determinants are though to play the most important roles in the pathogenesis of this disease. During the last ten years, since the discovery of leptin, great advances were obtained in the characterization of the hypothalamic mechanisms involved in the control of food intake and thermogenesis. Such advances are unveiling a complex and integrated system and are opening a wide perspective for the finding of novel therapeutic targets for the treatment of this harming condition. This review will present some of the most recent findings in this field. It will be focused on the actions of leptin and insulin in the hypothalamus and will explore the hypothesis that hypothalamic resistance to the action of these hormones may play a role in the development of obesity and may act as a molecular link between obesity, type 2 diabetes mellitus and other clinical conditions on which insulin resistance plays an important pathogenetic role.

Topics: Diabetes Mellitus, Type 2; Eating; Humans; Hypothalamus; Insulin Resistance; Leptin; Life Style; Obesity; Thermogenesis; Transcription, Genetic

For better understanding the role of each element involved in the physiopathology of obesity and insulin resistance, researchers can use experimental models, which may in controlled manner evaluate the participation of each element on the obesity and insulin resistance and provide information for better understanding the physiopathology and treatment of obesity and insulin resistance. Experimental obesity and insulin resistance can be due to a deficient response to leptin, secondary to hypoleptinemia and/or mutations on leptin receptor, by modifications on insulin receptor, deletion or diminished insulin signal transduction, enhancement of the effects of orexigen peptides and/or diminution of anorexigen peptides actions on hypothalamus, as well as secondary to arterial hypertension, as in the spontaneously hypertension. Obesity and insulin resistance can also be induced by glucocorticoid excess, frutose enriched and cafeteria diet and due to hypothalamus lesions induced by neonatal administration of monossodium glutamate.

Topics: Adipose Tissue; Animals; Diet; Disease Models, Animal; Hypertension; Insulin Resistance; Leptin; Models, Genetic; Models, Immunological; Obesity

Review of the ontogeny of the controls of independent ingestion reveals that some of the direct and indirect controls of meal size identified in adult rats function in the first three postnatal weeks. The controls appear sequentially and some of them change their potency after they emerge. Indirect controls exerted by metabolism and adiposity do not emerge until the fourth postnatal week or later in the postweaning period. Recent experiments in rats with monogenic obesities involving the leptin and cholecystokinin receptors have demonstrated the usefulness of independent ingestion in the detection of the earliest expression of hyperphagia. Although much remains to be learned about the normal controls of independent ingestion, it is clear that it provides relevant information about the development of normal and abnormal controls of meal size in rodents that is useful for translational research into the controls of meal size in normal and obese children.

Topics: Animals; Animals, Newborn; Cholecystokinin; Deoxyglucose; Dopamine; Energy Intake; Environment; Feedback; Feeding Behavior; Food Deprivation; Glucose; Leptin; Obesity; Physical Stimulation; Vagus Nerve

There has been a rapid rise in the incidence of obesity, primarily as a result of changes in lifestyle (diet and activity levels). Obesity has provided considerable impetus for the investigation of the fundamental mechanisms involved in the regulation of energy balance. Important developments include the identification of novel factors involved in the control of appetite, such as ghrelin, orexin A, and the endogenous cannabinoids, and the emergence of the concept of "nonexercise activity thermogenesis" (NEAT) provided new perspectives on energy expenditure. Studies on white adipose tissue have led to the recognition that it is an important endocrine organ, communicating with the brain and peripheral tissues through the secretion of leptin and other adipokines. There is a rapidly expanding list of protein factors released by white adipose tissue, including the key hormone, adiponectin. Of particular note is the range of cytokines, chemokines, and other inflammation-related proteins secreted by white fat as tissue mass rises; indeed, obesity is characterized by chronic mild inflammation. The adipokines provide an extensive network of communication both within adipose tissue and with other organs, and some are implicated directly in the pathologies associated with obesity, particularly the metabolic syndrome. Although the focus remains very much on obesity in humans, the disorder and its sequelae are also a growing concern in companion animals.

Topics: Adiponectin; Adipose Tissue; Animals; Cytokines; Energy Metabolism; Humans; Inflammation; Leptin; Obesity

Topics: Agouti-Related Protein; Diagnosis, Differential; Energy Metabolism; Feeding Behavior; Ganglia, Autonomic; Humans; Hypothalamic Area, Lateral; Hypothalamic Diseases; Intercellular Signaling Peptides and Proteins; Leptin; Neuropeptide Y; Obesity; Paraventricular Hypothalamic Nucleus; Proteins; Syndrome; Ventromedial Hypothalamic Nucleus

Although the presence of hyperleptinemia with leptin resistance and obesity has long been recognized, a causal role of elevated leptin in these biological states remains unclear. This article summarizes some recent work from our laboratory supporting the concept that leptin, in and of itself, promotes leptin resistance and such resistance compounds the metabolic impact of diet-induced obesity. Results from multiple studies demonstrate that (1) chronically elevated central leptin decreases hypothalamic leptin receptor expression and protein levels and impairs leptin signaling; (2) leptin resistance and obesity are associated with reduced leptin receptors and diminished maximal leptin signaling capacity; and (3) leptin resistance confers increased susceptibility to diet-induced obesity. In essence, the augmented leptin accompanying obesity contributes to leptin resistance, and this leptin resistance promotes further obesity, leading to a vicious cycle of escalating metabolic devastation.

Topics: Age Factors; Animals; Body Weight; Dietary Fats; Energy Metabolism; Humans; Hypothalamus; Leptin; Mice; Mice, Transgenic; Obesity; Receptors, Cell Surface; Receptors, Leptin; Signal Transduction

Obese women are characterized by similar comorbidities to men, particularly type 2 diabetes mellitus and cardiovascular diseases. Moreover, they also develop some specific problems, including fertility-related disorders and some hormone-dependent forms of cancer. The relationship between excess body fat and reproductive disturbances appears to be stronger for early-onset obesity. Early onset of obesity, particularly during adolescence, favours the development of menses irregularities, chronic oligo-anovulation and infertility in adulthood. Moreover, obesity in women can increase the risk of miscarriage and impair the outcome of assisted reproductive technologies. The main factor implicated in the association between obesity and fertility-related disorders is insulin excess, which accompanies insulin resistance. Hyperinsulinaemia may be directly responsible for the development of androgen excess, through its effects in reducing sex hormone-binding globulin synthesis and circulating concentrations, and in stimulating ovarian androgen production rates. Androgen excess, in turn, represents one of the major factors leading to altered ovarian physiology and associated ovulatory disturbances. Obesity-associated hyperleptinaemia may represent an additional factor involved in anovulation, not only through the induction of insulin resistance, but also through a direct impairment of ovarian function.

Topics: Androgens; Animals; Female; Humans; Hyperinsulinism; Infertility, Female; Insulin Resistance; Leptin; Metabolic Syndrome; Obesity; Polycystic Ovary Syndrome; Reproduction

Leptin restricts intake of calories as a satiety hormone. It probably stimulates neoplastic proliferation in breast cancer, too. Growth of malignant cells could be regulated by various leptin-induced second messengers like STAT3 (signal transducers and activators of transcription 3), AP-1 (transcription activator protein 1), MAPK (mitogen-activated protein kinase) and ERKs (extracellular signal-regulated kinases). They seem to be involved in aromatase expression, generation of estrogens and activation of estrogen receptor alpha (ERalpha) in malignant breast epithelium. Leptin may maintain resistance to antiestrogen therapy. Namely, it increased activation of estrogen receptors, therefore, it was suspected to reduce or even overcome the inhibitory effect of tamoxifen on breast cell proliferation. Although several valuable reviews have been focused on the role of leptin in breast cancer, the status of knowledge in this field changes quickly and our insight should be continuously revised. In this summary, we provide refreshed interpretation of intensively reported scientific queries of the topic.

Topics: Animals; Breast Neoplasms; Cell Proliferation; Cell Transformation, Neoplastic; Drug Resistance, Neoplasm; Estrogen Receptor Modulators; Estrogens; Humans; Leptin; Lipid Metabolism; Obesity

Topics: Adiponectin; Amenorrhea; Drug Therapy, Combination; Estrogens; Female; Humans; Hypothalamic Diseases; Leptin; Menstrual Cycle; Obesity; Pituitary Diseases; Progesterone; Thinness

Topics: Animals; Anti-Obesity Agents; Disease Models, Animal; Energy Metabolism; Humans; Hypothalamic Hormones; Leptin; Melanins; Obesity; Pituitary Hormones; Receptors, Somatostatin

The polycystic ovary syndrome (PCOS) is one of the most common causes of infertility due to anovulation in women. The clinical features of PCOS are heterogeneous and may change throughout the lifespan, starting from adolescence to postmenopausal age. This is largely dependent on the influence of obesity and metabolic alterations, including an insulin-resistant state and the metabolic syndrome, which consistently affect most women with PCOS. Obesity does in fact have profound effects on both the pathophysiology and the clinical manifestation of PCOS, by different mechanisms leading to androgen excess and increased free androgen availability and to alterations of granulosa cell function and follicle development. Notably, simple obesity per se represents a functional hyperandrogenic state. These mechanisms involve early hormonal and metabolic factors during intrauterine life, leptin, insulin and the insulin growth factor system and, potentially, the endocannabinoid system. Compared with normal weight women with PCOS, those with obesity are characterised by a worsened hyperandrogenic and metabolic state, poorer menses and ovulatory performance and, ultimately, poorer pregnancy rates. The importance of obesity in the pathogenesis of PCOS is emphasised by the efficacy of lifestyle intervention and weight loss, not only on metabolic alterations but also on hyperandrogenism, ovulation and fertility. The increasing prevalence of obesity among adolescent and young women with PCOS may partly depend on the increasing worldwide epidemic of obesity, although this hypothesis should be supported by long-term prospective epidemiological trials. This may have great relevance in preventive medicine and offer the opportunity to expand our still limited knowledge of the genetic and environmental background favouring the development of the PCOS.

Topics: Adipose Tissue; Adult; Cannabinoid Receptor Modulators; Female; Humans; Hyperandrogenism; Infertility, Female; Insulin Resistance; Leptin; Male; Menstruation Disturbances; Obesity; Phenotype; Polycystic Ovary Syndrome; Pregnancy; Prenatal Exposure Delayed Effects

Obesity is a major public health concern and environmental factors are involved in its development. The hypothalamus is a primary site for the integration of signals for the regulation of energy homeostasis. Dysregulation of these pathways can lead to weight loss or gain. Some drugs in development can have favourable effects on body weight, acting on some of these pathways and leading to responses resulting in weight loss. Strategies for the management of weight reduction include exercise, diet, behavioural therapy, drug therapy and surgery. Investigational antiobesity medications can modulate energy homeostasis by stimulating catabolic or inhibiting anabolic pathways. Investigational drugs stimulating catabolic pathways consist of leptin, agonists of melanocortin receptor-4, 5-HT and dopamine; bupropion, growth hormone fragments, cholecystokinin subtype 1 receptor agonist, peptide YY3-36, oxyntomodulin, ciliary neurotrophic factor analogue, beta3-adrenergic receptor agonists, adiponectin derivatives and glucagon-like peptide-1. On the other hand, investigational drugs inhibiting anabolic pathways consist of the ghrelin receptor, neuropeptide Y receptor and melanin-concentrating hormone-1 antagonists; somatostatin analogues, peroxisome proliferator-activated receptor-gamma and -beta/delta antagonists, gastric emptying retardation agents, pancreatic lipase inhibitors, topiramate and cannabinoid-1 receptor antagonists. These differing approaches are reviewed and commented on in this article.

Topics: Animals; Anti-Obesity Agents; Body Weight; Drugs, Investigational; Energy Metabolism; Humans; Hypothalamus; Leptin; Obesity; Peroxisome Proliferator-Activated Receptors; Randomized Controlled Trials as Topic; Receptor, Melanocortin, Type 4; Receptor, Serotonin, 5-HT1B; Receptor, Serotonin, 5-HT2C; Receptors, G-Protein-Coupled; Receptors, Ghrelin; Receptors, Neuropeptide Y; Recombinant Proteins; Serotonin 5-HT1 Receptor Agonists; Serotonin 5-HT2 Receptor Agonists; Serotonin Receptor Agonists

We present the knowledge acquired in the field of the genetics of human obesity. The molecular approach proved to be powerful to define new syndromes associated to obesity. The pivotal role of leptin and melanocortin pathways were recognized but in rare obesity cases. In the commoner form of obesities, a multitude of polymorphisms located in genes and candidate regions participate in an individual susceptibility to weight gain in a permissive environment. The effects are often uncertain and the results not always confirmed. It is now necessary to integrate data of various origins (environment, genotype, expression) to clarify the domain.

Topics: alpha-MSH; Animals; Brain; Disease Models, Animal; DNA; Humans; Leptin; Mice; Mice, Obese; Mutation; Obesity; Polymorphism, Genetic; Receptor, Melanocortin, Type 4

Over the past decade we have witnessed a major increase in the scale of scientific activity devoted to the study of energy balance and obesity. This explosion of interest has, to a large extent, been driven by the identification of genes responsible for murine obesity syndromes, and the novel physiological pathways revealed by those genetic discoveries. Others and we have also recently identified several single gene defects causing severe human obesity. Many of these defects have been in molecules identical or similar to those identified as a cause of obesity in rodents. I will review the human monogenic obesity syndromes that have been characterised to date and discuss how far such observations support the physiological role of these molecules in the regulation of human body weight and neuroendocrine function.

Topics: Body Weight; Endocrine System; Humans; Leptin; Metabolic Diseases; Obesity; Pro-Opiomelanocortin

Adipose tissue plays a crucial role in energy homeostasis not only in storing triglyceride, but also responding to nutrient, neural, and hormonal signals, and producing factors which control feeding, thermogenesis, immune and neuroendocrine function, and glucose and lipid metabolism. Adipose tissue secretes leptin, steroid hormones, adiponectin, inflammatory cytokines, resistin, complement factors, and vasoactive peptides. The endocrine function of adipose tissue is typified by leptin. An increase in leptin signals satiety to neuronal targets in the hypothalamus. Leptin activates Janus-activating kinase2 (Jak2) and STAT 3, resulting in stimulation of anorexigenic peptides, e.g., alpha-MSH and CART, and inhibition of orexigenic peptides, e.g., NPY and AGRP. The reduction in leptin levels during fasting stimulates appetite, decreases thermogenesis, thyroid and reproductive hormones, and increases glucocorticoids. Leptin also stimulates fatty acid oxidation, insulin release, and peripheral insulin action. These effects involve regulation of PI-3 kinase, PTP-1B, suppressor of cytokine signaling-3 (SOCS-3), and AMP-activated protein kinase in the brain and peripheral organs. There is emerging evidence that leptin, adiponectin, and resistin act through overlapping pathways. Understanding the signal transduction of adipocyte hormones will provide novel insights on the pathogenesis and treatment of obesity, diabetes, and various metabolic disorders.

Topics: Adipose Tissue; Animals; Diabetes Mellitus; Enzyme Activation; Humans; Hypothalamus; Janus Kinase 2; Leptin; Lipid Metabolism; Obesity; Signal Transduction; STAT2 Transcription Factor

Traditionally, nutrients such as glucose and amino acids have been viewed as substrates for the generation of high-energy molecules and as precursors for the biosynthesis of macromolecules. However, it is now apparent that nutrients also function as signaling molecules in functionally diverse signal transduction pathways. Glucose and amino acids trigger signaling cascades that regulate various aspects of fuel and energy metabolism and control the growth, proliferation, and survival of cells. Here, we provide a functional and regulatory overview of three well-established nutrient signaling pathways-the hexosamine signaling pathway, the mTOR (mammalian target of rapamycin) signaling pathway, and the adenosine monophosphate-activated protein kinase (AMPK) signaling pathway. Nutrient signaling pathways are interconnected, coupled to insulin signaling, and linked to the release of metabolic hormones from adipose tissue. Thus, nutrient signaling pathways do not function in isolation. Rather, they appear to serve as components of a larger "metabolic regulatory network" that controls fuel and energy metabolism (at the cell, tissue, and whole-body levels) and links nutrient availability with cell growth and proliferation. Understanding the diverse roles of nutrients and delineating nutrient signaling pathways should facilitate drug discovery research and the search for novel therapeutic compounds to prevent and treat various human diseases such as diabetes, obesity, and cancer.

Topics: Adiponectin; Amino Acids; AMP-Activated Protein Kinase Kinases; Diabetes Mellitus, Type 2; Energy Metabolism; Glucose; Hexosamines; Homeostasis; Humans; Insulin; Leptin; Metabolism; Neoplasms; Obesity; Protein Kinases; Signal Transduction; TOR Serine-Threonine Kinases