neuropeptide-y and Obesity

Independent from homeostatic needs, the consumption of foods originating from hyperpalatable diets is defined as hedonic eating. Hedonic eating can be observed in many forms of eating phenotypes, such as compulsive eating and stress-eating, heightening the risk of obesity development. For instance, stress can trigger the consumption of palatable foods as a type of coping strategy, which can become compulsive, particularly when developed as a habit. Although eating for pleasure is observed in multiple maladaptive eating behaviours, the current understanding of the neurobiology underlying hedonic eating remains deficient. Intriguingly, the combined orexigenic, anxiolytic and reward-seeking properties of Neuropeptide Y (NPY) ignited great interest and has positioned NPY as one of the core neuromodulators operating hedonic eating behaviours. While extensive literature exists exploring the homeostatic orexigenic and anxiolytic properties of NPY, the rewarding effects of NPY continue to be investigated. As deduced from a series of behavioural and molecular-based studies, NPY appears to motivate the consumption and enhancement of food-rewards. As a possible mechanism, NPY may modulate reward-associated monoaminergic pathways, such as the dopaminergic and serotoninergic neural networks, to modulate hedonic eating behaviours. Furthermore, potential direct and indirect NPYergic neurocircuitries connecting classical homeostatic and hedonic neuropathways may also exist involving the anti-reward centre the lateral habenula. Therefore, this review investigates the participation of NPY in orchestrating hedonic eating behaviours through the modulation of monoaminergic pathways.

Topics: Adaptation, Psychological; Dopaminergic Neurons; Feeding Behavior; Homeostasis; Humans; Motivation; Neural Pathways; Neuropeptide Y; Obesity; Reward; Serotonergic Neurons

Obesity leads to several metabolic disorders and, unfortunately, current pharmacological treatments for obesity are not very effective. In feeding mechanisms, the hypothalamus and some neuropeptides play an important role. Many data show that neuropeptide Y (NPY) is involved in these mechanisms. The aim of this review is to update the physiological actions mediated by the orexigenic peptide NPY, via its receptors, in the control of food intake and to review its involvement in food intake disorders. The relationships between NPY and other substances involved in food intake mechanisms, hypothalamic and extra-hypothalamic pathways involved in feeding and the potential pharmacological strategies to treat obesity will be discussed. Some research lines, focused on NPY, to be developed in the future are suggested. Neuropeptide systems are associated with redundancy and then therapies directed against a single target are generally ineffective. For this reason, other targets for the treatment of obesity are mentioned. It seems that combination therapies are the best option for successful anti-obesity treatments: new and more specific NPY receptor antagonists must be tested as anti-obesity drugs alone and in combination therapies.

Topics: Eating; Homeostasis; Humans; Hypothalamus; Neuropeptide Y; Neuropeptides; Obesity; Receptors, Neuropeptide Y

Ovulatory disorders are the most common clinical feature exhibited among obese women. Initiation of ovulation physiologically requires a surge of gonadotropin-releasing hormone (GnRH) released from GnRH neurons located in the hypothalamus. These GnRH neurons receive metabolic signals from circulation and vicinal neurons to regulate GnRH release. Leptin acts indirectly on GnRH via adjacent leptin receptor (LEPR)-expressing neurons such as proopiomelanocortin (POMC), neuropeptide Y (NPY)/agouti-related peptide (AgRP), and neuronal nitric oxide (NO) synthase (nNOS) neurons to affect GnRH neuronal activities. Additionally, hypothalamic inflammation also affects ovulation independent of obesity. Therefore, this review focuses on hypothalamic mechanisms that underlie the disturbance of hypothalamic-pituitary-ovarian (HPO) axis during obesity with an attempt to promote future studies and/or novel therapeutic strategies for ovulatory disorders in obesity.

Topics: Female; Gonadotropin-Releasing Hormone; Humans; Hypothalamus; Neuropeptide Y; Obesity; Ovary; Pituitary Gland; Pro-Opiomelanocortin

Obesity and mood disorders are often overlapping pathologies that are prevalent public health concerns. Many studies have indicated a positive correlation between depression and obesity, although weight loss and decreased appetite are also recognized as features of depression. Accordingly, DSM-5 defines two subtypes of depression associated with changes in feeding: melancholic depression, characterized by anhedonia and associated with decreased feeding and appetite; and atypical depression, characterized by fatigue, sleepiness, hyperphagia, and weight gain. The central nervous system plays a key role in the regulation of feeding and mood, thus suggesting that overlapping neuronal circuits may be involved in their modulation. However, these circuits have yet to be completely characterized. The central melanocortin system, a circuitry characterized by the expression of specific peptides (pro-opiomelanocortins, agouti-related protein, and neuropeptide Y) and their melanocortin receptors, has been shown to be a key player in the regulation of feeding. In addition, the melanocortin system has also been shown to affect anxiety and depressive-like behavior, thus suggesting a possible role of the melanocortin system as a biological substrate linking feeding and depression. However, more studies are needed to fully understand this complex system and its role in regulating metabolic and mood disorders. In this review, we will discuss the current literature on the role of the melanocortin system in human and animal models in feeding and mood regulation, providing evidence of the biological interplay between anxiety, major depressive disorders, appetite, and body weight regulation.

Topics: Animals; Depressive Disorder, Major; Energy Metabolism; Melanocortins; Mood Disorders; Neuropeptide Y; Obesity

We are currently facing an obesity pandemic, with worldwide obesity rates having tripled since 1975. Obesity is one of the main risk factors for the development of non-communicable diseases, which are now the leading cause of death worldwide. This calls for urgent action towards understanding the underlying mechanisms behind the development of obesity as well as developing more effective treatments and interventions. Appetite is carefully regulated in humans via the interaction between the central nervous system and peripheral hormones. This involves a delicate balance in external stimuli, circulating satiating and appetite stimulating hormones, and correct functioning of neuronal signals. Any changes in this equilibrium can lead to an imbalance in energy intake versus expenditure, which often leads to overeating, and potentially weight gain resulting in overweight or obesity. Several lines of research have shown imbalances in gut hormones are found in those who are overweight or obese, which may be contributing to their condition. Therefore, this review examines the evidence for targeting gut hormones in the treatment of obesity by discussing how their dysregulation influences food intake, the potential possibility of altering the circulating levels of these hormones for treating obesity, as well as the role of short chain fatty acids and protein as novel treatments.

Topics: Acetic Acid; Animals; Appetite; Appetite Regulation; Butyrates; Central Nervous System; Cholecystokinin; Dipeptides; Energy Intake; Energy Metabolism; Fatty Acids, Volatile; Gastrointestinal Hormones; Gastrointestinal Tract; Ghrelin; Glucagon-Like Peptide 1; Humans; Hyperphagia; Mice; Neuropeptide Y; Obesity; Overweight; Oxyntomodulin; Pancreatic Polypeptide; Propionates; Satiation

Topics: Animals; Eating; Energy Metabolism; Galanin; Humans; Hypothalamus; Neuropeptide Y; Obesity

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

Neuropeptide Y (NPY), which is widely distributed in the nervous system, is involved in regulating a variety of biological processes, including food intake, energy metabolism, and emotional expression. However, emerging evidence points to NPY also as a critical transmitter between the nervous system and immune system, as well as a mediator produced and released by immune cells.

Topics: Animals; Body Temperature; Emotions; Energy Metabolism; Glucose; Humans; Immunity; Immunomodulation; Neuropeptide Y; Obesity

Obesity is one of the main challenges of public health in the 21st century. Obesity can induce a series of chronic metabolic diseases, such as diabetes, dyslipidemia, hypertension and nonalcoholic fatty liver, which seriously affect human health. Gut-brain axis, the two-direction pathway formed between enteric nervous system and central nervous system, plays a vital role in the occurrence and development of obesity. Gastrointestinal signals are projected through the gut-brain axis to nervous system, and respond to various gastrointestinal stimulation. The central nervous system regulates visceral activity through the gut-brain axis. Brain-gut peptides have important regulatory roles in the gut-brain axis. The brain-gut peptides of the gastrointestinal system and the nervous system regulate the gastrointestinal movement, feeling, secretion, absorption and other complex functions through endocrine, neurosecretion and paracrine to secrete peptides. Both neuropeptide Y and peptide YY belong to the pancreatic polypeptide family and are important brain-gut peptides. Neuropeptide Y and peptide YY have functions that are closely related to appetite regulation and obesity formation. This review describes the role of the gutbrain axis in regulating appetite and maintaining energy balance, and the functions of brain-gut peptides neuropeptide Y and peptide YY in obesity. The relationship between NPY and PYY and the interaction between the NPY-PYY signaling with the gut microbiota are also described in this review.

Topics: Animals; Brain; Gastrointestinal Tract; Homeostasis; Humans; Neuropeptide Y; Obesity; Peptide YY

Psychosocial stress alters several physiological parameters resulting in multiple disorders, particularly compromising the immune system thereby provoking various diseases including liver disorders. However, the plausible underlying mechanisms remain elusive. Recent literature provides mechanistic evidences of detrimental effects of psychosocial stress on physiology of different body organs including liver. The data of stress-induced pathophysiological changes in liver functions and obesity were systematically collected from PubMed, ScienceDirect and the Web of Science Databases published in English. Stress and glucocorticoids (GCs) control food intake and energy expenditure through appetite stimulators neuropeptide Y (NYP) and agouti-related protein (AgRP) in hypothalamus. Principle effectors of the activated hypothalamic-pituitary-adrenal (HPA) axis in response to psychosocial stress are proopiomelanocortin (POMC)-derived adrenocorticotropic hormone (ACTH) and GCs. Stress-induced GCs hyper-secretion triggers glucocorticoid receptor (GR)-dependent transcriptional factor, nuclear factor kappa B (NFκB), which interferes TNFα-IL6 and keap1-Nrf2 pathways in liver regeneration and obesity through fine-tuning of TNFα, IL6 and Nrf2 signaling. In this review, it is contrived upon existing evidence to put forward a model whereby exposure to life-stress has a prominent impact over weight gain and can alter the regenerative mode of a damaged liver through Keap1-Nrf2 and TNFa-IL6 pathways.

Topics: Agouti-Related Protein; Animals; Glucocorticoids; Interleukin-6; Kelch-Like ECH-Associated Protein 1; Liver Regeneration; Neuropeptide Y; NF-E2-Related Factor 2; Obesity; Pituitary-Adrenal System; Receptors, Glucocorticoid; Signal Transduction; Stress, Psychological; Tumor Necrosis Factor-alpha

Ghrelin, an acylated peptide hormone of 28 amino acids, is an endogenous ligand of the released growth hormone secretagogue receptor (GHSR). Ghrelin has been isolated from human and rat stomach and is also detected in the hypothalamic arcuate nucleus. Ghrelin receptor is primarily located in the neuropeptide Y and agouti-related protein neurons. Many previous studies have shown that ghrelin and GHSR are involved in the regulation of energy homeostasis, and its administration can increase food intake and body weight gain. AMP-activated protein kinase is activated by ghrelin in the hypothalamus, which contributes to lower intracellular long-chain fatty acid level. Ghrelin appears to modulate the response to food cues via a neural network involved in the regulation of feeding and in the appetitive response to food cues. It also increases the response of brain areas involved in visual processing, attention, and memory to food pictures. Ghrelin is also an important factor linking the central nervous system with peripheral tissues that regulate lipid metabolism. It promotes adiposity by the activation of hypothalamic orexigenic neurons and stimulates the expression of fat storage-related proteins in adipocytes. Meanwhile, ghrelin exerts direct peripheral effects on lipid metabolism, including increase in white adipose tissue mass, stimulation of lipogenesis in the liver, and taste sensitivity modulation.

Topics: Animals; Eating; Energy Metabolism; Ghrelin; Humans; Hypothalamus; Lipid Metabolism; Neuropeptide Y; Obesity; Rats; Receptors, Ghrelin

Since the discovery of the remarkable properties of adipose tissue as a metabolically active organ, several evidences on the possible link between obesity and the pathogenesis of multiple sclerosis (MS) have been gathered. Obesity in early life, mainly during adolescence, has been proposed as a relevant risk factor for late MS development. Moreover, once MS is initiated, obesity can contribute to increase disease severity by negatively influencing disease progress. Despite the fact that clinical data are not yet conclusive, many biochemical links have been recently disclosed. The "low-grade inflammation" that characterizes obesity can lead to neuroinflammation through different mechanisms, including choroid plexus and blood-brain barrier disruption. Furthermore, it is well known that resident immune cells of central nervous system and peripheral immune cells are involved in the pathogenesis of MS, and adipokines and neuropeptides such as neuropeptide Y may mediate the cross talk between them.

Topics: Adipokines; Animals; Blood-Brain Barrier; Brain; Choroid Plexus; Disease Models, Animal; Encephalomyelitis, Autoimmune, Experimental; Humans; Hydroxyethylrutoside; Inflammation; Multiple Sclerosis; Neuropeptide Y; Obesity

Neuropeptide Y (NPY) in noradrenergic neurons plays an important role in modulating the release and effects of catecholamines in a prolonged stress response. Among other functions, it controls energy metabolism. Transgenic expression of Npy in noradrenergic neurons in mice allowed showing that it is critical for diet- and stress-induced gain in fat mass. When overexpressed, NPY in noradrenergic neurons increases adiposity in gene-dose-dependent fashion, and leads to metabolic disorders such as impaired glucose tolerance. However, the mechanisms of obesity seem to be different in mice heterozygous and homozygous for the Npy transgene. While in heterozygous mice the adipogenic effect of NPY is important, in homozygous mice inhibition of sympathetic tone leading to decreased lipolytic activity and impaired brown fat function, as well as increased endocannabinoid levels contribute to obesity. The mouse model provides novel insight to the mechanisms of human diseases with increased NPY due to chronic stress or gain-of-function gene variants, and a tool for development of novel therapeutics.

Topics: Adrenergic Neurons; Animals; Disease Models, Animal; Humans; Mice, Transgenic; Neuropeptide Y; Obesity; Receptors, Neuropeptide Y

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

Obesity is a major health problem characterized by accumulated fat mass. The availability of an energy-dense, highly palatable diet plays an important role in obesity development. Neuropeptide Y (NPY), an orexigenic peptide, is affected by dietary composition and NPY can affect dietary preference. The hypothalamic NPY system is well characterized and has been studied in several models of obesity. However, findings from models of diet-induced obesity are not straightforward. In addition, NPY plays a role in (food-)motivated behaviors and interacts with the mesolimbic dopamine system, both of which are altered in obesity. We here review the effect of obesogenic diets on NPY levels in the hypothalamus and reward-related regions.

Topics: Animals; Brain; Diet, High-Fat; Dietary Carbohydrates; Eating; Humans; Neuropeptide Y; Obesity; Reward; Time Factors

The incidence of obesity, one of the main risks for type 2 diabetes and cardiovascular disease, has been rising, and changes in eating behavior are associated with this increasing rate. Body weight is maintained via a complex integration of endocrine and neuronal inputs that regulate the control of orexigenic and anorexigenic neuropeptides in the arcuate nucleus of the hypothalamus. Overfeeding may disrupt the mechanisms of feeding control, increasing orexigenic peptides such as neuropeptide Y (NPY), and/or decreasing the anorexigenic peptide proopiomelanocortin (POMC) leading to a change in energy balance and body-weight index. Despite of the great interest in this field, the mechanism by which expression of POMC and NPY is modified is not entirely clear. Over the past decades, studies have demonstrated that epigenetic modifications such as DNA methylation, histone modification and changes in miRNA dynamics, could be modulated by external stimuli and these could affect protein expression in different cells. Therefore, this review discusses the recent reports that link epigenetic modifications in the hypothalamus to changes on long-term feeding control and its role in the onset of obesity.

Topics: Appetite Regulation; Body Weight; Energy Metabolism; Epigenesis, Genetic; Feeding Behavior; Humans; Hypothalamus; Neuropeptide Y; Obesity; Pro-Opiomelanocortin

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

Neuropeptide Y (NPY), one of the most abundant peptides in the nervous system, exerts its effects via five receptor types, termed Y1, Y2, Y4, Y5 and Y6. NPY's pleiotropic functions comprise the regulation of brain activity, mood, stress coping, ingestion, digestion, metabolism, vascular and immune function. Nerve-derived NPY directly affects immune cells while NPY also acts as a paracrine and autocrine immune mediator, because immune cells themselves are capable of producing and releasing NPY. NPY is able to induce immune activation or suppression, depending on a myriad of factors such as the Y receptors activated and cell types involved. There is an intricate relationship between psychological stress, mood disorders and the immune system. While stress represents a risk factor for the development of mood disorders, it exhibits diverse actions on the immune system as well. Conversely, inflammation is regarded as an internal stressor and is increasingly recognized to contribute to the pathogenesis of mood and metabolic disorders. Intriguingly, the cerebral NPY system has been found to protect against distinct disturbances in response to immune challenge, attenuating the sickness response and preventing the development of depression. Thus, NPY plays an important homeostatic role in balancing disturbances of physiological systems caused by peripheral immune challenge. This implication is particularly evident in the brain in which NPY counteracts the negative impact of immune challenge on mood, emotional processing and stress resilience. NPY thus acts as a unique signalling molecule in the interaction of the immune system with the brain in health and disease.

Topics: Affect; Animals; Behavior; Brain; Emotions; Gastrointestinal Tract; Homeostasis; Humans; Immune System; Inflammation; Neuropeptide Y; Obesity; Receptors, Neuropeptide Y; Signal Transduction; Stress, Psychological

The central nervous system (CNS) controls food intake and energy expenditure via tight coordinations between multiple neuronal populations. Specifically, two distinct neuronal populations exist in the arcuate nucleus of hypothalamus (ARH): the anorexigenic (appetite-suppressing) pro-opiomelanocortin (POMC) neurons and the orexigenic (appetite-increasing) neuropeptide Y (NPY)/agouti-related peptide (AgRP) neurons. The coordinated regulation of neuronal circuit involving these neurons is essential in properly maintaining energy balance, and any disturbance therein may result in hyperphagia/obesity or hypophagia/starvation. Thus, adequate knowledge of the POMC and NPY/AgRP neuron physiology is mandatory to understand the pathophysiology of obesity and related metabolic diseases. This review will discuss the history and recent updates on the POMC and NPY/AgRP neuronal circuits, as well as the general anorexigenic and orexigenic circuits in the CNS.

Topics: Agouti-Related Protein; Animals; Appetite; Arcuate Nucleus of Hypothalamus; Central Nervous System; Humans; Hypothalamus; Melanocortins; Mice; Neurons; Neuropeptide Y; Obesity; Paraventricular Hypothalamic Nucleus; Pro-Opiomelanocortin

Obesity develops when energy intake exceeds energy expenditure over time. Numerous neurotransmitters, hormones, and factors have been implicated to coordinately control energy homeostasis, centrally and peripherally. However, the neuropeptide Y (NPY) system has emerged as the one with the most critical functions in this process. While NPY centrally promotes feeding and reduces energy expenditure, peptide YY (PYY) and pancreatic polypeptide (PP), the other family members, mediate satiety. Importantly, recent research has uncovered additional functions for these peptides that go beyond the simple feeding/satiety circuits and indicate a more extensive function in controlling energy homeostasis. In this review, we will discuss the actions of the NPY system in the regulation of energy balance, with a particular focus on energy expenditure.

Topics: Energy Intake; Energy Metabolism; Homeostasis; Humans; Hypothalamus; Neuropeptide Y; Obesity; Peptide YY

Orexigenic actions mediated by neuropeptide-Y (NPY) promote body weight regulation. Genetic variations in the NPY gene could therefore influence susceptibility to obesity, but results have been conflicting. We have carried out, for the first time, a case-control study to examine the effect of NPY rs16147 and rs5574 variants with the risk of obesity in Asians and also a meta-analysis to summarize the effect of these variants including that of the widely studied rs16139.. Genotypes and biochemistry data were determined for 942 children (262 cases and 680 controls) recruited from 23 randomly selected schools in Malaysia. Relevant articles were identified from Pubmed, Embase, Web of Science and Google Scholar. Data were extracted and summary estimates of the association between the NPY variants and obesity were examined.. The frequency of the rs16147 T allele was significantly higher in the cases than controls (odds ratio 1.27, 95% confidence interval 1.04-1.55, P = 0.022), whereas the rs5574 T allele was significantly higher in the controls (odds ratio 0.76, 95% confidence interval 0.61-0.96, P = 0.020). In addition, NPY rs16147 was significantly correlated with obesity parameters including BMI, waist circumference, triglyceride and body fat percentage (P < 0.05). Meta-analysis including nine case-control studies further confirmed the findings of the association of the two variants with the risk of obesity and also found that rs16139 was associated with increased risk.. This study suggests that NPY rs16147 T and rs16139 C minor alleles are associated with increased risk, whereas the minor allele T of the rs5574 is associated with a reduced risk of obesity.

Topics: Case-Control Studies; Demography; Female; Genetic Predisposition to Disease; Humans; Male; Neuropeptide Y; Obesity; Polymorphism, Single Nucleotide; Publication Bias; Risk Factors

The need for addressing posttraumatic stress disorder (PTSD) among combat veterans returning from Afghanistan and Iraq is a growing public health concern. Current PTSD management addresses psychiatric parameters of this condition. However, PTSD is not simply a psychiatric disorder. Traumatic stress increases the risk for inflammation-related somatic diseases and early mortality. The metabolic syndrome reflects the increased health risk associated with combat stress and PTSD. Obesity, dyslipidemia, hypertension, diabetes mellitus, and cardiovascular disease are prevalent among PTSD patients. However, there has been little appreciation for the need to address these somatic PTSD comorbidities. Medical professionals treating this vulnerable population should screen patients for cardiometabolic risk factors and avail themselves of existing preventive diet, exercise, and pharmacologic modalities that will reduce such risk factors and improve overall long-term health outcomes and quality of life. There is the promise that cardiometabolic preventive therapy complementing psychiatric intervention may, in turn, help improve the posttraumatic stress system dysregulation and favorably impact psychiatric and neurologic function. © 2013 S. Karger AG, Basel.

Topics: Arousal; Autonomic Nervous System Diseases; Blood Coagulation Disorders; Coronary Disease; Diabetes Complications; Dyslipidemias; Endoplasmic Reticulum Stress; Health Status; Humans; Inflammation; Insulin Resistance; Mental Healing; Mental Health; Metabolic Syndrome; Mortality, Premature; Neuropeptide Y; Neurosecretory Systems; Neurotransmitter Agents; Obesity; Risk Factors; Sleep Wake Disorders; Stress Disorders, Post-Traumatic; Suicide; Weight Gain

Energy homoeostasis is maintained through a complex interplay of nutrient intake and energy expenditure. The central nervous system is an essential component of this regulation, as it integrates circulating signals of hunger and satiety to develop adaptive responses at the behavioural and metabolic levels, while the hypothalamus is regarded as a particularly crucial structure in the brain in terms of energy homoeostasis. The arcuate nucleus (ARC) of the hypothalamus contains at least two intermingled neuronal populations: the neurons that produce neuropeptide Y (NPY); and the Agouti-related protein (AgRP) produced by AgRP/NPY neurons situated below the third ventricle in close proximity to proopiomelanocortin (POMC)-producing neurons. POMC neurons exert their catabolic and anorectic actions by releasing α-melanocyte-stimulating hormone (α-MSH), while AgRP neurons oppose this action by exerting tonic GABAergic inhibition of POMC neurons and releasing the melanocortin receptor inverse agonist AgRP. The release of neurotransmitters and neuropeptides by second-order AgRP neurons appears to take place on a multiple time scale, thereby allowing neuromodulation of preganglionic neuronal activity and subsequent control of nutrient partitioning - in other words, the coordinated regulation of conversion, storage and utilization of carbohydrates vs. lipids. This suggests that the function of AgRP neurons extends beyond the strict regulation of feeding to the regulation of efferent organ activity, such that AgRP neurons may now be viewed as an important bridge between central detection of nutrient availability and peripheral nutrient partitioning, thus providing a mechanistic link between obesity and obesity-related disorders.

Topics: Agouti-Related Protein; alpha-MSH; Arcuate Nucleus of Hypothalamus; Energy Intake; Energy Metabolism; Homeostasis; Humans; Intercellular Signaling Peptides and Proteins; Lipid Metabolism; Metabolic Syndrome; Neuropeptide Y; Neuropeptides; Obesity; Pro-Opiomelanocortin; Weight Gain

peripheral nervous system. Considering the structure and evolutionary origin, neuropeptide Y (NPY) is a peptide of the same family as peptide YY (PYY) and pancreatic polypeptide (PP). These proteins were discovered relatively recently, however, knowledge about them is deepened. They are 36-amino acid peptide acting through G-protein coupled receptors, Y1, Y2, Y3, Y4, Y5 and Y6. The diverse structure C-terminus of the peptide and protein binding to receptors affect the biological activity and the physiological effects on the digestive system, blood vessels, and the center of hunger and satiety in the hypothalamus. Peptides have anorexic properties, they regulate appetite and food intake mainly through the intestinal cerebrospinal axis and the hypothalamus. These substances represent an important potential target of new drugs in the long-term treatment and prevention of obesity. Furthermore, neuropeptide Y affects many processes depending on the central nervous system modifies ethanol consumption, affect circadian rhythms, memory processes, anxiety behavior. Peripherally NPY affects smooth muscle contraction of the blood vessels, blood pressure, and atherogenic processes. Conducted more thorough research trying to define the role and participation of various neuropeptides in the development of diseases of the pancreas and the gastrointestinal tract, cardiovascular system and use it for diagnosis.

Topics: Animals; Anxiety; Appetite; Circadian Rhythm; Eating; Gastrointestinal Tract; Humans; Hypothalamus; Neuropeptide Y; Obesity; Pancreatic Polypeptide; Peptide YY; Receptors, Neuropeptide Y

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

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

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

Both reduction of melanocortin signaling and increase in neuropeptide Y signaling in the brain result in obesity. However, where in the brain reduced melanocortin or increased neuropeptide Y signaling mediate these effects is poorly understood. In separate experiments we have injected recombinant adeno-associated viral vectors that overexpressed agouti-related peptide or neuropeptide Y in specific brain regions namely the paraventricular nucleus and the lateral hypothalamus. In this review we compare the results from these studies and discuss these data with previous data from intracerebroventricular or local brain injections. This review shows that the effects of agouti-related peptide clearly differ from those of neuropeptide Y. In addition, these data suggests complementary roles for these neuropeptides in energy balance.

Topics: Agouti-Related Protein; Animals; Gene Expression; Humans; Hypothalamic Area, Lateral; Neuropeptide Y; Obesity; Organ Specificity; Paraventricular Hypothalamic Nucleus; Peptide Fragments

NPY, PYY and PP constitute the so-called NPY hormone family, which exert its biological functions in humans through YRs (Y₁, Y₂, Y₄ and Y₅). Systematic modulation of YR function became important as this multireceptor/multiligand system is known to mediate various essential physiological key functions and is involved in a variety of major human diseases such as epilepsy, obesity and cancer. As several YRs have been found to be overexpressed on different types of malignant tumors they emerge as promising target in modern drug development. Here, we summarize the current understanding of YRs function and the molecular mechanisms of ligand binding and trafficking. We further address recent advances in YR-based drug design, the development of promising future drug candidates and novel approaches in YR-targeted tumor diagnostics and therapy opportunities.

Topics: Drug Design; Humans; Ligands; Molecular Structure; Neoplasms; Neuropeptide Y; Obesity; Pancreatic Polypeptide; Peptide YY; Protein Isoforms; Receptors, Neuropeptide Y

The neuropeptide Y (NPY) system--comprising of neuropeptide Y, peptide YY, pancreatic polypeptide and the corresponding Y receptors through which they act (Y1, Y2, Y4, Y5 and y6)--is well known for its role in the regulation of energy homeostasis and associated processes. Dysfunctions of the system have been implicated in human diseases such as obesity and cancer, raising the possibility that correction of the system may provide therapeutic benefits for these diseases. In addition to the regulation of appetite and satiety that has attracted most attention during the past years, insight has also been gained into the critical role of NPY in the control of energy expenditure, oxidative fuel selection and bone metabolism. Studies using conditional knockout models further shed light on the central versus peripheral, and hypothalamic versus extra-hypothalamic mechanisms of these regulatory effects of NPY. Moreover, a role of NPY family peptides and Y receptors in modulating the growth of tumours has emerged. These findings provide the basis for novel NPY system-targeted strategies to treat obesity as well as cancer. Such strategies include modifying both sides of the energy balance equation--energy intake versus energy expenditure--to achieve a greater weight/fat loss by particularly modulating peripheral Y receptor(s) to ameliorate metabolic conditions without interfering with central functions of Y receptors. In addition, targeting multiple Y receptors and/or multiple systems involved in the regulation of energy balance will have greater beneficial effects. However, long-term interference with the NPY system to target obesity or cancer related aspects needs to consider potential side effects on bone health.

Topics: Animals; Energy Intake; Energy Metabolism; Humans; Molecular Targeted Therapy; Neoplasms; Neuropeptide Y; Obesity

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

Ghrelin, a peptide hormone predominantly produced by the stomach, was isolated as the endogenous ligand for the growth hormone secretagogue receptor. Ghrelin is a potent stimulator of growth hormone (GH) secretion and is the only circulatory hormone known to potently enhance feeding and weight gain and to regulate energy homeostasis following central and systemic administration. Therapeutic intervention with ghrelin in catabolic situations may induce a combination of enhanced food intake, increased gastric emptying and nutrient storage, coupled with an increase in GH thereby linking nutrient partitioning with growth and repair processes. These qualities have fostered the idea that ghrelin-based compounds may have therapeutic utility in treating malnutrition and wasting induced by various sub-acute and chronic disorders. Conversely, compounds that inhibit ghrelin action may be useful for the prevention or treatment of metabolic syndrome components such as obesity, impaired lipid metabolism or insulin resistance. In recent years, the effects of ghrelin on glucose homeostasis, memory function and gastrointestinal motility have attracted considerable amount of attention and revealed novel therapeutic targets in treating a wide range of pathologic conditions. Furthermore, discovery of ghrelin O-acyltransferase has also opened new research opportunities that could lead to major understanding of ghrelin physiology. This review summarizes the current knowledge on ghrelin synthesis, secretion, mechanism of action and biological functions with an additional focus on potential for ghrelin-based pharmacotherapies.

Topics: Agouti-Related Protein; Amino Acid Sequence; Animals; Blood Glucose; Blood-Brain Barrier; Body Weight; Cachexia; Eating; Energy Metabolism; Gastrointestinal Motility; Ghrelin; Homeostasis; Human Growth Hormone; Humans; Insulin Resistance; Molecular Sequence Data; Neuropeptide Y; Obesity; Receptors, Ghrelin; Weight Gain

The hypothalamic-pituitary-thyroid (HPT) axis plays a critical role in mediating changes in metabolism and thermogenesis. Thus, the central regulation of the thyroid axis by Thyrotropin Releasing Hormone (TRH) neurons in the paraventricular nucleus of the hypothalamus (PVN) is of key importance for the normal function of the axis under different physiological conditions including cold stress and changes in nutritional status. Before the TRH peptide becomes biologically active, a series of tightly regulated processes occur including the proper folding of the prohormone for targeting to the secretory pathway, its post-translational processing, and targeting of the processed peptides to the secretory granules near the plasma membrane of the cell ready for secretion. Multiple inputs coming from the periphery or from neurons present in different areas of the brain including the hypothalamus are responsible for the activation or inhibition of the TRH neuron and in turn affect the output of TRH and the set point of the axis.

Topics: Animals; Cold Temperature; Hypothalamo-Hypophyseal System; Neurons; Neuropeptide Y; Obesity; Paraventricular Hypothalamic Nucleus; Pituitary Hormone-Releasing Hormones; Protein Precursors; Protein Processing, Post-Translational; Thyroid Gland; Thyroid Hormones; Thyrotropin-Releasing Hormone

Neuropeptide Y (NPY) is a central neuromodulator and peripheral sympathetic neurotransmitter that also has important regulatory roles in cardiovascular, neuroendocrine, immune and metabolic functions during stress. Focusing on the peripheral actions of the peptide in rodent models, we summarize recent studies from our laboratory demonstrating that stress-induced release of NPY mediates accelerated atherosclerosis/restenosis, obesity and metabolic-like syndrome, particularly when combined with a high fat, high sugar diet. In this review, we propose mechanisms of NPY's actions, its receptors and cellular substrates that increase the risk for cardiovascular and metabolic diseases when chronic stress is associated with pre-existing vascular injury and/or states of hypernutrition.

Topics: Animals; Atherosclerosis; Cardiovascular Diseases; Humans; Metabolic Diseases; Models, Biological; Neuropeptide Y; Obesity; Overnutrition; Stress, Physiological

Neuropeptide Y (NPY) has been demonstrated to have critical roles in the physiological control of appetite and energy homeostasis through NPY Y1, Y2, Y4 and Y5 receptors. A number of synthetic ligands for NPY receptor subtypes have been developed to date, with Y5 receptor antagonists and Y2 and Y4 receptor agonists advancing into clinical trials.. A survey of the scientific and patent literature since mid-2006 is presented.. In addition to the specific modulation of respective NPY receptor subtypes, recent investigations have revealed that modulation of multiple NPY receptor subtypes produces additive or even synergistic anti-obesity effects. Development of reliable small molecule Y1, Y2 and Y4 receptor ligands would greatly accelerate investigations and drug discovery.

Topics: Animals; Anti-Obesity Agents; Drug Design; Humans; Ligands; Molecular Structure; Neuropeptide Y; Obesity; Receptors, Neuropeptide Y; Signal Transduction; Structure-Activity Relationship; Treatment Outcome

Feeding behavior is tightly regulated by peptidergic transmission within the hypothalamus. Neuropeptide Y (NPY) is one of the most potent known stimulators of food intake and has robust effects on the hypothalamic feeding neuronal networks. A vast body of literature has documented the substantial effects of NPY on feeding behavior. However, the cellular mechanisms underlying the actions of NPY have only recently begun to be explored. The NPYergic signal, including its expression in hypothalamic neurons, its release into the synaptic space, and its direct or indirect receptor-mediated actions, is highly responsive to decreases in the metabolic state. The orexigenic NPY signal can suppress the anorexigenic drive to restore energy balance homeostasis when energy levels are low, such as after food deprivation. The NPY signal interacts with glucose- and fat-sensitive signals arriving in the hypothalamus and effects changes in anorexigenic pathways, such as those mediated by the melanocortins. Recent applications of electrophysiological methods to examine the neuronal activity and pathways engaged by NPY-mediated signaling have advanced our understanding of this orexigenic system. Furthermore, crucial roles for NPY pathways in the development of hypothalamic feeding circuitry have been identified by these means. Orexigenic NPY signaling is critical during development and its absence is lethal in adults, thus reflecting the essential role of NPY for the regulation of energy homeostasis.

Topics: Animals; Anorexia; Appetite Regulation; Behavior, Animal; Disease Models, Animal; Feeding Behavior; Hypothalamus; Neuropeptide Y; Obesity; Rats

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

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

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

Following the discovery of secretin in 1902, a host of further peptide hormones that are synthesised and released from the gastrointestinal tract have been identified. While their roles in the regulation of gastrointestinal function have been known for some time, it is now evident that many of these hormones also physiologically regulate energy balance. Our understanding of how gut hormones signal to the brain has advanced significantly in recent years. Several hormones, including peptide YY, pancreatic polypeptide, oxyntomodulin, glucagon-like peptide 1 and cholecystokinin function as satiety signals. In contrast, only ghrelin, produced by the stomach, has emerged as a putative hunger signal, appearing to act both as a meal initiator and a long-term body weight regulator. Recent research suggests that gut hormones can be manipulated to regulate energy balance in man and that obese subjects retain sensitivity to the actions of gut hormones. The worldwide obesity pandemic continues unabated, despite public health initiatives and current best therapy. Future gut hormone-based therapies may provide an effective and well-tolerated treatment for obesity.

Topics: Animals; Area Postrema; Cholecystokinin; Diet Therapy; Energy Metabolism; Feedback, Physiological; Gastrointestinal Hormones; Ghrelin; Glucagon-Like Peptide 1; Homeostasis; Humans; Hunger; Hypothalamus; Neuropeptide Y; Obesity; Oxyntomodulin; Pancreatic Polypeptide; Peptide YY; Receptors, Ghrelin; Satiety Response; Solitary Nucleus

Neuropeptide Y (NPY) is an abundant and widespread peptide in mammalian nervous system, both in the central and peripheral nervous systems. NPY is a multifunctional neurotransmitter with multiple modulator effects in the regulation of physiological functions and responses in the body. NPY is a potent orexigenic peptide, which has effects on energy balance at the level of energy intake, expenditure, and partition. There are many association studies between the NPY gene variants and cardiovascular and metabolic disease. Most of them are done by using p.L7P substitution as a marker. At the moment it seems that the p.L7P substitution of preproNPY protein causes altered NPY secretion, which leads to haemodynamic disturbances caused by sympathetic hyperactivity and to various effects caused by altered local signalling by NPY. SNP association studies using p.L7P polymorphism suggest that this functional substitution may be a strong independent risk factor for various metabolic and cardiovascular diseases.

Topics: Animals; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Humans; Metabolic Diseases; Neuropeptide Y; Obesity; Polymorphism, Genetic

States of increased metabolic demand are associated with up-regulation of NPY and hyperphagia. However, we present some instances of hyperphagia in which NPY is not up-regulated. Ablation or functional disruption of specific sites in the hypothalamus, such as the ventromedial or paraventricular nuclei, or transection of inputs to the hypothalamus from the hindbrain results in hyperphagia and excess body weight gain. However, NPY expression and concentration in these experimental models is either decreased or unchanged. While there is no up-regulation of NPY in these models, there is increased sensitivity to the orexigenic effects of NPY. This enhanced responsiveness to NPY may more than compensate for the reduced levels of NPY and result in hyperphagia and excess body weight gain. The hyper-responsiveness may be due either to an increase in NPY receptors or to other changes in target cells and response pathways that may result from the treatments used in these models.

Topics: Humans; Hyperphagia; Hypothalamus; Neuropeptide Y; Obesity

Neuropeptide Y (NPY) has long been known to be involved in stress, centrally as an anxiolytic neuromodulator, and peripherally as a sympathetic nerve- and in some species, platelet-derived vasoconstrictor. The peptide is also a vascular mitogen, via Y1/Y5, and is angiogenic via Y2/Y5 receptors. Arterial injury activates platelet NPY and vascular Y1 receptors, inducing medial hypertrophy and neointima formation. Exogenous NPY, dipeptidyl peptidase IV (DPPIV, forming an Y2/Y5-selective agonist) and chronic stress augment these effects and occlude vessels with atherosclerotic-like lesions, containing thrombus and lipid-laden macrophages. Y1 antagonist blocks stress-induced vasoconstriction and post-angioplasty occlusions, and hence may be therapeutic in angina and atherosclerosis/restenosis. Conversely, tissue ischemia activates neuronal and platelet-derived NPY, Y2/Y5 and DPPIV, which stimulate angiogenesis/arteriogenesis. NPY-Y2-DPPIV agonists may be beneficial for ischemic revascularization and wound healing, whereas antagonists may be therapeutic in retinopathy, tumors, and obesity. Since stress is an underestimated risk factor in many of these conditions, NPY-based drugs may offer new treatment possibilities.

Topics: Blood Platelets; Humans; Neovascularization, Physiologic; Neuropeptide Y; Obesity; Stress, Physiological; Vasoconstriction

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

Obesity is a serious public health problem throughout the world, affecting both developed societies and developing countries. The central nervous system has developed a meticulously interconnected circuitry in order to keep us fed and in an adequate nutritional state. One of these consequences is that an energy-dense environment favors the development of obesity. Neuropeptide Y (NPY) is one of the most abundant and widely distributed peptides in the central nervous system of both rodents and humans and has been implicated in a variety of physiological actions. Within the hypothalamus, NPY plays an essential role in the control of food intake and body weight. Centrally administered NPY causes robust increases in food intake and body weight and, with chronic administration, can eventually produce obesity. NPY activates a population of at least six G protein-coupled Y receptors. NPY analogs exhibit varying degrees of affinity and specificity for these Y receptors. There has been renewed speculation that ligands for Y receptors may be of benefit for the treatment of obesity. This review highlights the therapeutic potential of Y(1), Y(2), Y(4), and Y(5) receptor agonists and antagonists as additional intervention to treat human obesity.

Topics: Animals; Animals, Genetically Modified; Eating; Energy Metabolism; Genetic Variation; Homeostasis; Humans; Ligands; Neuropeptide Y; Obesity; Receptors, Neuropeptide Y; Rodentia

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

Topics: Animals; Anti-Obesity Agents; Energy Metabolism; Homeostasis; Humans; Neuropeptide Y; Obesity

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

With an ever-growing population of obese people as well as comorbidities associated with obesity, finding effective weight loss strategies is more imperative than ever. One of the challenges in curbing the obesity crisis is designing successful strategies for long-term weight loss and weight-loss maintenance. Currently, weight-loss strategies include promotion of therapeutic lifestyle changes (diet and exercise), pharmacological therapy, and bariatric surgery. This review focuses on several pharmacological targets that activate central nervous system pathways that normally limit food intake and body weight. Though it is likely that no single therapy will prove effective for everyone, this review considers several recent pre-clinical targets, and several compounds that have been in human clinical trials.

Topics: Agouti-Related Protein; alpha-MSH; AMP-Activated Protein Kinases; Anti-Obesity Agents; Appetite Regulation; Body Weight; Cannabinoid Receptor Modulators; Central Nervous System; Ciliary Neurotrophic Factor; Energy Metabolism; Fructose; Humans; Hypothalamic Hormones; Hypothalamus; Intercellular Signaling Peptides and Proteins; Melanins; Multienzyme Complexes; Nerve Tissue Proteins; Neuropeptide Y; Obesity; Pituitary Hormones; Protein Serine-Threonine Kinases; Proteins; Receptors, Melanocortin; Signal Transduction; Topiramate

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

Neuropeptide Y (NPY) is one the most potent orexigenic peptides found in the brain. It stimulates food intake with a preferential effect on carbohydrate intake. It decreases latency to eat, increases motivation to eat and delays satiety by augmenting meal size. The effects on feeding are mediated through at least two receptors, the Y1 and Y5 receptors. The NPY system for feeding regulation is mostly located in the hypothalamus. It is formed of the arcuate nucleus (ARC), where the peptide is synthesized, and the paraventricular (PVN), dorsomedial (DMN) and ventromedial (VMN) nuclei and perifornical area where it is active. This activity is modulated by the hindbrain and limbic structures. It is dependent on energy availability, e.g. upregulation with food deprivation or restriction, and return to baseline with refeeding. It is also sensitive to diet composition with variable effects of carbohydrates and fats. Leptin signalling and glucose sensing which are directly linked to diet type are the most important factors involved in its regulation. Absence of leptin signalling in obesity models due to gene mutation either at the receptor level, as in the Zucker rat, the Koletsky rat or the db/db mouse, or at the peptide level, as in ob/ob mouse, is associated with increased mRNA abundance, peptide content and/or release in the ARC or PVN. Other genetic obesity models, such as the Otsuka-Long-Evans-Tokushima Fatty rat, the agouti mouse or the tubby mouse, are characterized by a diminution in NPY expression in the ARC nucleus and by a significant increase in the DMN. Further studies are necessary to determine the exact role of NPY in these latter models. Long-term exposure to high-fat or high-energy palatable diets leads to the development of adiposity and is associated with a decrease in hypothalamic NPY content or expression, consistent with the existence of a counter-regulatory mechanism to diminish energy intake and limit obesity development. On the other hand, an overactive NPY system (increased mRNA expression in the ARC associated with an upregulation of the receptors) is characteristic of rats or rodent strains sensitive to dietary-induced obesity. Finally, NPY appears to play an important role in body weight and feeding regulation, and while it does not constitute the only target for drug treatment of obesity, it may nevertheless provide a useful target in conjunction with others.

Topics: Animals; Diet; Feeding Behavior; Health; Neuropeptide Y; Obesity

Obesity represents the most prevalent nutritional problem worldwide which in the long run predisposes to development of diabetes mellitus, hypertension, endometrial carcinoma, osteoarthritis, gall stones and cardiovascular diseases. Despite significant reductions in dietary fat consumption, the prevalence of obesity is on a rise and is taking on pandemic proportions. Obesity develops when energy intake exceeds energy expenditure over time. Recently, a close evolutionary relationship between the peripheral and hypothalamic neuropeptides has become apparent. The hypothalamus being the central feeding organ mediates regulation of short-term and long-term dietary intake via synthesis of various orexigenic and anorectic neuropeptides. The structure and function of many hypothalamic peptides (neuropeptide Y (NPY), melanocortins, agouti-related peptide (AGRP), cocaine and amphetamine regulated transcript (CART), melanin concentrating hormone (MCH), orexins have been characterized in rodent models The peripheral neuropeptides such as cholecystokinin (CCK), ghrelin, peptide YY (PYY3-36), amylin, bombesin regulate important gastrointestinal functions such as motility, secretion, absorption, provide feedback to the central nervous system on availability of nutrients and may play a part in regulating food intake. The pharmacological potential of several endogenous peripheral peptides released prior to, during and/or after feeding are being explored. Long-term regulation is provided by the main circulating hormones leptin and insulin. These systems implicated in hypothalamic appetite regulation provide potential targets for treatment of obesity which could potentially pass into clinical development in the next 5 years. This review summarizes various effects and interrelationship of these central and peripheral neuropeptides in metabolism, obesity and their potential role as targets for treatment of obesity.

Topics: Agouti-Related Protein; Amyloid; Analgesics, Opioid; Animals; Appetite; Cannabinoids; Humans; Hypothalamus; Intercellular Signaling Peptides and Proteins; Islet Amyloid Polypeptide; Models, Biological; Nerve Tissue Proteins; Neuropeptide Y; Neuropeptides; Obesity; Pro-Opiomelanocortin

Obesity has reached epidemic proportions across the developed world. Even though there have been numerous scientific advances in terms of the understanding of the regulation of energy homeostasis, few novel anti-obesity drugs have emerged. Furthermore, those that are available have limited efficacy in producing and maintaining a weight loss beyond 10%. This is partly attributable to the complex neuronal circuitry at play within the central nervous system and periphery, which acts to regulate food intake and energy expenditure. This article will focus on a selection of the many products (peptides, neurotransmitters and others) such as endocannabinoids, Neuropeptide Y, Orexins, Melanin-Concentrating Hormone, Melanocortins, Cocaine and Amphetamine Regulated Transcript and Serotonin, expressed within the brain, that have been shown to influence energy balance. The true relevance of many of these to the regulation of human energy balance remains uncertain, but some novel anti-obesity drugs aimed at these targets are likely to emerge in the next few years.

Topics: Anti-Obesity Agents; Appetite; Energy Metabolism; Humans; Hypothalamus; Nerve Tissue Proteins; Neuropeptide Y; Obesity; Orexin Receptors; Receptor, Cannabinoid, CB1; Receptors, G-Protein-Coupled; Receptors, Neuropeptide; Receptors, Somatostatin; Serotonin

Regulated energy homeostasis is fundamental for maintaining life. Unfortunately, this critical process is affected in a high number of mentally ill patients. Eating disorders such as anorexia nervosa are prevalent in modern societies. Impaired appetite and weight loss are common in patients with depression. In addition, the use of neuroleptics frequently produces obesity and diabetes mellitus. However, the neural mechanisms underlying the pathophysiology of these behavioral and metabolic conditions are largely unknown. In this review, we first concentrate on the established brain machinery of food intake and body weight, especially on the melanocortin and neuropeptide Y (NPY) systems as illustration. These systems play a critical role in receiving and processing critical peripheral metabolic cues such as leptin and ghrelin. It is also notable that both systems modulate emotion and motivated behavior as well. Secondly, we discuss the significance and potential promise of multidisciplinary molecular and neuroanatomic techniques that will likely increase the understanding of brain circuitries coordinating energy homeostasis and emotion. Finally, we introduce several lines of evidence suggesting a link between the melanocortin/NPY systems and several neurotransmitter systems on which many of the psychotropic agents exert their influence.

Topics: alpha-MSH; Animals; Antipsychotic Agents; Appetite Regulation; Body Weight; Diabetes Mellitus; Emotions; Energy Metabolism; Feeding and Eating Disorders; Homeostasis; Humans; Leptin; Neuropeptide Y; Obesity; RNA, Messenger

Obesity is increasing in severity and prevalence in the United States and represents a major public health issue. No effective pharmacologic treatment leading to sustained weight loss currently exists. The growing interest in the regulation of food intake stems from the current drug treatments for obesity, almost all of which interfere with the monoamine system. Our knowledge of potential interactions between the orexigenic and anorexigenic pathways is limited and fragmented, making the development of targeted drug therapy for obesity difficult. The present review of the interaction of neuropeptides and monoamines emphasizes the complexity of the central mechanisms that regulate feeding behavior. Two main systems are implicated in food intake regulation: neuropeptide Y (NPY) and pro-opiomelanocortin. alpha-Melanocyte-stimulating hormone is a tridecapeptide cleaved from pro-opiomelanocortin that acts to inhibit food intake. The predominant NPY orexigenic receptors are NPY-Y1 and NPY-Y5, and the two anorexigenic melanocortin receptors involved in hypothalamic food intake control are MC3-R and MC4-R. Both neuropeptides interact with monoamines in the hypothalamus to control physiologic states such as hunger, satiation, and satiety. Serotonin suppresses food intake and body weight, acting mainly through the serotonin 1B receptor. Dopamine regulates hunger and satiety by acting in specific hypothalamic areas, through the D1 and D2 receptors. Noradrenaline activation of alpha1- and beta2-adrenoceptors decreases food intake, and stimulation of the alpha2-adrenoceptor increases food intake. A better understanding of the detailed mechanisms underlying the pathogenesis of hyperphagia and hypophagia is needed to develop new therapeutic approaches to obesity.

Topics: alpha-MSH; Biogenic Monoamines; Eating; Energy Intake; Energy Metabolism; Homeostasis; Humans; Neuropeptide Y; Obesity

Topics: Body Weight; Central Nervous System; Energy Metabolism; Ghrelin; Glucocorticoids; Humans; Hypothalamus; Insulin; Leptin; Neuropeptide Y; Obesity; Peptide Hormones; Pro-Opiomelanocortin; Signal Transduction

Obesity in humans causes hypertension, myocardial hypertrophy and coronary atherosclerosis, and increased cardiovascular morbidity and mortality that is thought to be related to sympathetic overactivity. Leptin is an adipocyte-derived hormone that acts in the hypothalamus to regulate appetite, energy expenditure and sympathetic nervous system outflow. One of the major mechanisms leading to the development of obesity-induced hypertension appears to be leptin-mediated sympatho-activation. Leptin adversely shifts the renal pressure-natriuresis curve, leading to relative sodium retention. Although obesity is generally associated with resistance to the anorexic and weight-reducing actions of leptin, our work has shown preservation of its sympatho-excitatory and pressor actions. This selective leptin resistance of obesity, coupled with hyperleptinaemia, may play a critical role in the cardiovascular complications of obesity. Increased information about leptin and its mechanisms of actions should help the development of safe and effective pharmacological treatments of obesity and obesity-related hypertension.

Topics: alpha-MSH; Animals; Blood Pressure; Corticotropin-Releasing Hormone; Drug Resistance; Humans; Hypertension; Leptin; Neuropeptide Y; Obesity; Receptors, Cell Surface; Receptors, Leptin; Sympathetic Nervous System

Postnatal development in most mammals is accompanied by the acquisition of controls of ingestion. In rodents, the initial and default controller appears to be gastric stretch. In the second week of life, rat pups acquire the ability to sense the presence of nutrients within the gut and appropriately modulate ingestion. In the third week of life, rat pups start to become weaned from the dam's milk and begin independent ingestion. There have been strong indications that neuropeptide Y is a stimulator of ingestion in adults, although there was very little information in pups. Dr. Gerard Smith initiated a series of studies that provide strong evidence to indicate that hypothalamic neuropeptide Y (NPY) neurons are strong candidates for providing the ability of preweaning rat pups to modulate ingestion according to caloric intake. Moreover, the studies also suggest that the overactivity of hypothalamic NPY neurons presage the onset of hyperphagia in syndromes associated with defects in leptin signaling.

Topics: Aging; Animals; Disease Models, Animal; Feeding Behavior; Gene Expression Regulation, Developmental; Hypothalamus; Mice; Neurons; Neuropeptide Y; Obesity; Rats

Neuropeptide Y is the most potent physiological appetite transducer known. The NPY network is the conductor of the hypothalamic appetite regulating orchestra in the arcuate nucleus-paraventricular nucleus (ARC-PVN) of the hypothalamus. NPY and cohorts, AgrP, GABA and adrenergic transmitters, initiate appetitive drive directly through Y1, Y5, GABAA and alpha1 receptors, co-expressed in the magnocellular PVN (mPVN) and ARC neurons and by simultaneously repressing anorexigenic melanocortin signaling in the ARC-PVN axis. The circadian and ultradian rhythmicities in NPY secretion imprint the daily circadian and episodic feeding patterns. Although a number of afferent hormonal signals from the periphery can directly modulate NPYergic signaling, the reciprocal circadian and ultradian rhythmicities of anorexigenic leptin from adipocytes and orexigenic ghrelin from stomach, encode a corresponding pattern of NPY discharge for daily meal patterning. Subtle and progressive derangements produced by environmental and genetic factors in this exquisitely intricate temporal relationship between the two opposing humoral signals and the NPY network promote hyperphagia and abnormal rate of weight gain culminating in obesity and attendant metabolic disorders. Newer insights at cellular and molecular levels demonstrate that a breakdown of the integrated circuit due both to high and low abundance of NPY at target sites, underlies hyperphagia and increased adiposity. Consequently, interruption of NPYergic signaling at a single locus with NPY receptor antagonists may not be the most efficacious therapy to suppress hyperphagia and obesity. Central leptin gene therapy in rodents has been shown to subjugate, i.e. bring under homeostatic control, NPYergic signaling and suppress the age-related and dietary obesity for extended periods and thus shows promise as a newer treatment modality to curb the pandemic of obesity and metabolic syndrome.

Topics: Animals; Appetite; Arcuate Nucleus of Hypothalamus; Circadian Rhythm; Feeding and Eating Disorders; Genetic Therapy; Metabolic Syndrome; Neuropeptide Y; Obesity; Paraventricular Hypothalamic Nucleus; Receptors, Neuropeptide Y; Signal Transduction

Maintaining a stable body weight set-point is assumed to rely on a homeostatic central nervous system (CNS) regulation of body fat with the particular involvement of hypothalamic pathways. The peripheral adiposity signals insulin and leptin convey information on the amount of energy stored as body fat to the arcuate nucleus of the hypothalamus, where anabolic/orexigenic and catabolic/anorexigenic pathways interact to regulate food intake and energy expenditure. One of the most prominent orexigenic messengers is neuropeptide Y (NPY), whereas melanocortins, including alpha-melanocyte-stimulating hormone (alpha-MSH), are essential for inducing anorexigenic effects. The melanocortin receptor 4 (MC4-R) plays the most important role in mediating catabolic effects of alpha-MSH. In this review, we present a series of own studies on NPY, insulin and MSH/ACTH4-10, an MC4-R agonist. The studies were all based on the intranasal route of administration which enables a direct access of the peptides to hypothalamic functions. NPY acutely attenuated electrocortical signs of meal-related satiety. Prolonged intranasal administration of insulin as well as of MSH induced weight loss in healthy human subjects. However, overweight subjects did not lose body fat after MSH administration. The results corroborate in humans the significance of all three messengers for the central nervous regulation of adiposity and might contribute to the future development of medical strategies against body-weight-related disorders.

Topics: Administration, Intranasal; Body Weight; Central Nervous System; Eating; Humans; Hypoglycemic Agents; Insulin; Melanocyte-Stimulating Hormones; Neuropeptide Y; Neuropeptides; Obesity; Satiety Response

Apolipoprotein A-IV (apo A-IV) is secreted by the intestine associated with chylomicron. Intestinal apo A-IV synthesis is stimulated by fat absorption, which is probably mediated by chylomicron formation. The stimulation of apo A-IV synthesis in the jejunum and ileum is attenuated by intravenous leptin infusion. Intestinal apo A-IV synthesis is also stimulated by a factor from the ileum, probably peptide tyrosine-tyrosine (PYY), which has been demonstrated to affect satiety. Apo A-IV has been proposed to physiologically control food intake, a function not shared by apo A-I, and this inhibitory effect is centrally mediated. Recently, apo A-IV was demonstrated in the hypothalamus. The hypothalamic apo A-IV level was reduced by food deprivation and restored by lipid feeding. Intracerebroventricular administration of apo A-IV antiserum increased feeding and decreased the hypothalamic apo A-IV mRNA level, implying that feeding is normally limited by endogenous apo A-IV. Central administration of neuropeptide Y (NPY) significantly increased hypothalamic apo A-IV mRNA levels in a dose-dependent manner. The stimulation of intestinal synthesis and secretion of apo A-IV by lipid absorption are rapid; thus, apo A-IV is capable of short-term regulation of food intake. Evidence also suggests apo A-IV's involvement in the long-term regulation of food intake and body weight. Chronic ingestion of high fat blunts the hypothalamic apo A-IV response to lipid feeding and may therefore explain why chronic intake of high fat predisposes animals and humans to obesity.

Topics: Adrenalectomy; Animals; Apolipoproteins A; Circadian Rhythm; Dipeptides; Dose-Response Relationship, Drug; Eating; Humans; Hypothalamus; Intestine, Small; Leptin; Lipid Metabolism; Neuropeptide Y; Obesity; Vagotomy

The hypothalamus integrates metabolic, neural and hormonal signals to evoke an intermittent appetitive drive in the daily management of energy homeostasis. Three major players identified recently in the feedback communication between the periphery and hypothalamus are leptin, ghrelin and neuropeptide Y (NPY). We propose that reciprocal circadian and ultradian rhythmicities in the afferent humoral signals, anorexigenic leptin from adipocytes and orexigenic ghrelin from stomach, encode a corresponding discharge pattern in the appetite-stimulating neuropeptide Y network in the hypothalamus. An exquisitely intricate temporal relationship among these signaling modalities with varied sites of origin is paramount in sustenance of weight control on a daily basis. Our model envisages that subtle and progressive derangements in temporal communication, imposed by environmental shifts in energy intake, impel a positive energy balance culminating in excessive weight gain and obesity. This conceptual advance provides a new target for designing pharmacologic or gene transfer therapies that would normalize the rhythmic patterns of afferent hormonal and efferent neurochemical messages.

Topics: Activity Cycles; Adipocytes; Animals; Circadian Rhythm; Fasting; Ghrelin; Growth Hormone; Humans; Hypothalamus; Leptin; Neuropeptide Y; Obesity; Peptide Hormones; Signal Transduction

Early onset obesity and type II diabetes is rapidly becoming an epidemic, especially within the United States. This dramatic increase is likely due to many factors including both prenatal and postnatal environmental cues. The purpose of this review is to highlight some of the recent advances in our knowledge of the development of the hypothalamic circuits involved in the regulation of energy balance, with a focus on the neuropeptide Y (NPY) system. Unlike the adult rat, during the postnatal period NPY is transiently expressed in several hypothalamic regions, along with the expected expression within the arcuate nucleus (ARH). These transient populations of NPY neurons during the postnatal period may provide local NPY production to sustain the necessary energy intake during this critical growth phase. This may be physiologically important since ARH-NPY projections do not fully develop until the 3rd postnatal week. The significance of this ontogeny is that many peripheral metabolic signals have little effect of feeding prior to the development of the ARH projections. The essential questions now are whether prenatal and/or postnatal exposure to high levels of insulin or leptin during development can cause permanent changes in the function of hypothalamic circuits. It is vital to understand not only the natural development of the hypothalamic circuits that regulate energy homeostasis, but also their abnormal development caused by maternal and postnatal environmental cues. This will be pivotal for designing intervention and therapeutics to treat early onset obesity/type II diabetes, which may very well need to be different from those designed to prevent/treat adult onset obesity/type II diabetes.

Topics: alpha-MSH; Animals; Arcuate Nucleus of Hypothalamus; Diabetes Mellitus; Diabetes Mellitus, Type 2; Female; Humans; Hypothalamus; Insulin; Leptin; Male; Nerve Net; Neuropeptide Y; Obesity; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Inbred Strains

Neuropeptide Y (NPY), a 36-amino-acid neuropeptide is the most potent physiological appetite transducer known. Episodic NPY neurosecretion in hypothalamic target sites is temporally linked with onset of the daily feeding pattern. Upregulation of NPY signaling in the arcuate nucleus-paraventricular nucleus (ARC-PVN) neural axis is responsible for the hyperphagia evoked by dieting, fasting, hormonal and genetic factors, and disruption in intrahypothalamic signaling. Clusters of NPY-producing neurons in the ARC that coexpress gamma- amino butyric acid and agouti-related peptide, and those in the brain stem (BS) that coexpress catecholamines and galanin, participate in disparate manners to regulate appetitive behavior. NPY receptors, Y1, Y2, and Y5, expressed by various components of the NPY network, mediate NPY-induced feeding. Imbalance in NPY signaling due either to high or low abundance of NPY at target sites elicits hyperphagia leading to increased fat accretion and obesity. Recent studies show that intermittent, feedback action of opposing afferent hormonal signals-leptin from adipose tissue and ghrelin from stomach-regulate the episodic secretion of orexigenic NPY in the PVN-ARC. Apparently, the hypothalamic NPY network is the primary common pathway intimately involved in genesis of appetite- stimulating impulses.

Topics: Animals; Appetite; Appetite Stimulants; Feeding and Eating Disorders; Humans; Neuropeptide Y; Obesity

Continuing research has increased our understanding of regulatory factors involving appetite, food intake, and energy metabolism. There appears to be a complex interaction among insulin, leptin, and ghrelin. A new study explored these interactions and indicates that leptin may regulate ghrelin levels and affect body weight changes.

Topics: Animals; Body Weight; Energy Intake; Energy Metabolism; Ghrelin; Humans; Insulin; Leptin; Mice; Neuropeptide Y; Obesity; Peptide Hormones; Rats

Ethanol is a caloric compound, and ethanol drinking and food intake are both appetitive and consummatory behaviors. Furthermore, both ethanol and food have rewarding properties. It is therefore possible that overlapping central pathways are involved with uncontrolled eating and excessive ethanol consumption. A growing list of peptides has been shown to regulate food intake and/or energy homeostasis. Peptides such as the melanocortins, corticotropin releasing factor, and cholecystokinin promote reductions of food intake while others such as galanin and neuropeptide Y stimulate feeding. The present review highlights research aimed at determining if ingestive peptides also regulate voluntary ethanol intake, with an emphasis on the melanocortins and neuropeptide Y. It is suggested that research directed at ingestive peptides may expand our understanding of the neurobiological mechanisms that drive ethanol self-administration, and may reveal new therapeutic candidates for treating alcohol abuse and alcoholism.

Topics: Adrenocorticotropic Hormone; Alcoholism; alpha-MSH; Animals; beta-MSH; Brain; Cholecystokinin; Corticotropin-Releasing Hormone; Eating; Ethanol; Galanin; gamma-MSH; Humans; Narcotics; Neuropeptide Y; Obesity; Receptors, Melanocortin

Obesity is associated with numerous health complications, which range from non-fatal debilitating conditions such as osteoarthritis, to life-threatening chronic diseases such as coronary heart disease, diabetes and certain cancers. The psychological consequences of obesity can range from lowered self-esteem to clinical depression. Despite the high prevalence of obesity and the many advances in our understanding of how it develops, current therapies have persistently failed to achieve long-term success. This review focuses on how fat mass can be reduced by altering the balance between energy intake and expenditure.

Topics: Adipose Tissue, Brown; Carrier Proteins; Energy Intake; Energy Metabolism; Humans; Hypothalamic Hormones; Leptin; Melanins; Neuropeptide Y; Obesity; Pituitary Hormones; Pro-Opiomelanocortin; Receptor, Muscarinic M1; Receptors, Cell Surface; Receptors, Corticotropin; Receptors, Leptin; Receptors, Melanocortin; Receptors, Muscarinic; Receptors, Pituitary Hormone; Transcription, Genetic

Obesity results from a chronic imbalance between energy intake and energy expenditure. Environmental factors, such as the increased availability of high caloric food or the decreased need for physical activity, contribute to its development and their influence is amplified by genetic predisposition. In recent years remarkable progress has been made in the understanding of the pathophysiology of obesity. Although most of the insights into the regulation of energy balance have been obtained in rodent models, the rare clinical cases of monogenic obesity provided evidence for the importance of several of these mechanisms in humans. The identification of leptin as a factor originating from adipose tissue and informing the brain about the status of energy reserves firmly established the concept of long-term regulation of body fat stores. The disappointing therapeutic results with leptin in obese patients could be explained by the fact that during evolution this hormone developed rather as a starvation signal than as an adiposity signal. It is conceivable that the pharmacological interference with mechanisms downstream of leptin, for example with the melanocortin pathway, might be therapeutically more promising. The discovery of new molecular mechanisms involved in the regulation of the differentiation and proliferation of adipocytes and the elucidation of their paracrine and endocrine functions have changed the traditional view of adipose tissue as an inert depot for triglycerides. The identification of new uncoupling proteins could modify the current concepts of the regulation of thermogenesis in humans. The remarkable progress in the identification of novel targets involved in the regualtion of energy balance should have a positive impact on the search for new antiobesity agents.

Topics: Animals; Biological Evolution; Brain; Eating; Energy Metabolism; Environment; Homeostasis; Humans; Leptin; Neuropeptide Y; Obesity

The co-ordinated regulation of food intake and energy expenditure takes place in the hypothalamic regions of the brain. Current understanding of the systems involved in this regulation suggests that, in the hypothalamus, there are two major groups of neuropeptides involved in orexigenic and anorexic processes. The orexigenic neuropeptides are neuropeptide Y (NPY) and agouti-related peptide (AgRP) and the anorexic neuropeptides are alpha-melanocyte-stimulating hormone (alpha-MSH) and cocaine and amphetamine-related transcript (CART). Theneurons expressing these neuropeptides interact with each other and with signals from the periphery (such as leptin, insulin, ghrelin and glucocorticoids) to regulate feeding behaviour, energy expenditure and various endocrine axes. Although direct evidence is limited, there are examples of genetic obesity in humans which suggest that the balance between orexigenic and anorexic pathways in the hypothalamus is also pivotally important in the maintenance of energy homeostasis in humans.

Topics: Agouti-Related Protein; alpha-MSH; Animals; Eating; Energy Metabolism; Homeostasis; Humans; Hypothalamus; Intercellular Signaling Peptides and Proteins; Mice; Mice, Knockout; Nerve Tissue Proteins; Neurons; Neuropeptide Y; Obesity; Proteins

The prevalence of obesity is rising at an alarming rate worldwide, with consequent increases in type 2 diabetes, hypertension and cardiovascular morbidity and mortality. Central neural mechanisms, via the activation of the sympathetic nervous system may contribute to obesity-related cardiovascular diseases through the promotion of hypertension, dysrhythmia and atherosclerosis. However, the mechanisms responsible for this sympatho activation have not been identified. Leptin is an adipocyte-derived hormone that promotes weight loss by reducing appetite and by increasing energy expenditure through sympathetic stimulation to thermogenic tissue. Leptin also produces sympathoactivation to kidneys, hindlimb and adrenal glands, suggesting that the obesity-associated increase in sympathetic nerve activity could be due in part to these sympathetic effects of leptin. However, most human obesity appears to be associated with leptin resistance. Recent studies indicate that leptin resistance may be selective, with preservation of adverse sympathetic effects despite the loss of the metabolic actions of leptin. The leptin receptor is expressed in several hypothalamic nuclei including the arcuate nucleus. The melanocortin system, neuropeptide Y and corticotrophin-releasing factor have emerged as principal neuropeptide mediators of leptin action in the arcuate nucleus. These neuropeptides exert varying effects by different pathways. Several other candidate hypothalamic pathways that can mediate the effects of leptin have been identified. The understanding of neuronal signaling pathways involved in leptin signaling and energy balance has opened new research possibilities for the treatment of obesity.

Topics: Animals; Anti-Obesity Agents; Brain; Drug Resistance; Humans; Hypertension; Hypothalamus; Leptin; Neuropeptide Y; Obesity; Receptors, Cell Surface; Receptors, Corticotropin; Receptors, Leptin; Receptors, Melanocortin; Receptors, Neuropeptide Y; Sympathetic Nervous System

Genetic advances have made remarkable progress towards our understanding of body weight regulation. Much of our current knowledge has come from the cloning and characterisation of the genes responsible for obesity syndromes in the mouse, and the identification of homologous mutations causing rare forms of obesity in humans. Gene targeting experiments in mice have been instrumental in confirming the importance of many genes in the aetiology of obesity, and the existence of a fundamental physiological pathway that controls energy balance is becoming clear. The genetic determinants that underlie common forms of human obesity are largely polygenic, with most genes producing small effects. Thus, elucidating the many genetic determinants of obesity is a current challenge for modern geneticists. Despite the inherent difficulties, progress has been made through linkage/association studies and a genetic map of quantitative trait loci for human obesity is beginning to emerge. Obesity research is now very much in a transition period. Not so long ago, access to high throughput screening, as well as microarray and proteomic techniques, was prohibitively expensive and available only to the few. In recent years, these technologies have become more accessible to the larger scientific community and, in this paper, we will discuss how such technological advances are likely to drive the next wave of progress in obesity research. For example, large-scale mutagenesis screens in rodents coupled with high throughput screening are likely to emerge as important technologies for identifying genes previously unexpected to be involved in body weight regulation. Furthermore, applications of microarray and proteomic techniques will further refine our understanding of currently known peptides as well as identify novel pathways and molecules which are involved in energy homeostasis.

Topics: Agouti Signaling Protein; Agouti-Related Protein; alpha-MSH; Animals; Body Weight; Cloning, Molecular; Disease Models, Animal; Genomics; Humans; Intercellular Signaling Peptides and Proteins; Leptin; Mice; Neuropeptide Y; Obesity; Pro-Opiomelanocortin; Proprotein Convertase 1; Proteins; Proteomics; Receptors, Cell Surface; Receptors, Leptin; Receptors, Melanocortin

Several studies have shown the association between obesity and hypertension. The pathophysiologic mechanisms of obesity-related hypertension remain unknown. Clinical and experimental studies have shown that obesity is associated with enhanced sympathetic nervous activity. Thus, sympathetic nerve activation seems to play a major role in obesity-associated hypertension. However, the factors responsible for this sympathoactivation have not been identified. Leptin is an adipocyte-derived hormone that promotes weight loss by reducing appetite and food intake and by increasing energy expenditure through sympathetic stimulation to brown adipose tissue. Leptin also produces sympathoactivation to kidneys, hindlimb, and adrenal glands, indicating that the obesity-associated increase in sympathetic nerve activity could be due in part to these sympathetic effects of leptin. However, obesity is associated with leptin resistance, since high circulating levels of leptin were observed in obese subjects. Recent evidences indicate that this leptin resistance could be selective with preservation of sympathetic effects despite the loss of metabolic action of leptin. This suggests divergent central pathways underlying metabolic and sympathetic effects of leptin. Several neuropeptides have emerged as potent candidate mediators of leptin action in the central nervous system, including the melanocortin system, neuropeptide Y, and cortico-trophin releasing factor. A detailed understanding of the multitude and complexity of integrated neuronal circuits and neuropeptide-containing pathways in leptin action will help in understanding the pathogenesis of obesity and related disorders.

Topics: Animals; Cardiovascular System; Humans; Hypertension; Hypothalamus; Leptin; Neuropeptide Y; Obesity; Sympathomimetics

Topics: Animals; Ghrelin; Humans; Neuropeptide Y; Obesity; Peptide Hormones; Receptors, Cell Surface; Receptors, G-Protein-Coupled; Receptors, Ghrelin

Neuropeptide Y is a widely distributed neuropeptide that elicits a plethora of physiological effects via interaction with six different receptors (Y(1)-y(6)). Recent attention has focused on the role of neuropeptide Y in the regulation of energy homeostasis. Neuropeptide Y stimulates food intake, inhibits energy expenditure, increases body weight and increases anabolic hormone levels by activating the neuropeptide Y Y(1) and Y(5) receptors in the hypothalamus. Based on these findings, several neuropeptide Y Y(1) and Y(5) receptor antagonists have been developed recently as potential anti-obesity agents. In addition, mice lacking neuropeptide Y, the neuropeptide Y Y(1) receptor or the neuropeptide Y Y(5) receptor have been generated. The data obtained to date with these newly developed tools suggests that neuropeptide Y receptor antagonists, particularly neuropeptide Y Y(1) receptor antagonists, may be useful anti-obesity agents. However, the redundancy of the neurochemical systems regulating energy homeostasis may limit the effect of ablating a single pathway. In addition, patients in whom the starvation response is activated, such as formerly obese patients who have lost weight or patients with complete or partial leptin deficiency, may be the best candidates for treatment with a neuropeptide Y receptor antagonist.

Topics: Animals; Anti-Obesity Agents; Arginine; Body Weight; Energy Metabolism; Humans; Neuropeptide Y; Obesity; Pharmaceutical Preparations; Receptors, Neuropeptide Y; Structure-Activity Relationship

Body weight homeostasis is maintained via a series of complex interactions that occur between the brain (particularly the hypothalamus) and the periphery, notably via the hormone leptin, which is synthesized in and secreted from adipose tissue. Under normal conditions, a dynamic equilibrium exists between anabolic neuropeptides (orexigenic peptides), which favor food intake, decrease energy expenditure, and facilitate fat storage, and catabolic ones (anorexigenic peptides), which decrease food intake, increase energy expenditure, and facilitate the loss of fat stores. Secreted leptin, although it may have some direct peripheral effects, exerts its action principally within the brain. Following its transport through the blood-brain barrier, leptin reaches the hypothalamic area, where it binds to its long receptor isoform. After a specific signaling cascade, leptin inhibits many of the orexigenic neuropeptides while favoring many of the anorexigenic ones. Thus, leptin decreases food intake and body weight, and it increases fat oxidation and energy expenditure, ultimately favoring leanness. Lack of leptin secretion, the inability of leptin to reach the brain, or the inability of leptin to interact with hypothalamic leptin receptors, prevent leptin's effects and lead to obesity.

Topics: alpha-MSH; Body Weight; Corticotropin-Releasing Hormone; Eating; Energy Metabolism; Homeostasis; Humans; Hypothalamic Hormones; Leptin; Melanins; Nerve Tissue Proteins; Neuropeptide Y; Neuropeptides; Obesity; Opioid Peptides; Pituitary Hormones

Recent advances in our understanding of the regulation of body weight, appetite, and metabolic rate have highlighted the role of the adipose-derived hormone leptin and its receptor as fundamental modulators of these processes. Investigations of the neural targets for leptin action--as well as characterization of the agouti obesity syndrome--have, in turn, led to the discovery of fundamental neural pathways involved in the central regulation of energy homeostasis. In particular, the central melanocortin system has been shown to regulate appetite and metabolic rate in rodents; mutations in this system have been demonstrated to result in obesity in humans. Overall, the melanocortin system appears to function as a bidirectional rheostat in the regulation of energy intake and expenditure in rodents and potentially in humans. The first section of this chapter will focus on the development of our understanding of melanocortin physiology in the context of obesity. In particular, recent data regarding the interplay between melanocortin and neuropeptide Y (NPY) signaling at a cellular level will be discussed. The following section will discuss the hypothesis that melanocortin signaling plays a role in pathological weight loss and hypermetabolism observed in murine cachexia models. The potential role of this system in integrating a variety of anorexic and cachexic signals, as well as the potential for its pharmacological manipulation in the treatment of human cachexia, will be discussed.

Topics: alpha-MSH; Animals; Cachexia; Cytokines; Humans; Mice; Models, Biological; Neuropeptide Y; Obesity; Protein Binding; Rats; Signal Transduction

Our understanding of body weight regulation has been greatly advanced by the characterization of previously existing mutations in mice that cause obesity. Subsequent analysis of a number of mouse knockout models has greatly expanded the number of genes known to influence adiposity by affecting metabolic rate, physical activity, and/or appetite.

Topics: Animals; Disease Models, Animal; Gonadal Steroid Hormones; Humans; Mice; Mice, Knockout; Neuropeptide Y; Neurotransmitter Agents; Obesity; Pro-Opiomelanocortin; Receptors, Adrenergic, beta-3; Receptors, Corticotropin; Receptors, Cytoplasmic and Nuclear; Receptors, Melanocortin; Receptors, Neuropeptide Y; Transcription Factors

Topics: Adipose Tissue; Animals; Fatty Acids, Nonesterified; Feeding Behavior; Growth Hormone-Releasing Hormone; Human Growth Hormone; Humans; Insulin-Like Growth Factor I; Leptin; Neuropeptide Y; Obesity

The importance of the melanocortin system in obesity has been confirmed by the recent discovery of mutations in the melanocortin MC4 receptor in morbidly obese patients and the finding that intranasal administration of a fragment of melanocortin decreases body fat in humans. Transgenic mice overexpressing melanin-concentrating hormone (MCH) are obese and a second MCH receptor has been identified. In addition, ghrelin, endocannabinoids and glucagon-like peptide 2 have been identified as potentially important central regulators of food intake.

Topics: Agouti-Related Protein; Animals; Cannabinoid Receptor Modulators; Cannabinoids; Eating; Energy Metabolism; Ghrelin; Glucagon-Like Peptide 2; Glucagon-Like Peptides; Humans; Hypothalamic Hormones; Hypothalamus; Intercellular Signaling Peptides and Proteins; Melanins; Nerve Tissue Proteins; Neuropeptide Y; Obesity; Peptide Hormones; Peptides; Pituitary Hormones; Pro-Opiomelanocortin; Proteins; Receptor, Melanocortin, Type 3; Receptor, Melanocortin, Type 4; Receptors, Corticotropin

Over the past several years, new modulators of feeding and body weight have been discovered, and our knowledge of the mechanisms and neurohumoral interactions between anorexigenic and orexigenic compounds has increased dramatically. This review aims to summarize the present knowledge of the role of leptin and several hypothalamic neuropeptides, such as neuropeptide Y (NPY), corticotropin-releasing hormone (CRH) and melanocortins, in the regulation of appetite and body weight. It also presents the progress made in the design of interactions between leptin and hypothalamic peptides in the regulation of feeding. The role of these compounds in the pathogenesis of obesity in animals and humans, and their potential usefulness in the treatment of this disorder, are discussed.

Topics: Animals; Appetite; Body Weight; Corticotropin-Releasing Hormone; Drug Interactions; Humans; Leptin; Melanocyte-Stimulating Hormones; Neuropeptide Y; Obesity

The obesity-like effects produced by the chronic intracerebroventricular (i.c.v.) neuropeptide Y (NPY) infusion in normal rats require the presence of glucocorticoids, as none of them occurs when NPY is similarly infused in adrenalectomized rats. NPY effects are present again when i.c.v. NPY is infused together with i.c.v. dexamethasone in adrenalectomized animals. The inhibitory effect of leptin on food intake and body weight observed when the hormone is i.c.v. administered to normal rats is markedly enhanced and longer lasting when the same dose of leptin is i.c.v. administered to adrenalectomized rats. Glucocorticoid administration to adrenalectomized rats dose-dependently reduces, then abolishes, this potent effect of leptin. Thus, glucocorticoids limit leptin-induced effects. The chronic i.c.v. infusion of glucocorticoids (dexamethasone) to normal rats produces an obesity syndrome with its several abnormalities. This appears to be due to glucocorticoid-elicited increases in hypothalamic NPY levels together with decreases in those of CRH. Thus, the status of the hypothalamo-pituitary-adrenal axis and related glucocorticoid output is a relevant facet of body weight homeostasis. It may be a deleterious environmental factor responsible for the development of obesity, insulin as well as leptin resistance, and type 2 diabetes.

Topics: Animals; Body Weight; Central Nervous System; Glucocorticoids; Homeostasis; Insulin Resistance; Leptin; Neuropeptide Y; Obesity; Peripheral Nervous System; Rats

Recent experimental evidence supports the role of glucocorticoids in the neuroendocrine control of food intake and energy expenditure. In particular, glucocorticoids promote food consumption directly through stimulation of NPY and inhibition of CRH and melanocortin release. CRH and NPY are also functionally linked by a mutual regulation. CRH is anorexigenic when secreted acutely while it exerts the opposite effect when, upon sustained secretion, it stimulates the hypothalamo-pituitary-adrenal (HPA) axis. The orexigenic effects of glucocorticoids are counteracted by a steroid-induced rise in leptin levels that closes a regulatory loop regarding food consumption. Furthermore, glucocorticoids may alter body fat distribution, increasing truncal adiposity both directly and by inhibition of growth hormone secretion. No clearcut alterations of the HPA function are apparent in obesity as a whole. However, subtle and specific abnormalities may be noted in subsets of obese patients. Indeed, obesity, mostly visceral type, is associated with an increased cortisol clearance and 11-beta hydroxysteroid dehydrogenase activity in the omental fat. In the same vein, an increased cortisol rise following a mixed meal has been observed in obese subjects. Finally, it has been proposed that adrenal incidentalomas, often characterized by enhanced cortisol secretion, might be a clinical expression of the X syndrome.

Topics: Animals; Body Constitution; Corticotropin-Releasing Hormone; Eating; Energy Metabolism; Glucocorticoids; Humans; Leptin; Neuropeptide Y; Neurosecretory Systems; Obesity; Viscera

The hypothalamus is the focus of many peripheral signals and neural pathways that control energy homeostasis and body weight. Emphasis has moved away from anatomical concepts of 'feeding' and 'satiety' centres to the specific neurotransmitters that modulate feeding behaviour and energy expenditure. We have chosen three examples to illustrate the physiological roles of hypothalamic neurotransmitters and their potential as targets for the development of new drugs to treat obesity and other nutritional disorders. Neuropeptide Y (NPY) is expressed by neurones of the hypothalamic arcuate nucleus (ARC) that project to important appetite-regulating nuclei, including the paraventricular nucleus (PVN). NPY injected into the PVN is the most potent central appetite stimulant known, and also inhibits thermogenesis; repeated administration rapidly induces obesity. The ARC NPY neurones are stimulated by starvation, probably mediated by falls in circulating leptin and insulin (which both inhibit these neurones), and contribute to the increased hunger in this and other conditions of energy deficit. They therefore act homeostatically to correct negative energy balance. ARC NPY neurones also mediate hyperphagia and obesity in the ob/ob and db/db mice and fa/fa rat, in which leptin inhibition is lost through mutations affecting leptin or its receptor. Antagonists of the Y5 receptor (currently thought to be the NPY 'feeding' receptor) have anti-obesity effects. Melanocortin-4 receptors (MC4-R) are expressed in various hypothalamic regions, including the ventromedial nucleus and ARC. Activation of MC4-R by agonists such as alpha-melanocyte-stimulating hormone (a cleavage product of pro-opiomelanocortin which is expressed in ARC neurones) inhibits feeding and causes weight loss. Conversely, MC4-R antagonists such as 'agouti' protein and agouti gene-related peptide (AGRP) stimulate feeding and cause obesity. Ectopic expression of agouti in the hypothalamus leads to obesity in the AVY mouse, while AGRP is co-expressed by NPY neurones in the ARC. Synthetic MC4-R agonists may ultimately find use as anti-obesity drugs in human subjects Orexins-A and -B, derived from prepro-orexin, are expressed in specific neurones of the lateral hypothalamic area (LHA). Orexin-A injected centrally stimulates eating and prepro-orexin mRNA is up regulated by fasting and hypoglycaemia. The LHA is important in receiving sensory signals from the gut and liver, and in sensing glucose, and orexin neurone

Topics: Animals; Eating; Energy Metabolism; Homeostasis; Humans; Hypothalamic Area, Lateral; Hypothalamus; Mice; Neuropeptide Y; Neuropeptides; Obesity; Rats; Receptor, Melanocortin, Type 4; Receptors, Corticotropin

Neuropeptide Y (NPY) is a 36 amino acid amidated peptide which has now emerged as an important regulator of feeding behaviour. Upon intracerebroventricular (icv.) administration, NPY produces a pronounced feeding response in a variety of species. The actions of NPY are believed to be mediated by a family of receptor subtypes named Y1 - y6. Recent studies suggest that the Y1 and Y5 receptor subtypes are intimately involved in NPY induced feeding. This review presents preclinical data obtained with receptor subtype selective agonists and antagonists as well as findings from knockout mice. These new data suggest that NPY receptor antagonists may become an additional option for treating human obesity.

Topics: Animals; Homeostasis; Humans; Mice; Mice, Knockout; Neuropeptide Y; Obesity; Receptors, Neuropeptide Y

Topics: 4-Butyrolactone; Acetyl-CoA Carboxylase; Animals; Eating; Enzyme Inhibitors; Fatty Acid Synthases; Humans; Mice; Neuropeptide Y; Obesity; Triglycerides; Weight Loss

The aim of this paper is to review the present knowledge of interactions between the neuropeptide Y (NPY) system and the hypothalamic-pituitary-adrenal (HPA) axis. On the basis of in vitro and in vivo studies of various animal species, we review the effects of NPY on all levels of HPA axis activity. We also describe the effects of glucocorticosteroids on the NPY system in the hypothalamus, including interactions between glucocorticosteroids and insulin. On the basis of available literature, we discuss the role of these interactions in the control of food intake and in the pathogenesis of obesity.

Topics: Animals; Eating; Humans; Hypothalamo-Hypophyseal System; Neuropeptide Y; Obesity; Pituitary-Adrenal System

Mounting evidence supports a 'lipostatic' model for the regulation of adipose mass. In such a model, signals are generated in the periphery in proportion to adipose mass that act on hypothalamic control centers in the brain to regulate food intake and energy expenditure. Two such signals, leptin and insulin, have been identified and found to dramatically lower food intake and body weight. Several signalling molecules in the effector pathways that mediate the response to these signals in the brain have also been identified. The regulation of these factors and the nature of the adipose-CNS regulatory loop will be discussed.

Topics: Adipocytes; Adipose Tissue; alpha-MSH; Animals; Central Nervous System; Homeostasis; Humans; Insulin; Leptin; Neuropeptide Y; Obesity; Proteins; Signal Transduction

Topics: Amino Acids; Animals; Chromosome Aberrations; Chromosome Disorders; Diabetes Mellitus; Humans; Mice; Neuropeptide Y; Obesity; Rats; RNA, Messenger

The pharmacological management of obesity has gained increasing attention as new weight loss treatments are approved and a significant proportion of the public strives to lose weight. Obesity is associated with a high mortality rate, multiple chronic medical conditions, and carries an enormous financial burden. Obesity is a multifactorial condition, most often due to an imbalance in energy intake and expenditure. Despite the greater focus on management of obesity, weight loss remains a difficult goal to achieve. Obesity is a chronic medical condition that may require long term treatment, therefore the risks and benefits of all pharmacological agents must be carefully considered. Noradrenergic appetite suppressants (ie. phenyl-propanolamine, phentermine) result in weight loss but stimulatory effects limit their use. The serotonergic agents (fenfluramine, dexfenfluramine) were effective weight loss drugs, but were voluntarily withdrawn from the US market last year because of cardiovascular and pulmonary complications. The combination noradrenergic/serotonergic agent sibutramine is indicated for the management of obesity, particularly in the presence of other cardiovascular risk factors. Modest weight loss is achieved with sibutramine, although weight gain is significant after discontinuation. In addition, long term safety data are not yet available. The thermogenic combination of ephedrine plus caffeine is minimally effective, and adverse effects are usually transient. Other thermogenic agents, such as beta3-agonists, are still under investigation. Agents may alter digestion through lipase inhibition (orlistat) or fat substitution (olestra). Orlistat decreases systemic absorption of dietary fat, decreasing body weight and cholesterol. Olestra is a fat substitute that has been incorporated into snack foods. Olestra substitution for dietary fat has not been studied as a weight loss strategy, although olestra has no caloric value and may be beneficial. The use of orlistat and olestra may be limited by gastrointestinal adverse effects. Finally, the manipulation of leptin and neuropeptide Y are under investigation for the treatment of obesity. Pharmacological agents should be used as an aid to a structured diet and exercise regimen in the treatment of obesity. Weight loss agents may result in initial weight loss, but sustained weight loss is not always achieved even with continuation of treatment. The effect of weight loss obtained while using pharmacotherapeuti

Topics: Appetite Depressants; Digestion; Hormones; Humans; Hyperthermia, Induced; Leptin; Neuropeptide Y; Obesity; Proteins

The 36-amino-acid peptide, neuropeptide Y (NPY), is the most abundant peptide in the rat brain. When administered into the brain, NPY produces a variety of physiological actions including a pronounced stimulation of feeding in satiated rats. Elevations in hypothalamic NPY have been reported after food deprivation and in genetically obese rodents. NPY is believed to produce its actions through a portfolio of G-protein coupled receptors, Y1, Y2, Y4 and Y5. Studies using peptide analogs, receptor knockout animals and specific receptor antagonists suggest the Y1 and Y5 receptors are important in mediating the effects of NPY on food intake in rats. Development of specific receptor antagonists with improved pharmacokinetic properties will be required to determine the importance of NPY in human obesity and appetite disorders.

Topics: Animals; Eating; Feeding Behavior; Humans; Hypothalamus; Neuropeptide Y; Obesity; Receptors, Neuropeptide Y

Leptin is a satiety factor which acts within the hypothalamus to decrease the levels of several neuropeptides stimulating food intake (among them, neuropeptide Y [NPY]), while increasing those that inhibit food intake. These effects of leptin bring about decreased body weight. In vivo, leptin potentiates basal and insulin-stimulated glucose utilization, presumably its oxidation, and decreases fat storage. Leptin increases sympathetic-mediated energy dissipation, and the expression of uncoupling proteins-1, -2, and -3. In peripheral tissues (muscles, adipose, others), leptin decreases triglyceride content by increasing fatty acid oxidation, decreasing the activity/expression of esterification and lipogenic enzymes, and favoring lipolysis. It decreases the lipogenic activity of insulin. Ultimately, leptin depletes fat stores and promotes leanness. NPY, taken as one example of what an orexigenic agent may produce, increases food intake and body weight. It favors fat storage in adipose tissue by stimulating lipogenic activity. It decreases glucose utilization by muscles, making more glucose carbon available for lipogenesis. Effects of NPY result from vagus nerve-mediated hyperinsulinemia and overactivity of the hypothalamo-pituitary-adrenal axis. Thus, NPY favors fat stores, and ultimately obesity. Glucocorticoids are necessary for NPY effects to occur, because central administration of the neuropeptide in adrenalectomized animals is ineffective. Glucocorticoids also have genuine effects when administered centrally to normal rats. They increase the hypothalamic content of NPY and decrease that of CRH. This double neuro-peptidic change stimulates food intake, insulin output, adipose tissue storage ability, decreases the expression of uncoupling proteins-1 and -3, and increases body weight. Body weight homeostasis appears to require a finely tuned regulation of both leptin and glucocorticoids, with their respective opposite effects.

Topics: Adipose Tissue; Animals; Eating; Energy Metabolism; Glucocorticoids; Humans; Insulin; Insulin Secretion; Leptin; Neuropeptide Y; Obesity; Thinness

The prevalence of obesity in children and adults in the United States has increased by more than 30% over the past decade. Recent studies of the physiology and molecular genetics of obesity in humans have provided evidence that body weight (fat) is regulated. Some of the genes encoding the molecular components of this regulatory system have been isolated from rodents. The increasing prevalence of obesity in the United States apparently represents the interaction of these genes with an environment that encourages a sedentary lifestyle and consumption of calories. The rapid increase in the prevalence of obesity emphasizes the role of environmental factors, because genetic changes could not occur at this rate. Thus, understanding of the relevant genes and how their effects are mediated by environment and development should lead to more effective prophylaxis and therapy of obesity. Although no clear environmental factors have been identified as causative of obesity, the rapid increases in the prevalence of obesity and the seeming voluntary immutability of adult body fatness can be taken as tacit evidence that the pediatric environment can be altered in a way that affects adult body weight.

Topics: Adipose Tissue; Age Factors; Agouti Signaling Protein; Animals; Body Mass Index; Body Weight; Energy Metabolism; Health Surveys; Humans; Hypothalamus; Intercellular Signaling Peptides and Proteins; Leptin; Mice; Molecular Biology; Neuropeptide Y; Nutrition Surveys; Obesity; Paraventricular Hypothalamic Nucleus; Prevalence; Proteins; Rats; United States

The study of obesity is one of the most active and fast moving area in the basic biomedical research. In the past three years, scientists had cloned the obese gene, clarified the structure of leptin, nailed down and cloned the gene of leptin receptor, partly revealed the mechanisms of leptin's effects which make the study of obesity entering the molecular age. It shows an attractive perspective for human being to control the body weight and increase the health level. The recent progress of all these aspects is discussed in this review.

Topics: Animals; Body Weight; Gene Expression Regulation; Humans; Leptin; Neuropeptide Y; Obesity; Receptors, Cell Surface; Receptors, Leptin

Neuropeptide Y (NPY), a 36 amino acid neuromodulator that is secreted by neurons throughout the peripheral and central nervous system, has been implicated in the control of many physiological processes. We have begun to examine its role in regulation of appetite, behavior, and excitotoxicity by examining mice that are unable to produce NPY as a consequence of gene inactivation. These mutant mice are remarkably normal when reared under standard vivarium conditions. Despite considerable evidence that NPY plays a central role in stimulating appetite, NPY-deficient mice eat normally, grow normally, and refeed after a fast normally. Furthermore, all of their endocrine responses to fasting are normal. The response of NPY-null mice to diet-induced obesity, chemically induced obesity (monosodium glutamate and gold thioglucose), and genetic-based obesity (lethal yellow agouti, Ay; uncoupling protein-diphtheria toxin transgenics, UCP-DT) were all normal. However, NPY deficiency does partially ameliorate the obesity and all of the adverse endocrine effects of leptin deficiency in ob/ob mice. NPY-null mice as well as mice deficient in both NPY and leptin are more sensitive to leptin, suggesting that NPY may normally have a tonic inhibitory action on leptin-mediated satiety signals. NPY-null mice display the normal voracious feeding response to injected NPY. Thus, the only condition where we have observed a role for NPY in body-weight regulation is in the context of complete leptin deficiency--where absence of NPY is beneficial. The activity and general behavior of NPY-null mice are normal. They appear to have normal spatial and contextual learning ability; however, they manifest more anxiety under some conditions. NPY-null mice occasionally display spontaneous, seizure-like events. They also are less able to terminate seizures induced by GABA receptor antagonists or glutamate receptor agonists. These observations are consistent with previous data suggesting that NPY plays an important role in dampening excitotoxicity.

Topics: Animals; Body Weight; Life; Mice; Mice, Knockout; Neuropeptide Y; Obesity

The concept of interrelationships between the central nervous system and the periphery aimed at maintaining normal body weight homeostasis has been strengthened by the discovery of hypothalamic neuropeptide Y (NPY) and adipose tissue leptin. NPY, when infused intracerebroventricularly in normal animals produces hyperphagia and hormono-metabolic changes (hyperinsulinemia, hypercorticism) channeling nutrients preferentially toward lipogenesis and storage in adipose tissue and away from their utilization by muscles (muscle insulin resistance). Storage in NPY-infused rats is further favored by the observed decrease in the expression of uncoupling proteins. NPY-induced hyperinsulinemia and hypercorticosteronemia also promote leptin over-secretion. Released leptin, acting within the hypothalamus, decreases hypothalamic NPY levels (probably those of other hypothalamic neuropeptides as well), food intake, insulinemia, insulin sensitivity of white adipose tissue, while increasing that of muscles. Leptin acting centrally additionally favors the expression of uncoupling protein 1, 2, and 3, in keeping with an eflect on energy dissipating mechanisms. The respective hormono-metabolic eflects of NPY and leptin maintain a normal body homeostasis. In most obesity syndromes, the functional relationships between NPY and leptin are altered. Due to hypothalamic leptin receptor mutations or dysfunctions, leptin cannot exert its eflects: NPY levels (possibly those of other neuropeptides) remain elevated, maintaining excess storage, insulin as well as leptin resistance.

Topics: Adipose Tissue; Animals; Body Weight; Carrier Proteins; France; History, 19th Century; History, 20th Century; Homeostasis; Humans; Hypothalamus; Leptin; Models, Biological; Neuropeptide Y; Obesity; Physiology; Proteins; Rats; Receptors, Cell Surface; Receptors, Leptin

Obesity is a serious health problem in the Western societies, therefore its treatment has become the subject of intense interest in the scientific community. A significant number of recent publications enlist different central and peripheral factors which play important roles in the regulation of food intake, body weight and energy expenditure. Neuropeptide Y, a 36 amino acid peptide, which is quite abundant in the brain, seems to be one of the more important players in these regulations. Recently five NPY receptors have been cloned and pharmacological evidence strongly supports the existence of a sixth receptor. There are many contradictory findings regarding which NPY receptor mediates the effect of NPY on food intake. This article will review the effects of NPY on the regulation of food intake and energy expenditure and will discuss the pharmacological and molecular evidence as to which NPY receptor(s) mediate this effect. The review will also summarize the progress which has been made in the design of novel NPY-ergic ligands, especially NPY receptor antagonists, for potential use in the treatment of obesity.

Topics: Animals; Body Weight; Brain Chemistry; Eating; Energy Metabolism; Feeding Behavior; Humans; Molecular Structure; Neuropeptide Y; Obesity; Receptors, Neuropeptide Y

A growing body of evidence suggests that energy balance (the difference between energy intake and expenditure) and body fuel stores in the form of adipose tissue are maintained by the body within a narrow range. This regulation of adiposity is mediated by the secretion of hormonal signals into the circulation in proportion to body adipose stores and their subsequent actions on brain systems that control caloric intake and energy expenditure. As a result, changes in energy balance sufficient to alter fuel stores elicit compensatory changes in energy intake and expenditure that return fat stores to their regulated level. Recent scientific break-through have identified the key components of this physiologic system. These include the circulating signals, leptin (the hormone encoded by the ob gene that is secreted by fat cells) and the pancreatic hormone insulin; and brain peptides such as neuropeptide Y, which is released from nerve terminals in the hypothalamus to elicit changes in feeding behavior and energy expenditure that mediate adaptive changes in energy balance. This article reviews the discovery of leptin and its receptor and discusses the interaction of leptin and insulin with the hypothalamic neuropeptide Y system. These observations provide a basis for understanding how weight lost during a period of negative energy balance (because of the inability to consume and/or store sufficient energy to meet ongoing energy demands) is eventually recovered. As our understanding of this weight-regulatory system increases, new insights into the causes of human obesity are likely to follow. Such insights may yield improvements in the medical and nutrition management of obese patients.

Topics: Animals; Body Weight; Brain; Corticotropin-Releasing Hormone; Feedback; Humans; Insulin; Leptin; Neuropeptide Y; Obesity; Proteins

Thirty-five years ago, Lois and Theodore Zucker reported the discovery of a genetic mutation in the rat that resulted in juvenile-onset obesity, increased food intake, decreased energy expenditure, and insulin resistance. The mutation was called fatty (fa). The fatty gene is passed on to successive generations by an autosomal recessive mode of inheritance. In the intervening years, much work has been done to characterize the many abnormalities of this animal model of obesity. Nearly 10 years ago, we reviewed the evidence for a central nervous system mechanism in the etiology of obesity in the fatty Zucker rat. Since that time, the discovery of novel peptides and genes has revolutionized the study of the etiology of genetically linked obesities. In this review, we update the evidence for a central nervous system mechanism of obesity in Zucker rats by focusing on the possible role of neuropeptide Y (NPY) and leptin in the etiology of obesity. We also discuss the role of glucocorticoids and insulin in the regulation of NPY.

Topics: Animals; Central Nervous System; Leptin; Neuropeptide Y; Obesity; Proteins; Rats; Rats, Zucker

Short-term variations in caloric intake and energy expenditure-including attempts by obese patients to lose weight-tend to be modified by the body's long-term weight regulatory system. Hormones such as leptin and insulin participate in this system, which links changes in body fat content to appropriate compensatory responses in the hypothalamus. Correction of defects in the system might permit sustained weight loss in obese patients.

Topics: Appetite Regulation; Body Weight; Energy Intake; Energy Metabolism; Humans; Hypothalamus; Insulin; Leptin; Neuropeptide Y; Obesity; Proteins

The discovery of both neuropeptide Y and of leptin has led to a better understanding of the pathophysiology of obesity syndromes in animal models. It has strengthened the concept of the importance of the hypothalamus in the etiology of these syndromes. Due to alterations in the regulation of the hypothalamus, e.g. by insulin, by leptin or by decreases in the availability of glucose in specific brain areas, most animal models of obesity have higher than normal hypothalamic neuropeptide Y levels. As neuropeptide Y is a potent orexigenic agent, this hypothalamic defect explains why obese rodents are hyperphagic. Increased hypothalamic neuropeptide Y levels produce hyperinsulinemia and hypercorticism, two abnormalities previously reported in obesity, but whose origin is now known to be driven by neuropeptide Y. As hyperinsulinemia favors lipid accretion and muscle insulin resistance, and as hypercorticism favors the occurrence of both high circulating triglyceride levels and muscle insulin resistance, it may be appreciated that most disorders previously reported in obesity can now be explained by high hypothalamic neuropeptide Y levels. Leptin, produced and secreted by adipose tissue, is a potent anorectic agent whose main action is exerted within the hypothalamus in which it has been shown to decrease neuropeptide Y, therefore food intake. Leptin secretion is favored, in particular, by insulin as well as by glucocorticoids. When leptin is administered to obese mice of the ob/ob strain (which do not produce nor secrete leptin due to a gene mutation), their food intake, body weight and most metabolic abnormalities are normalized. However, in the majority of genetically obese rodents, as well as in obese humans, circulating levels of leptin are high. This is related to hyperinsulinemia- and hypercorticosteronemia-induced leptin oversecretion, as well as to central leptin receptor dysfunctions preventing normal leptin access to and action within specific brain areas. Under these conditions and to prevent the effects of elevated hypothalamic neuropeptide Y levels, neuropeptide Y antagonists or active leptin agonists must be found. Neuropeptide Y and leptin further underline the existence of functional relationship between the brain (hypothalamus) and the periphery (adipose tissue, muscle). Lack of leptin (mutated leptin gene) or inefficient leptin action (leptin receptor defect) results in increased hypothalamic neuropeptide Y levels. The latter favor hyperinsuli

Topics: Adipose Tissue; Animals; Body Weight; Central Nervous System; Leptin; Mice; Mice, Obese; Muscle, Skeletal; Neuropeptide Y; Obesity; Proteins

The role of neuropeptide Y (NPY), leptin and 5-HT and other neurotransmitters implicated in the regulation of energy balance are only now being fully investigated. Little is known about how they may interact with each other in this complex process. In evolutionary terms, the availability of excess food, and the risk of obesity, is only a recent occurrence in humans. Man, and perhaps other species, may not have developed a specialised neurochemical system for adjusting food intake during obesity. Hence perturbation of a single system, such as hypothalamic NPY or leptin, is unlikely to be directly responsible for the development of most obesity. In contrast, periods of food deprivation and partial starvation have been common in the animal kingdom and the multitude of neurotransmitters implicated in energy balance are more likely to be directed towards increasing food consumption and conserving energy than reducing appetite and increasing thermogenesis in the presence of excess. The last few years have witnessed rapid advances in the understanding of the fundamental mechanisms that regulate body weight and fat content. This progress will undoubtedly continue in the future, and it is hoped that this will be rewarded with the development of new drugs to treat obesity. At present, however, it is unclear whether NPY, leptin, or other apparently strong candidates will be the winner in the lucrative race for the ideal anti-obesity drug.

Topics: Body Weight; Diet; Humans; Hypothalamus; Leptin; Neuropeptide Y; Neurotransmitter Agents; Obesity; Proteins; Receptors, Neurotransmitter

Topics: Adipose Tissue; Animals; Body Mass Index; Central Nervous System; Diabetes Mellitus; Humans; Interleukin-6; Leptin; Melanocyte-Stimulating Hormones; Mutation; Neuropeptide Y; Obesity; Proteins; RNA, Messenger; Signal Transduction; Tumor Necrosis Factor-alpha

Topics: Animals; Brain; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Energy Metabolism; Homeostasis; Hormones; Humans; Hypothalamus; Neurons; Neuropeptide Y; Neuropeptides; Obesity; Rats

Topics: Adipocytes; Adipose Tissue; Animals; Diet; Energy Metabolism; Gene Expression Regulation; Glucocorticoids; Homeostasis; Hormones; Hypothalamus; Insulin; Leptin; Mice; Models, Biological; Neuropeptide Y; Obesity; Progesterone; Proteins

Topics: Animals; Dietary Carbohydrates; Dietary Fats; Energy Metabolism; Feeding Behavior; Homeostasis; Humans; Hypothalamus; Lipoprotein Lipase; Mice; Mice, Obese; Models, Biological; Neuropeptide Y; Obesity; Paraventricular Hypothalamic Nucleus; Rats; Rats, Zucker; Receptors, Neuropeptide Y

Several genes involved in the regulation of appetite and energy metabolism have been cloned and characterized recently. Each seems to form part of the complex regulatory network, centred in the hypothalamus, that is responsible for striking a balance between food intake and energy expenditure.

Topics: Animals; Appetite; Energy Metabolism; Mice; Mice, Obese; Neuropeptide Y; Obesity

Neuropeptide Y (NPY) neurones in the arcuate nucleus of the rodent hypothalamus may play a key role in responding to reductions in body energy stores with appropriate changes in energy homeostasis, namely an increase in food-seeking behaviour and hyperphagia, together with a reduction in heat production by brown adipose tissue. These adaptive responses are mimicked by the injection of NPY into the main sites of projection of the NPY neurones, and animals that are threatened by energy deficits (e.g. through starvation or insulin-deficient diabetes) show increased activity of these neurones. Genetically obese rodents also show hyperactivity of the NPY neurones, which is inappropriate to their energy needs and may contribute to their hyperphagia, reduced energy expenditure and excessive weight gain. The NPY neurones may be inhibited by insulin and leptin, which may both serve as signals of peripheral fat mass. Ultimately, characterization of the specific "feeding' receptors which mediate NPY's central effects on energy homeostasis may provide opportunities for designing drugs to manipulate and appetite and energy balance in man, notably obesity and the cachexia commonly associated with malignancy and chronic infection.

Topics: Animals; Arcuate Nucleus of Hypothalamus; Energy Metabolism; Glucocorticoids; Homeostasis; Humans; Hypothalamus; Insulin; Leptin; Mice; Neurons; Neuropeptide Y; Obesity; Proteins; Rats; Receptors, Neuropeptide Y

The high prevalence of obesity and its well documented association with the cardiovascular risk factors diabetes mellitus, dyslipidemia and hypertension represents a major problem for the general health status of industrialized societies. Although numerous studies have shown that genetic factors have a major influence on the regulation of energy homeostasis and the susceptibility to obesity, the genes and predisposing mutations involved are insufficiently understood. Among several known rodent models of obesity due to single gene mutations, mice homozygous for the obese (ob) gene exhibit massive early-onset obesity, hyperphagia, non-insulin-dependent diabetes mellitus, defective thermoregulation and infertility. Recently the ob gene was identified by positional cloning and shown to be mutated in ob/ob mice. Leptin, the product of the ob gene, is a 167-amino acid secreted protein that is synthesized exclusively in adipose tissue. With the exception of ob/ob mice, circulating plasma leptin is elevated in obesity. Administration of recombinant leptin to ob/ob mice reduces fat mass, food intake, hyperglycemia and hyperinsulinemia. The various effects of the hormone are mediated by leptin receptors expressed at high levels in the hypothalamus, but also in several other non-neuronal tissues. A mutation in the leptin receptor gene is responsible for the obese phenotype of db/db mice. Plasma leptin in humans is positively correlated with body fat mass, suggesting that leptin resistance rather than leptin deficiency is a common feature of human obesity. This review briefly summarizes the current status of the rapidly growing evidence that leptin plays an important role in the regulation of body weight and fat deposition.

Topics: Adipocytes; Animals; Body Mass Index; Body Weight; Carrier Proteins; Disease Models, Animal; Energy Metabolism; Humans; Leptin; Mice; Mice, Mutant Strains; Neuropeptide Y; Obesity; Protein Biosynthesis; Proteins; Receptors, Cell Surface; Receptors, Leptin

Topics: Adaptor Proteins, Signal Transducing; Adipose Tissue; Agouti Signaling Protein; Animals; Carboxypeptidase H; Carboxypeptidases; Carrier Proteins; CCAAT-Enhancer-Binding Proteins; Cell Differentiation; DNA-Binding Proteins; Feeding Behavior; Gene Expression Regulation; Homeostasis; Hormones; Humans; Hypothalamus; Insulin Resistance; Intercellular Signaling Peptides and Proteins; Leptin; Mice; Mice, Mutant Strains; Models, Biological; Neuropeptide Y; Nuclear Proteins; Obesity; Proteins; Receptors, Adrenergic, beta; Receptors, Adrenergic, beta-3; Receptors, Cell Surface; Receptors, Cytoplasmic and Nuclear; Receptors, Leptin; Sterol Regulatory Element Binding Protein 1; Transcription Factors

Leptin, the protein encoded by the recently cloned obese gene, has the properties of a hormone released by adipose tissue, regulating appetite and energy expenditure. Injected leptin reduces body weight and food intake in mice, and in obese, diabetic mice (with a mutated obese gene), it also reduces plasma insulin and glucose. Leptin release is stimulated by insulin; leptin appears to act on the hypothalamus by inhibiting the release of the neuropeptide Y.

Topics: Adipose Tissue; Animals; Appetite; Blood Glucose; Energy Metabolism; Humans; Hypothalamus; Insulin; Leptin; Mice; Mice, Inbred C57BL; Mice, Obese; Neuropeptide Y; Obesity; Proteins; Weight Loss

Over the years, the work of research laboratories in Baton Rouge (USA), Seattle (USA) and Geneva (Switzerland) have reached analogous conclusions regarding the main etiology of obesity as studied in animals: it largely lies within the brain, notably within the hypothalamus. The hypothalamus is indeed known to modulate food intake and energy partitioning, while the periphery has also been proposed to feed-back on the central nervous system (CNS) to provide information on the state of body energy stores, the two together constituting a loop system connecting the brain to the periphery (1,2,3). This etiologic viewpoint of a pivotal role of the hypothalamus in obesity syndromes has been strengthened by the discovery of one hypothalamic neuropeptide and one peripheral (adipose tissue) hormone, respectively neuropeptide Y (4), and quite particularly, leptin (5). As neuropeptide Y produces hyperphagia (6, 7) and as leptin produces hypophagia in normal animals (8,9,10), the loop system just mentioned was thought to comprise functional relationships, at least between these two factors. Other evidence also suggested that such a loop system was altered in obese animals.

Topics: Animals; Gene Expression; Hypothalamus; Leptin; Neuropeptide Y; Obesity; Proteins; Rats

Obesity etiology and treatment have been fraught with disappointment for researchers, because the mechanisms regulating fuel homeostasis and adiposity are incompletely understood. It can now be hypothesized in the light of new evidences that the control of body weight and composition depends upon an axis with three interrelated and self-controlled components: 1) food intake; 2) nutrient turnover and thermogenesis and 3) body fat stores, all of which underly complex feedback mechanisms. This approach considers two of the most relevant recent findings in the field (leptin and beta 3-adrenoceptors), adding new views to previous metabolic models of obesity. This perspective supplies some additional clues to the understanding of body composition regulation as well as the potential involvement of genetic and hypothalamic disorders in the onset of obesity.

Topics: Adipose Tissue; Adipose Tissue, Brown; Animals; Body Weight; Eating; Energy Metabolism; Hormones; Humans; Leptin; Models, Biological; Neuropeptide Y; Neuropeptides; Neurotransmitter Agents; Obesity; Proteins; Substrate Cycling

Neuropeptide Y (NPY), a major brain neurotransmitter, is expressed in neurons of the hypothalamic arcuate nucleus (ARC) that project mainly to the paraventricular nucleus (PVN), an important site of NPY release. NPY synthesis in the ARC is thought to be regulated by several factors, notably insulin, which may exert an inhibitory action. The effects of NPY injected into the PVN and other sites include hyperphagia, reduced energy expenditure and enhanced weight gain, insulin secretion, and stimulation of corticotropin and corticosterone release. The ARC-PVN projection appears to be overactive in insulin-deficient diabetic rats, and could contribute to the compensatory hyperphagia and reduced energy expenditure, and pituitary dysfunction found in these animals; overactivity of these NPY neurons may be due to reduction of insulin's normal inhibitory effect. The ARC-PVN projection is also stimulated in rat models of obesity +/- non-insulin diabetes, possibly because the hypothalamus is resistant to inhibition by insulin; in these animals, enhanced activity of ARC NPY neurons could cause hyperphagia, reduced energy expenditure, and obesity, and perhaps contribute to hyperinsulinemia and altered pituitary secretion. Overall, these findings suggest that NPY released in the hypothalamuss, especially from the ARC-PVN projection, plays a key role in the hypothalamic regulation of energy balance and metabolism. NPY is also found in the human hypothalamus. Its roles (if any) in human homeostasis and glucoregulation remain enigmatic, but the animal studies have identified it as a potential target for new drugs to treat obesity and perhaps NIDDM.

Topics: Animals; Arcuate Nucleus of Hypothalamus; Diabetes Mellitus; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Energy Metabolism; Homeostasis; Humans; Mice; Neural Pathways; Neuropeptide Y; Obesity; Paraventricular Hypothalamic Nucleus; Rats; Syndrome

Topics: Animals; Corticotropin-Releasing Hormone; Humans; Hypothalamus; Insulin Resistance; Mice; Neuropeptide Y; Neurosecretory Systems; Obesity; Rats; Ventromedial Hypothalamic Nucleus

Topics: Animals; Autonomic Nervous System; Cerebral Ventricles; Corticosterone; Insulin; Islets of Langerhans; Neuropeptide Y; Obesity

Topics: Animals; Brain; Corticotropin-Releasing Hormone; Humans; Hypothalamus; Insulin Resistance; Neuropeptide Y; Obesity

Topics: Adipose Tissue; Adipose Tissue, Brown; Animals; Appetite; Diabetes Mellitus, Type 2; Energy Metabolism; Humans; Mice; Mice, Obese; Neuropeptide Y; Obesity; Receptors, Adrenergic, beta; Receptors, Adrenergic, beta-3; Tumor Necrosis Factor-alpha

Knowledge of the effects of exercise in the regulation of energy balance is imperative for the assessment of the value (or limit) of exercise as a therapeutic adjunct in the treatment of obesity. This short review addresses the effects of exercise on the neurobiological control of food intake and energy expenditure. It has been proposed that exercise may affect the regulation of energy balance through the stimulation of corticotropin-releasing hormone (CRH) and neuropeptide Y (NPY). It is likely that the CRH and NPY neuropeptidergic systems exert some degree of control on food intake and energy expenditure. The increase in the CRHergic activity induced by moderately intense exercise would potentiate the effects of muscular activity in reducing energy stores by decreasing energy intake and increasing thermogenesis. Reduced food intake and increased thermogenesis are two of the more recognized biological actions of CRH. Exercise would also contribute to the stimulation of brain NPY neurons by reducing energy stores and plasma insulin levels. By producing orexigenic effects and reducing thermogenesis, activation of the NPY system would tend to oppose the physiological effects of CRH and therefore cancel out the effects of exercise on energy loss.

Topics: Body Temperature Regulation; Corticotropin-Releasing Hormone; Eating; Energy Metabolism; Exercise; Humans; Neuropeptide Y; Obesity

Obesity results from an imbalance between nutrient ingestion and metabolism, with more calories being ingested than utilized. The brain plays an important role in coordinating these complex behavioral and physiological functions, operating through multiple neurochemical systems with distinct properties. This review focuses on two hypothalamic peptide systems, neuropeptide Y (NPY) and galanin (GAL), that illustrate how the brain operates through different mechanisms to control the body's nutrient stores, in different states or conditions. These peptides have different behavioral and physiological effects and are, themselves, differentially responsive to feedback signals from circulating steroids, peptides, and nutrients. They can be distinguished by their relation to natural feeding patterns and endogenous hormones and by their specificity of action in relation to natural biological rhythms. The neuroanatomical substrates involved in these actions of NPY and GAL are also distinct. The neurocircuit mediating NPY's actions originates in the arcuate nucleus and terminates in the medial portion of the paraventricular nucleus; the GAL-containing neurons, in contrast, are concentrated in the lateral portion of the paraventricular nucleus, in addition to the medial preoptic area, which contribute to local GAL innervation as well as projections to the median eminence. Regarding their distinct functions, the evidence suggests that the NPY system is more closely related to patterns of carbohydrate ingestion and carbohydrate utilization, channeling nutrients towards the synthesis of fat. It is most strongly activated at the start of the active feeding cycle or after weaning, in close association with the adrenal steroid, corticosterone. The GAL system, in contrast, is more closely associated with patterns of fat consumption and signals related to fat oxidation. This peptide system is most active during the middle of the feeding cycle or immediately after puberty, in close association with the gonadal steroids. The gene expression and synthesis of these peptides in their respective neuronal cell groups is inhibited by circulating insulin and altered by dietary nutrients. Disturbances in sensitivity to insulin and steroid feedback regulation in the brain are believed to be involved in producing abnormal patterns of peptide function that result in overeating and body weight gain.

Topics: Animals; Brain; Dietary Carbohydrates; Dietary Fats; Feedback; Food Preferences; Galanin; Humans; Neuropeptide Y; Nutritional Physiological Phenomena; Obesity

Topics: Animals; Brain; Brain Chemistry; Corticotropin-Releasing Hormone; Energy Metabolism; Epinephrine; Galanin; Humans; Mice; Mice, Obese; Neuropeptide Y; Obesity; Rats; Serotonin

To study the impact on glucose handling of the observed hyperinsulinaemia and hypercorticism of the genetically obese fa/fa rats, simplified animal models were used. In the first model, normal rats were exposed to hyperinsulinaemia for 4 days and compared to saline-infused controls. At the end of this experimental period, the acute effect of insulin was assessed during euglycaemic-hyperinsulinaemic clamps. White adipose tissue lipogenic activity was much more insulin responsive in the "insulinized" than in the control groups. Conversely muscles from "insulinized" rats became insulin resistant. Such divergent consequences of prior "insulinization" on white adipose tissue and muscle were corroborated by similar divergent changes in glucose transporter (GLUT 4) mRNA and protein levels in these respective tissues. In the second model, normal rats were exposed to stress levels of corticosterone for 2 days. This resulted in an insulin resistance of all muscle types that was due to an increased glucose-fatty acid cycle, without measurable alteration of the GLUT 4 system. In genetically obese (fa/fa) rats, local cerebral glucose utilization was decreased compared to lean controls. This could be the reason for adaptive changes leading to increased levels in their hypothalamic neuropeptide Y levels and median eminence corticotropin-releasing-factor. Thus, in a third model, neuropeptide Y was administered intracerebroventricularly to normal rats for 7 days. This produced hyperinsulinaemia, hypercorticosteronaemia, as well as most of the metabolic changes observed in the genetically obese fa/fa rats, including muscle insulin resistance. These data together suggest that the aetiology of obesity-insulin resistance of genetically obese rodents has to be searched within the brain, not peripherally.

Topics: Animals; Awards and Prizes; Brain; Central Nervous System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Europe; Glucose; Glucose Transporter Type 4; History, 20th Century; Humans; Hyperinsulinism; Hypothalamus; Monosaccharide Transport Proteins; Muscle Proteins; Neuropeptide Y; Obesity; Peripheral Nervous System Diseases; Rats; Rats, Mutant Strains; Societies, Medical; Switzerland

Obesity is a vast and ever-expanding problem in affluent societies, which we have so far failed to confront. Over 20% of Western European and North American adults are overweight to a degree which may potentially shorten their life expectancy. Obesity has well-known associations with non-insulin-dependent diabetes (NIDDM), hypertension, dyslipidaemia and coronary heart disease, as well as less obvious links with diseases such as osteoarthrosis and various malignancies; it also causes considerable problems through reduced mobility and decreased quality of life. The overall financial burden of obesity is impossible to calculate precisely, but may account for 6-8% of total health-care expenditure in North America [1] (similar estimates probably apply to Western Europe). Obesity is difficult to treat and many patients remain obstinately overweight despite our best efforts. The available options range from behavioural therapy to gastrointestinal surgery and include numerous drugs designed to suppress appetite or increase energy expenditure. As in many other areas of medicine, the length and diversity of this list are reliable signs that effective treatment is still beyond our reach. This article argues that new anti-obesity drugs may emerge from recent advances in understanding the control of energy balance in rodents. The discussion is structured around neuropeptide Y (NPY), a major brain peptide which at present appears to be important in regulating energy balance and seems a promising candidate for therapeutic exploitation.

Topics: Animals; Energy Metabolism; Humans; Hypothalamus; Neuropeptide Y; Neurotransmitter Agents; Obesity

Topics: Adipose Tissue; Animals; Brain; Central Nervous System; Energy Intake; Energy Metabolism; Food Deprivation; Humans; Insulin; Models, Biological; Neuropeptide Y; Obesity; Rats; Rats, Zucker; Receptor, Insulin

Viewed from a clinical perspective, it is difficult to generate enthusiasm for the likelihood of finding a peptide that could be helpful in the treatment of obesity. A deeper understanding of obesity, as will emerge from molecular biology, is more likely to point the way to a useful peptide than further evaluations of the clinical dilemmas posed by obesity. However, a clinical perspective may be useful in pointing the way to a system that needs to be examined by molecular biology and also to inject caution in the evaluation of early findings when peptides are used in treatment.

Topics: Adipose Tissue; Animals; Eating; Energy Metabolism; Humans; Hypothalamus; Muscles; Neuropeptide Y; Obesity

Topics: Afferent Pathways; Animals; Bombesin; Brain Mapping; Calcitonin; Calcitonin Gene-Related Peptide; Cholecystokinin; Corticotropin-Releasing Hormone; Disease Models, Animal; Endorphins; Feeding Behavior; Glucagon; Humans; Insulin; Motilin; Nerve Tissue Proteins; Neuropeptide Y; Neurotensin; Obesity; Pancreatic Polypeptide; Satiety Response; Somatostatin; Species Specificity; Stress, Psychological; Taste; Thyrotropin-Releasing Hormone

Effects of dietary fiber on obesity-related traits in previous studies were inconsistent. The aim of the present study was to explore whether variants in genes related to satiety and appetite can modulate the effect of dietary fiber on obesity-related traits. Fifty-one overweight or obese adults were randomly allocated to two groups to consume control biscuits (n = 24) or biscuits containing defatted flaxseed flour (n = 27) at breakfast for 8 wk. Four single-nucleotide polymorphisms related to satiety and appetite were genotyped: rs11076023 on the FTO gene, rs16147 on the NPY gene, rs155971 on the PCSK1 gene, and rs6265 on the BDNF gene. A linear regression model was used to evaluate the gene-diet interaction between obesity-related traits. Compared with control biscuits, defatted flaxseed-flour biscuits significantly reduced body weight (P = 0.001) and body mass index (BMI) (P = 0.001) in A-allele carriers (AA + AT) of rs11076023 on the FTO gene but not in non-carriers (TT) (P for the interaction = 0.005 and 0.006) and decreased fasting serum glucose in participants with CC genotype (P = 0.019) but had less effect in T-allele carriers (TT + TC) (P = 0.021) of rs16147 on the NPY gene (P for the interaction = 0.002). Compared with the control biscuits, defatted flaxseed flour significantly reduced body weight (P < 0.001) in T-allele carriers (TT + TC) of rs155971 on the PCSK1 gene but not in non-carriers (CC) (P for the interaction = 0.041) and reduced body weight (P = 0.001) and BMI (P < 0.001) in A-allele carriers (AA + AG) of rs6265 on the BDNF gene but not non-carriers (GG) (P for the interaction = 0.017 and 0.018). Variants of genes related to satiety and appetite could modulate the effect of defatted flaxseed flour on obesity-related traits.

Topics: Adult; Alpha-Ketoglutarate-Dependent Dioxygenase FTO; Body Mass Index; Body Weight; Brain-Derived Neurotrophic Factor; China; Diet; Dietary Fiber; Dietary Supplements; Flax; Flour; Genotype; Humans; Neuropeptide Y; Obesity; Overweight; Polymorphism, Single Nucleotide; Seeds

Topics: Adiponectin; Adolescent; Adult; Aged; Blood Glucose; Body Mass Index; Breast Neoplasms; Cancer Survivors; Dietary Supplements; Female; Humans; Insulin; Insulin Resistance; Leptin; Middle Aged; Neuropeptide Y; Obesity; Young Adult

Grape seed extract (GSE) is a natural supplement known for its various health benefits, including anti-inflammatory effect. This study aimed to evaluate the effects of GSE supplementation on inflammatory markers, neuropeptide Y, anthropometric measurements, and appetite in obese or overweight individuals.. A randomized, double-blind clinical trial was performed on 40 obese or overweight subjects who were randomly assigned to receive GSE (300 mg/day) or placebo for a period of 12-weeks. Both groups were under a restricted calorie diet (RCD)(~250 kcal lower than the estimated energy requirement). Anthropometric measurements, biochemical biomarkers and dietary intakes were determined during the study period.. The reductions of body weight, body mass index, waist circumference, and waist to hip ratio were significantly higher in the GSE group compared to the placebo group (P = 0.045, 0.033, 0.029, and 0.021, respectively). Lower levels of neuropeptide Y, tumor necrosis factor alpha, and high sensitivity C-reactive protein were observed in the GSE group in comparison with the placebo group (P = 0.041, 0.001, and 0.034, respectively).. GSE supplement with a RCD has favorable effects in reducing anthropometric measurements and inflammatory markers in obese or overweight individuals, and may play an effective role in the treatment of obesity.

Topics: Adult; Appetite; Biomarkers; Body Mass Index; Body Weight; C-Reactive Protein; Caloric Restriction; Dietary Supplements; Double-Blind Method; Female; Grape Seed Extract; Humans; Inflammation; Male; Neuropeptide Y; Obesity; Overweight; Vitis; Waist Circumference; Waist-Hip Ratio

Background and aims: intervention studies that evaluate the effect of rs16147 on metabolic response and weight change after dietary intervention are scarce. We propose to evaluate the role of the rs16147 genetic variant in the metabolic effects produced by a hypocaloric Mediterranean-pattern diet with high content of omega-9. Material and methods: a sample of 363 obese subjects was recruited. At the baseline visit the patients were randomly assigned to one of two hypocaloric diets for 12 weeks (diet M, Mediterranean pattern; diet C, standard hypocaloric). All patients, at baseline and at 12 weeks, had biochemical and anthropometric variables measured, and genotyping performed for the rs16147 variant. Results: in all subjects, and with both diets, the parameters of adiposity, blood pressure, and circulating leptin improved. In obese subjects with allele (A) insulin levels (GG vs. GA + AA) (-0.9 ± 1.1 IU/L vs. -4.4 ± 1.0 IU/L; p = 0.01) and HOMA-IR (-0.3 ± 0.1 units vs. -1.2 ± 0.3 units; p = 0.02) decreased significantly with diet M. Subjects carrying the minor allele showed a significant decrease in basal insulin levels (GG vs. GA + AA) (0.7 ± 0.3 IU/L vs. -2.2 ± 0.9 IU/L: p = 0.02) and HOMA-IR (-0.3 ± 0.2 units vs. -0.7 ± 0.1 units: p = 0.01) after diet C. This decrease in circulating insulin and HOMA-IR levels in patients with allele A was significantly higher with diet M than with diet C. Conclusions: the A allele of the rs16147 variant produces a better metabolic response in terms of insulin resistance and basal insulin secondary to weight loss with two different hypocaloric diets in obese subjects, with improvement being higher with the Mediterranean diet.. Introducción y objetivos: los estudios de intervención que evalúan el efecto del rs16147 sobre la respuesta metabólica y el cambio de peso después de una intervención dietética son escasos. Evaluamos el papel de la variante genética rs16147 en los efectos metabólicos que produce una dieta hipocalórica de patrón mediterráneo y alto contenido en omega-9. Material y métodos: se reclutó una muestra de 363 sujetos obesos. En visita basal, los pacientes se asignaron aleatoriamente, durante 12 semanas, a recibir una de dos dietas: dieta M, de patrón mediterráneo, o dieta C, hipocalórica estándar. Se determinaron momento basal y a las 12 semanas, una serie de variables bioquímicas y antropométricas, realizándose el genotipado de la variante rs16147. Resultados: en todos los sujetos con ambas dietas mejoraron los parámetros de adiposidad, tensión arterial y leptina circulante. En sujetos obesos con el alelo menor (A), los niveles de insulina (GG vs. GA + AA) (-0,9 ± 1,1 UI/L vs. -4,4 ± 1,0 UI/L; p = 0,01) y HOMA-IR (-0,3 ± 0,1 unidades vs. -1,2 ± 0,3 unidades; p = 0,02) disminuyeron significativamente con dieta M. Los sujetos portadores del alelo menor tras dieta C mostraron disminución significativa de niveles de insulina basal (GG vs. GA + AA) (0,7 ± 0,3 UI/L vs. -2,2 ± 0,9 UI/L: p = 0,02) y HOMA-IR (-0,3 ± 0,2 unidades vs. -0,7 ± 0,1 unidades: p = 0,01). Esta disminución de los niveles de insulina circulante y HOMA-IR en los pacientes con alelo A fue significativamente superior con la dieta M que con la dieta S. Conclusiones: el alelo A de la variante rs16147 se relaciona con mejor respuesta metabólica, en términos de resistencia a insulina e insulina basal secundaria a pérdida de peso, a dos dietas hipocalóricas, siendo superior el efecto obtenido con una dieta de patrón mediterráneo.

Topics: Adult; Diet, Mediterranean; Female; Humans; Male; Middle Aged; Neuropeptide Y; Obesity; Polymorphism, Single Nucleotide; Weight Loss

Our aim was to evaluate the relationship of weight loss and changes in adipokine levels after two hypocaloric diets in obese subjects with polymorphism rs16147 of the neuropeptide Y gene.. A population of 283 obese patients was analyzed. At the basal visit, patients were randomly allocated to one of two diets for a period of 3 months (diet I, low in carbohydrates; diet II, low in fat).. With diet I and in both genotype groups (major versus minor allele), body mass index (BMI), weight, fat mass, waist circumference, and leptin decreased. With diet II and in all genotypes, BMI, weight, fat mass, waist circumference, and leptin decreased. With both diets and in subjects with the minor allele, insulin levels (diet I: major allele -1.7 ± 7.8 IU/L versus minor allele -4.2 ± 6.1 IU/L, p = 0.01; diet II: major allele -2.3 ± 6.1 IU/L versus minor allele -4.0 ± 5.2 IU/L, p = 0.02) and insulin resistance (diet I: major allele -0.2 ± 3.1 units versus minor allele -1.7 ± 3.0 units, p = 0.03; diet II: major allele -0.9 ± 2.0 units versus minor allele -1.7 ± 1.3 units, p = 0.01) decreased.. The rs16147 genotype affected the reduction in insulin resistance and insulin levels in response to two different hypocaloric diets in obese subjects, with a lack of response in subjects with the major allele.

Topics: Adipokines; Adult; Cardiovascular Diseases; Diet, Carbohydrate-Restricted; Diet, Fat-Restricted; Diet, Reducing; Female; Genetic Markers; Humans; Insulin; Insulin Resistance; Male; Middle Aged; Neuropeptide Y; Nutrigenomics; Obesity; Polymorphism, Single Nucleotide; Prospective Studies; Risk Factors; Weight Loss

Obesity is a chronic inflammatory disease and is considered a risk factor for metabolic syndrome. In this study, 57 obese adolescents with and without metabolic syndrome underwent 1 year of weight loss therapy. At baseline, the metabolic syndrome (MS) patients presented higher values of PAI-1 than the non-metabolic syndrome patients (n-MS). After therapy, significant improvements in anthropometrics and biochemical, inflammatory, and neuroendocrine variables were observed in both groups. However, the n-MS group presented better results than the MS group. Indeed, we found positive correlations in both groups between PAI-1 and neuropeptide Y (NPY) and between PAI-1 and NPY/AgRP. Inflammatory biomarkers may thus play a role in energy balance. The clinical trial registration number is NCT01358773.

Topics: Adiponectin; Adiposity; Adolescent; Agouti-Related Protein; Body Composition; Body Mass Index; Energy Metabolism; Exercise; Female; Humans; Inflammation; Male; Metabolic Syndrome; Neuropeptide Y; Obesity; Plasminogen Activator Inhibitor 1; Weight Reduction Programs; Young Adult

Neuropeptide Y (NPY) is implicated in the regulation of blood pressure (BP), and NPY pathways in the hypothalamus are sensitive to dietary fat. We evaluated the potential effect of a functional variant rs16147 located in the NPY gene promoter region on the association between 2-year diet intervention and change in multiple BP measures in the randomized Preventing Overweight Using Novel Dietary Strategies Trial. The NPY rs16147 was genotyped in 723 obese adults who were randomly assigned to 1 of 4 diets differing in the target percentages of energy derived from fat, protein, and carbohydrate. The changes of 4 BP phenotypes, including systolic BP, diastolic BP, pulse pressure, and mean arterial pressure, during 2-year diet intervention were analyzed. In the total participants and participants with hypertension, we observed significant and consistent interactions between rs16147 genotype and dietary fat intake on changes in multiple BP phenotypes at 2 years (all P for interactions <0.05). The risk allele (C allele) was associated with a greater reduction of BP phenotypes in response to low-fat diet, whereas an opposite genetic effect was observed in response to high-fat diet. In addition, the C allele was related to greater changes in 4 BP phenotypes in hypertensive compared with nonhypertensive participants. Our data suggest that NPY rs16147 may modulate the association between dietary fat intake and changes in BP phenotypes, and the C allele exerts a long-term beneficial effect on lowering BP in response to low-fat diet in obese and hypertensive subjects.

Topics: Adult; Alleles; Blood Pressure; Diet, Reducing; Female; Gene Frequency; Genotype; Humans; Male; Middle Aged; Neuropeptide Y; Obesity; Overweight; Polymorphism, Single Nucleotide; Promoter Regions, Genetic; Time Factors; Treatment Outcome

The aim of this study was to verify the effects of a multidisciplinary therapy (24 weeks) on neurohormonal control of food intake, specifically in orexigenic (total ghrelin, agouti-related protein [AgRP], neuropeptide Y [NPY], and melanin-concentrating hormone) and anorexigenic factors (leptin, insulin, and alpha-melanocyte stimulating hormone [α-MSH]), in obese adolescents.. A total of 88 adolescents (38 boys and 50 girls), including 62 obese and 26 normal-weight, aged 15-19 years were recruited. Obese adolescents were submitted to a 24-week multidisciplinary therapy. AgRP, NPY, melanin-concentrating hormone, leptin, insulin, glucose, α-MSH, total ghrelin, and food intake were measured at three stages (at baseline, after 12 weeks, and after 24 weeks).. At baseline, obese adolescents showed hyperleptinemia (circulating leptin levels, which were, in boys and girls, 40 and 35 times higher than in normal-weight subjects, respectively). After 24 weeks, these values decreased in all obese patients. Our results showed no differences in ghrelin levels between obese and normal-weight adolescents, in both genders. However, obese boys reduced their plasma ghrelin concentration after 24 weeks of therapy (p < .05). The multidisciplinary therapy decreased NPY and AgRP values and increased α-MSH; simultaneously with these changes there was a decrease in total food intake after 24 weeks of therapy.. We can conclude that the multidisciplinary therapy was efficient to modulate neurohormonal control of food intake in obese adolescents.

Topics: Adolescent; Adolescent Health Services; Agouti-Related Protein; alpha-MSH; Body Weight; Combined Modality Therapy; Diet, Reducing; Exercise; Feeding Behavior; Female; Ghrelin; Humans; Hypothalamic Hormones; Leptin; Male; Melanins; Neuropeptide Y; Obesity; Peptide Hormones; Pituitary Hormones; Weight Loss

Insulin, ghrelin, neuropeptide Y (NPY) and leptin interact in the regulation of energy homeostasis. Most of these signals are altered in polycystic ovary syndrome (PCOS), which is characterized by a high prevalence of obesity. The present study was conducted to evaluate ghrelin-NPY and ghrelin-leptin interplays in relation to insulin secretion in obese PCOS subjects.. Pilot prospective study.. Seven obese PCOS women and seven age-weight matched controls.. Hormonal measurements, oral glucose tolerance test (OGTT) and a ghrelin test (1 microg/kg i.v. bolus). PCOS patients repeated the clinical work-up after 4 months of metformin treatment (1500 mg/day orally).. At baseline, PCOS women showed a significantly higher insulinaemic response to the OGTT compared to controls (P < 0.05). In basal conditions, PCOS women exhibited lower NPY levels than controls (P < 0.01). Ghrelin injection markedly increased NPY in controls (P < 0.01), whereas PCOS women showed a deeply blunted NPY response to the stimulus (area under the curve--AUC-NPY: P < 0.01 vs. controls.). Metformin treatment induced a significant decrease in insulin levels (P < 0.01) and the concomitant recovery of NPY secretory capacity in response to ghrelin (AUC-NPY: P < 0.05 vs. baseline) in PCOS women. Leptin levels, which were similar in the two groups, were not modified by ghrelin injection; metformin did not affect this pattern.. Hyperinsulinaemia seems to play a pivotal role in the alteration of NPY response to ghrelin in obese PCOS women. This derangement could be implicated in the physiopatology of obesity in these patients.

Topics: Adult; Female; Ghrelin; Glucose Tolerance Test; Humans; Hyperinsulinism; Hypoglycemic Agents; Insulin; Leptin; Metformin; Neuropeptide Y; Obesity; Pilot Projects; Polycystic Ovary Syndrome; Signal Transduction; Young Adult

Some neuropeptides and monoaminergic neurotransmitters may affect hypothalamic feeding centres, sympathetic activity and thermogenesis. Sibutramine (BTS54524; N-[1-[1(4-chloro phenyl) cyclobutyl]-3methyl N,N-dimethylamine hydrochloride monohydrate) is a new 5-HT serotonin and noradrenaline reuptake inhibitor (SNRI), antiobesity drug. The aim of this study was to evaluate the effects of the sibutramine therapy on plasma neuropeptide Y (NPY), insulin, leptin and beta-endorphin concentrations in obese patients.. Sibutramine, serotonin and noradrenaline reuptake antiobesity drug was administered for 6 months in a dose of 10 mg daily in 60 obese women (BMI 30-40 kg/m2) (mean 34 kg/m2). Plasma NPY, leptin, beta-endorphin and insulin concentrations were measured with RIA methods using commercial kits (Peninsula Lab, Linco, Peninsula Lab, Swierk respectively). The above neuropeptides levels were evaluated before and after the 6 month sibutramine therapy in 60 obese women as well as in 30 obese women on low caloric diet and in 30 of the control group.. In 85% obese patients a decrease of body weight was found after 6 month therapy with sibutramine. A decrease in total cholesterol, LDL and triglycerides and an increase in HDL were observed after the sibutramine treatment. We have demonstrated that the sibutramine therapy leads to the decrease of plasma NPY, beta-endorphin, insulin and leptin concentrations in obese patients. After low diet therapy we have observed a decrease in plasma leptin levels, however we did not find significant changes in plasma leptin, NPY, beta-endorphin and insulin concentrations.. We suggest that the effects on the disturbed activity of NPY, beta-endorphin, insulin and leptin may be involved in the mechanism of sibutramine action.

Topics: Adolescent; Adrenergic Uptake Inhibitors; Adult; Analysis of Variance; Appetite Depressants; Appetite Regulation; beta-Endorphin; Cyclobutanes; Female; Humans; Insulin; Leptin; Neuropeptide Y; Obesity; Reference Values; Selective Serotonin Reuptake Inhibitors; Statistics, Nonparametric

Prader-Willi syndrome (PWS) is a genetic disorder characterized by mild mental retardation, short stature, abnormal body composition, muscular hypotonia and distinctive behavioural features. Excessive eating causes progressive obesity with increased cardiovascular morbidity and mortality. In the PWS genotype loss of one or more normally active paternal genes in region q11-13 on chromosome 15 is seen. It is supposed that the genetic alteration leads to dysfunction of several hypothalamic centres and growth hormone (GH) deficiency (GHD) is common. PWS is well described in children, in whom GH treatment improves body composition, linear growth, physical strength and agility. Few studies have focused on adults. We examined a cohort of 19 young adults with clinical PWS (13 with positive genotype) and mean BMI of 35 kg/m2. At baseline the activity of the GH-insulin-like growth factor-I (IGF-I) system was impaired with low GH values, low total IGF-I and in relation to the obesity low levels of free IGF-I and non-suppressed IGF-binding-protein-1 (IGFBP-1). 2/3 were hypogonadal. Bone mineral density (BMD) was low. Four patients had impaired glucose tolerance and nine patients high homeostasis model assessment (HOMA) index, indicating insulin resistance. Seven patients had a moderate dyslipidemia. The 13 patients with the PWS genotype were shorter and had significantly lower IGF-I. Seventeen (9 men and 8 women), subsequently completed a 12 months GH treatment trial, and GH had beneficial effects on body composition without significant adverse effects. The effects were more pronounced in the patients with the PWS genotype. Analysis of peptides involved in appetite regulation showed that leptin levels were high reflecting obesity and as a consequence NPY levels were low. In relation to the patients obesity circulating oxytocin levels were abnormally low and ghrelin levels abnormally high. Thus, oxytocin and ghrelin might be involved in the hyperphagia. NPY, leptin and ghrelin did not change during GH treatment. In conclusion this pilot study showed that adults with PWS have a partial GH deficiency, and GH treatment has beneficial effects on body composition in adult PWS without significant side-effects. Larger and longer term studies on the effect of GH replacement in adult PWS are encouraged.

Topics: Adolescent; Adult; Appetite; Body Composition; Bone Density; Carbohydrate Metabolism; DNA Methylation; Endocrine System; Female; Ghrelin; Growth Hormone; Humans; Hyperphagia; Insulin-Like Growth Factor Binding Protein 1; Insulin-Like Growth Factor Binding Protein 2; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor I; Leptin; Lipid Metabolism; Male; Neuropeptide Y; Obesity; Oxytocin; Peptide Hormones; Prader-Willi Syndrome

The link between the human sympathoadrenalmedullary system and the adipocyte hormone leptin is controversial. We measured total and regional norepinephrine spillover, epinephrine secretion rate, and extra-adipocyte leptin release in 22 lean [body mass index (BMI) < 26] and 20 obese (BMI > 28) normotensive men who underwent arterial and central venous catheterization. Because plasma clearance of leptin is primarily by renal removal, for men at steady state we could estimate whole body leptin release to plasma from renal plasma leptin extraction. Whole body leptin release was 1,950 +/- 643 (means +/- SE) ng/min in obese men and 382 +/- 124 ng/min in lean men (P < 0.05). Total and renal norepinephrine spillover rates correlated directly with whole body leptin secretion rate. Leptin is released from multiple nonadipocyte sites, which we tested by use of simultaneous arteriovenous blood sampling. We found a surprisingly large contribution of brain leptin release to the plasma leptin pool, 529 +/- 175 ng/min (> 40% whole body leptin release), with greater leptin release in obese than in lean men, 935 +/- 321 vs. 160 +/- 59 ng/min (P = 0.045). In parallel with leptin measurements, we also quantified brain serotonin turnover and jugular overflow of neuropeptide Y (NPY). Brain serotonin turnover was higher in obese than in lean men, 227 +/- 112 vs. 21 +/- 14 ng/min (P = 0.019), as was overflow of NPY from the brain, 12.9 +/- 1.4 vs. 5.3 +/- 2.2 ng/min (P = 0.042). These results suggest that leptin is released within the brain and at an increased rate in obese humans, in whom activation of brain serotonergic and NPY mechanisms also exists.

Topics: Adrenal Medulla; Adult; Body Composition; Brain; Epinephrine; Humans; Jugular Veins; Leptin; Male; Metabolic Clearance Rate; Middle Aged; Neuropeptide Y; Norepinephrine; Obesity; Serotonin; Sympathetic Nervous System

Prader-Willi syndrome (PWS) is a complex genetic disorder characterised by mild mental retardation and distinct physical, behavioural, and psychiatric features. One of the cardinal symptoms is excessive eating, which--if left untreated--leads to extreme obesity. In the present study we have examined circulating levels of peptides with documented association to hyperphagia in young adults with PWS. Since growth hormone (GH) is often used nowadays to correct GH insufficiency during childhood PWS, we also studied the impact of GH administration on the peptides. Seventeen adults, 9 men and 8 women, 17-32 years of age with a mean BMI of 35+/-3.2 kg/m(2) participated. All had clinical PWS (Holm's criteria). Genetic testing was performed in all patients and in 11 the diagnosis was confirmed. They were randomized to treatment with either placebo or GH (Genotropin, Pharmacia Corporation) for 6 months. Subsequently all received open label treatment to provide all subjects with 12 months active GH treatment. Doses were individually titrated. Weight, BMI, oxytocin (baseline only), leptin, Neuropeptide Y (NPY), and ghrelin were evaluated at baseline and after 6 and 12 months. At baseline plasma mean oxytocin was within and serum ghrelin just above the normal range (14.7+/-1.2 pmol/L and 0.87+/-0.12 microg/L, respectively). Serum leptin levels were high above and plasma NPY levels within the lower normal range (47.8+/-29.1 microg/L and 13+/-1 pmol/L, respectively). Results were independent of genotype. No changes in mean BMI, ghrelin, leptin or NPY were seen following GH treatment.. Leptin levels were in general high reflecting obesity and as a consequence NPY levels were low. In simple obesity oxytocin levels are high, while ghrelin levels are suppressed. In view of the adiposity oxytocin circulated in abnormally low and ghrelin in abnormally high concentrations in our patients. GH treatment of PWS patients did not change ghrelin, leptin or NPY. We suggest that both oxytocin and ghrelin are involved in the pathogenesis of hyperphagia seen in PWS.

Topics: Adolescent; Adult; Body Mass Index; Eating; Fasting; Female; Ghrelin; Human Growth Hormone; Humans; Hyperphagia; Leptin; Male; Neuropeptide Y; Obesity; Oxytocin; Peptide Hormones; Prader-Willi Syndrome

High serum levels of total and LDL cholesterol are important risk factors in the development of atherosclerotic coronary artery disease. Cholesterol metabolism is affected by nutritional, environmental and genetic factors. Neuropeptide Y (NPY), which is widely expressed in both the central and peripheral nervous systems, has an important role in the hypothalamic regulation of energy balance by stimulating food intake and favoring energy storage through increased lipoprotein lipase activity in white adipose tissue. As a part of ongoing study of the genetic basis of obesity, we screened the NPY gene for sequence variants. We report here the identification of a common Leu(7)-to-Pro(7) polymorphism in the signal peptide of NPY. Presence of this Pro(7) in NPY was associated with higher serum levels of total and LDL cholesterol in obese subjects participating in two independent Finnish and Dutch studies. Furthermore, normal-weight Finns with Pro(7) also had higher serum levels of total and LDL cholesterol than did subjects with Leu(7)/Leu(7), as analyzed in three subsequent determinations at 5-year intervals during a 10-year follow-up period. The NPY polymorphism was not associated with higher cholesterol levels in normal-weight Dutch. Our study provides evidence that NPY is linked to cholesterol metabolism and that the polymorphism producing Pro(7) in NPY is one of the strongest genetic factors identified thus far affecting serum cholesterol, particularly in obese subjects.

Topics: Adult; Aged; Alleles; Amino Acid Substitution; Cholesterol; Cholesterol, LDL; Female; Gene Frequency; Genotype; Humans; Leucine; Male; Middle Aged; Neuropeptide Y; Obesity; Polymorphism, Genetic; Proline; Protein Sorting Signals

Correlations between serum leptin (LEP) and BMI and the percentage of fat mass (FM), as well as differences between male and female serum levels and their behaviour during weight loss have already been extensively described in adult obesity, whereas few cases have been examined in child and adolescent obesity. There are also few studies of the alterations in NPY in peripheral blood in obese subjects during weight loss.. This study aimed to evaluate the correlations between LEP and BMI, FM% and NPY in 72 obese subjects, with BMI > 35 (29 males and 43 females) aged between 9.6 and 19.8 years old, during weight loss together with any differences between the sexes.. LEP was positively correlated in both sexes with BMI and FM%, whereas no correlation emerged with NPY; LEP levels decreased gradually during weight loss, whereas no changes were observed in NPY except during the first phases of weight loss in males when the decrease was significant. LEP concentrations were significantly higher in females, who also showed a higher FM% with equal BMI. No difference was observed between NPY levels in both sexes.. The authors conclude that: 1) the behaviour of LEP in child-adolescent obesity is broadly comparable to that described in adult obesity; 2) the highest LEP concentrations with equal BMI in females appear to reflect the different body composition of the two sexes given that females have a higher FM%; 3) the control exerted by LEP on hypothalamic NPY cannot be seen in peripheral blood and no differences emerged between the two sexes.

Topics: Adolescent; Adult; Child; Female; Humans; Leptin; Male; Neuropeptide Y; Obesity; Proteins; Sex Factors; Weight Loss

Obesity increases the risk of developing hypertension by two-to fourfold, with more that one third of all cases of hypertension attributable to obesity. The present study tested the role of atrial natriuretic peptide (ANP), endothelin-1,2 (ET-1,2) and neuropeptide Y (NPY) in pathogenesis of obesity hypertension. The plasma concentrations of ANP, ET-1,2 and NPY were determined in the peripheral venous blood by radioimmunoassay in 27 obese hypertensive patients (group I), in 24 obese normotensive patients (group II), and in 35 normal subjects (group III).. Mean plasma ANP was significantly higher in obese than in normal subjects. ANP levels were higher in patients group I than in those group II and I. In patients of group I plasma ANP concentrations correlated with III BMI and mean blood pressure. Plasma levels of ET-1,2 and NPY were similar in patients group I, II and III.

Topics: Adolescent; Adult; Aged; Atrial Natriuretic Factor; Catecholamines; Endothelin-1; Endothelin-2; Humans; Hypertension; Male; Middle Aged; Neuropeptide Y; Obesity; Peptides

Apart from the positive effect of lumbar traction on structural changes within the spine in patients with low back pain, it is likely that therapeutic effects are correlated with pain biomarkers in the blood. Among them, systemic metabolic factors related to obesity may play an important role. This is the first study designed to examine the effectiveness of traction therapy in two experimental groups with considerably different BMI and to assess relationships between blood biomarkers and low back pain intensity.. In the prospective clinical trial, women suffering from chronic low back pain were allocated into the normal-weight or obesity groups. Patients in both groups underwent twenty sessions of lumbar traction therapy (30 min a day, continuous mode with a force level of 25-30% of body weight). Before and after therapy subjective assessments of pain (VAS and PPT) were performed, and serum concentrations of aggrecan chondroitin sulfate 846 epitope (CS-846), neuropeptide Y, leptin, adipsin and growth and differentiation factor 15 (GDF-15) were determined. The data were statistically evaluated for 28 women.. After therapy, the maximal low back pain decreased in both groups, GDF-15 concentration was reduced in the normal-weight group and increased in the obesity group, and CS-846 concentration decreased in the obesity group. The sensation of PPT in the lumbar spine and mean concentrations of neuropeptide Y, leptin and adipsin did not change in both groups. However, the relationships of GDF-15, leptin, and adipsin concentrations with the perception of pain were revealed.. Distinct differences between the normal-weight and obesity groups pointed on the role of excessive adipose tissue in aggravating the inflammatory processes and in the development of low back pain. Adipsin, CS-846 and GDF-15 aspire to be the low back pain biomarkers in women with obesity, but there is a need for further research to answer whether they might be considered reliable biomarkers for the prognosis and monitoring of chronic low back treatment.. NCT04507074, registered prospectively on July 6, 2020.

Topics: Body Mass Index; Complement Factor D; Female; Growth Differentiation Factor 15; Humans; Leptin; Low Back Pain; Lumbar Vertebrae; Neuropeptide Y; Obesity; Prospective Studies; Traction; Treatment Outcome

Neural regulation of adipose tissue is crucial in the homeostasis of energy metabolism. Adipose tissue neuropeptide Y (NPY) and its receptors contribute to the development of diet-induced obesity. NPY1R and NPY2R are major receptors for NPY in peripheral tissues including the adipose tissue. NPY receptor 4 (. 脂肪组织的神经支配与调节在能量代谢稳态的维持中发挥重要作用。神经肽Y (neuropeptide Y, NPY)及其脂肪细胞受体信号通路促进高脂饮食诱导的肥胖，其中NPY受体1 (NPY receptor Y1, NPY1R)与受体2(NPY2R)是主要的NPY外周受体。NPY受体4 (NPY4R)也在脂肪组织表达，然而尚不清楚其是否参与肥胖的发生发展机制。本研究建立了NPY及其受体的免疫荧光成像技术和脂肪细胞回复性表达

Topics: Adipocytes; Adipose Tissue; Animals; Diet; Mice; Neuropeptide Y; Obesity; Receptors, Neuropeptide Y

Exosomes (sEVs) are extracellular vesicles involved in the pathogenesis of obesity. Notably, exosomal microRNAs (miRNAs) have emerged as crucial mediators of communication between cells and are involved in the development of obesity. One region of the brain known to be dysregulated in obesity is the hypothalamus. It coordinates whole-body energy homeostasis through stimulation and inhibition of the orexigenic neuropeptide (NPY)/agouti-related peptide (AgRP) neurons and anorexigenic proopiomelanocortin (POMC) neurons. A role for hypothalamic astrocytic exosomes in communication with POMC neurons was previously elucidated. Yet, it was unknown whether NPY/AgRP neurons secreted exosomes. We previously established that the saturated fat palmitate alters the intracellular levels of miRNAs and we now questioned whether palmitate would also alter the miRNA content of exosomal miRNAs. We found that the mHypoE-46 cell line secreted particles consistent with the size of exosomes and that palmitate altered levels of a spectrum of miRNAs associated with exosomes. The predicted KEGG pathways of the collective miRNA predicted targets included fatty acid metabolism and type II diabetes mellitus. Of note, one of these altered secreted miRNAs was miR-2137, which was also altered within the cells. We also found that while sEVs collected from the mHypoE-46 neurons increased Pomc mRNA in the mHypoA-POMC/GFP-2 cells after 48 h, the effect was absent with sEVs isolated following palmitate treatment, indicating another potential route by which palmitate promotes obesity. Hypothalamic neuronal exosomes may therefore play a role in the control of energy homeostasis that may be disrupted in obese conditions.

Topics: Agouti-Related Protein; Diabetes Mellitus, Type 2; Extracellular Vesicles; Humans; Hypothalamus; Neurons; Neuropeptide Y; Obesity; Palmitates; Pro-Opiomelanocortin

The advanced cessation of lactation elevates the risk of programmed obesity and obesity-related metabolic disorders in adulthood. This study used multiomic analysis to investigate the mechanism behind this phenomenon and the effects of leucine supplementation on ameliorating programmed obesity development. Wistar/SD rat offspring were subjected to early weaning (EW) at day 17 (EWWIS and EWSD groups) or normal weaning at day 21 (CWIS and CSD groups). Half of the rats from the EWSD group were selected to create a new group with 2-month leucine supplementation at day 150. The results showed that EW impaired lipid metabolic gene expression and increased insulin, neuropeptide Y, and feed intake, inducing obesity in adulthood. Six lipid metabolism-related genes (Acot1, Acot2, Acot4, Scd, Abcg8, and Cyp8b1) were influenced by EW during the entire experimental period. Additionally, adult early-weaned rats exhibited cholesterol and fatty acid β-oxidation disorders, liver taurine reduction, cholestasis, and insulin and leptin resistance. Leucine supplementation partly alleviated these metabolic disorders and increased liver L-carnitine, retarding programmed obesity development. This study provides new insights into the mechanism of programmed obesity development and the potential benefits of leucine supplementation, which may offer suggestions for life planning and programmed obesity prevention.. Early-weaned adult rats showed excess lipid accumulation and metabolic defects. Early weaning disrupts lipid metabolism and secretion of neuropeptide Y and insulin. The altered lipid metabolic gene expression in this study is vital in programming. Leucine mitigates metabolic disorders and hampers programmed obesity development.

Topics: Animals; Dietary Supplements; Female; Insulin; Lactation; Leucine; Lipids; Neuropeptide Y; Obesity; Rats; Rats, Sprague-Dawley; Rats, Wistar

Neuropeptide Y (NPY) in the arcuate nucleus (ARC) is known as one of the most critical regulators of feeding. However, how NPY promotes feeding under obese conditions is unclear. Here, we show that positive energy balance, induced by high-fat diet (HFD) or in genetically obese leptin-receptor-deficient mice, leads to elevated Npy2r expression especially on proopiomelanocortin (POMC) neurons, which also alters leptin responsiveness. Circuit mapping identified a subset of ARC agouti-related peptide (Agrp)-negative NPY neurons that control these Npy2r expressing POMC neurons. Chemogenetic activation of this newly discovered circuitry strongly drives feeding, while optogenetic inhibition reduces feeding. Consistent with that, lack of Npy2r on POMC neurons leads to reduced food intake and fat mass. This suggests that under energy surplus conditions, when ARC NPY levels generally drop, high-affinity NPY2R on POMC neurons is still able to drive food intake and enhance obesity development via NPY released predominantly from Agrp-negative NPY neurons.

Topics: Agouti-Related Protein; Animals; Arcuate Nucleus of Hypothalamus; Leptin; Mice; Neurons; Neuropeptide Y; Obesity; Pro-Opiomelanocortin

Hypothalamic AgRP/NPY neurons are key players in the control of feeding behaviour. Ghrelin, a major orexigenic hormone, activates AgRP/NPY neurons to stimulate food intake and adiposity. However, cell-autonomous ghrelin-dependent signalling mechanisms in AgRP/NPY neurons remain poorly defined. Here we show that calcium/calmodulin-dependent protein kinase ID (CaMK1D), a genetic hot spot in type 2 diabetes, is activated upon ghrelin stimulation and acts in AgRP/NPY neurons to mediate ghrelin-dependent food intake. Global Camk1d-knockout male mice are resistant to ghrelin, gain less body weight and are protected against high-fat-diet-induced obesity. Deletion of Camk1d in AgRP/NPY, but not in POMC, neurons is sufficient to recapitulate above phenotypes. In response to ghrelin, lack of CaMK1D attenuates phosphorylation of CREB and CREB-dependent expression of the orexigenic neuropeptides AgRP/NPY in fibre projections to the paraventricular nucleus (PVN). Hence, CaMK1D links ghrelin action to transcriptional control of orexigenic neuropeptide availability in AgRP neurons.

Topics: Agouti-Related Protein; Animals; Calcium-Calmodulin-Dependent Protein Kinase Type 1; Diabetes Mellitus, Type 2; Eating; Ghrelin; Male; Mice; Mice, Knockout; Neurons; Neuropeptide Y; Obesity

Positive allosteric modulators targeting the Y

Topics: Allosteric Regulation; Animals; High-Throughput Screening Assays; Mice; Neuropeptide Y; Obesity; Quantitative Structure-Activity Relationship; Receptors, Neuropeptide Y; Structure-Activity Relationship

The anterior lobe of the insular cortex (aINS) is a cortical region that has reciprocal connections with limbic centers such as the anterior cingulate cortex, prefrontal cortex, amygdala and nucleus accumbens (NAc). In fact, the aINS has been involved in the integration of autonomic information for emotional and motivational functions. The compulsive consumption of drugs or high-fat foods induces alterations at both behavioural and brain levels. Brain reward circuits are altered in response to continued intake, in particular the dopaminergic projections from the ventral tegmental area (VTA) to the NAc. The aINS has multiple connections with the components of this system. In recent years, efforts have been made to better understand the fundamental role of the aINS in addiction, making it one of the key centres of interest for research into new treatments for addiction.. The present work focuses on studying 1.- whether the human aINS expresses orexigenic peptides such as neuropeptide Y (NPY), a peptide known to induce hyperphagia, and which has been implicated in the onset and development of obesity, 2.- the long-term effect of an obesogenic diet on NPY expression in the aINS and NAc of C57BL/6 mice.. A total of 17 female C57BL/6 J mice were used in this study. Female mice were fed ad libitum with water and, either a standard diet (SD) or a high-fat diet (HFD) to induce obesity. There were seven female mice on the SD and ten on the HFD. The duration of the experiment was 180 days. We also studied 3 human adult brains (1 male and 2 females, mean age 55.7 ± 5.2 years). The morphological study was performed using immunohistochemistry and double immunofluorescence techniques to study the neurochemical profile of NPY neurons of the aINS and NAc of humans and mice.. Our morphological analysis demonstrates for the first time the basal expression of NPY in different layers of the human cortex (II, III, IV, V/VI), in a pattern similar to previous studies in other species. Furthermore, we observed an increase in the number of NPY-positive cells and their intracytoplasmic signal in the aINS and NAc of the obese mice subjected to a long-term obesogenic diet.. To our knowledge, this is the first study to show the distribution and expression of NPY in the human INS and how its expression is altered after prolonged treatment with an obesogenic diet in obese mice. Our findings may contribute to the understanding of the pathophysiological mechanisms underlying obesity in regions related to the reward system and associated with uncontrolled intake of high-fat foods, thus facilitating the identification of novel therapeutic targets.

Topics: Animals; Diet, High-Fat; Female; Humans; Insular Cortex; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Middle Aged; Neuropeptide Y; Nucleus Accumbens; Obesity

The impact of obesity upon bone metabolism is controversial since both beneficial or harmful effects have been reported. Bone remodeling is modulated by the central nervous system through cytokines, hormones and neuromodulators. The present study aimed to evaluate the effects evoked by bilateral retroperitoneal white adipose tissue (rWAT) denervation (Dnx) upon bone mineral metabolism and remodeling in an experimental model of obesity in rats. Male Wistar rats were fed during 18 weeks with high-fat diet (HFD) or standard diet (SD) as controls, and rWAT Dnx or Sham surgery was performed at the 14th week. Biochemical and hormonal parameters, bone histomorphometry, rWAT and hypothalamus protein and gene expression were analyzed. The HFD group presented decreased bone formation parameters, increased serum and bone leptin and FGF23, increased serum and hypothalamic neuropeptide Y (NPY) and decreased serum 1,25-dihydroxyvitamin D

Topics: Adipose Tissue; Animals; Denervation; Leptin; Male; Neuropeptide Y; Obesity; Osteogenesis; Rats; Rats, Wistar

The nucleus accumbens (NAc) is central to motivation and action, exhibiting one of the highest densities of neuropeptide Y (NPY) in the brain. Within the NAc, NPY plays a role in reward and is involved in emotional behavior and in increasing alcohol and drug addiction and fat intake. Here, we examined NPY innervation and neurons of the NAc in humans and other anthropoid primates in order to determine whether there are differences among these various species that would correspond to behavioral or life history variables. We quantified NPY-immunoreactive axons and neurons in the NAc of 13 primate species, including humans, great apes, and monkeys. Our data show that the human brain is unique among primates in having denser NPY innervation within the NAc, as measured by axon length density to neuron density, even after accounting for brain size. Combined with our previous finding of increased dopaminergic innervation in the same region, our results suggest that the neurochemical profile of the human NAc appears to have rendered our species uniquely susceptible to neurophysiological conditions such as addiction. The increase in NPY specific to the NAc may represent an adaptation that favors fat intake and contributes to an increased vulnerability to eating disorders, obesity, as well as alcohol and drug dependence. Along with our findings for dopamine, these deeply rooted structural attributes of the human brain are likely to have emerged early in the human clade, laying the groundwork for later brain expansion and the development of cognitive and behavioral specializations.

Topics: Animals; Behavior, Addictive; Brain; Dopamine; Ethanol; Humans; Neuropeptide Y; Nucleus Accumbens; Obesity

Obesity is characterized by the expansion of the adipose tissue, usually accompanied by inflammation, with a prominent role of macrophages infiltrating the visceral adipose tissue (VAT). This chronic inflammation is a major driver of obesity-associated comorbidities. Four-and-a-half LIM-domain protein 2 (FHL2) is a multifunctional adaptor protein that is involved in the regulation of various biological functions and the maintenance of the homeostasis of different tissues. In this study, we aimed to gain new insights into the expression and functional role of FHL2 in VAT in diet-induced obesity. We found enhanced FHL2 expression in the VAT of mice with Western-type diet (WTD)-induced obesity and obese humans and identified macrophages as the cellular source of enhanced FHL2 expression in VAT. In mice with FHL2 deficiency (FHL2

Topics: Adipose Tissue; Animals; Diet; Diet, High-Fat; Humans; Inflammation; Intra-Abdominal Fat; LIM-Homeodomain Proteins; Lipids; Macrophages; Mice; Mice, Inbred C57BL; Muscle Proteins; Neuropeptide Y; Obesity; Transcription Factors

Topics: Animals; C-Reactive Protein; Diet, High-Fat; Dietary Supplements; Drinking Water; Leptin; Male; Neuropeptide Y; Nucleobindins; Obesity; Rats; Rats, Sprague-Dawley; Zinc

Polycystic ovary syndrome (PCOS) is a common reproductive and metabolic disorder characterized by high androgen levels. The aim of this study was to evaluate the effects of hyperandrogenism on the hypothalamus and subsequently on the food intake and obesity in females.. A dihydroxy testosterone (DHT)-induced rat model was established to recapitulate the hyperandrogenism features of PCOS patients. Body weight and food intake of the rats were recorded. The food intake of DHT-induced rats was restricted by pair feeding to exclude possible effects of weight gain on the hypothalamus. The expression levels of relevant proteins and mRNAs in the hypothalamus and primary hypothalamic neurons exposed to DHT were analyzed by Western blotting and RT-PCR, respectively. The leptin levels in the serum and cerebrospinal fluid (CSF) were measured, and leptin was injected via the intracerebroventricular (ICV) route to test the leptin sensitivity of the hypothalamus.. The excessive prepuberty androgen levels in the DHT-induced rats markedly elevated food intake prior to weight gain. Consistent with this, the expression of neuropeptide Y and agouti-related peptide mRNAs was upregulated, which occurred prior to obesity and even with restricted food intake. In addition, the hypothalamic sensitivity to insulin and leptin was also impaired in the DHT-induced rats before obesity and with restricted food intake. DHT significantly reduced the leptin levels in the CSF, and ICV injection of leptin inhibited the DHT-induced increase in food intake.. Androgen excess increased food intake in rats and promoted obesity by downregulating insulin and leptin signaling in the hypothalamus, most likely by suppressing leptin levels in the CSF.

Topics: Androgens; Animals; Body Weight; Eating; Female; Humans; Hyperandrogenism; Hypothalamus; Insulin; Leptin; Neuropeptide Y; Obesity; Polycystic Ovary Syndrome; Rats; RNA, Messenger; Signal Transduction; Testosterone; Weight Gain

Loss of functional β-cell mass is a key factor contributing to poor glycemic control in advanced type 2 diabetes (T2D). We have previously reported that the inhibition of the neuropeptide Y1 receptor improves the islet transplantation outcome in type 1 diabetes (T1D). The aim of this study was to identify the pathophysiological role of the neuropeptide Y (NPY) system in human T2D and further evaluate the therapeutic potential of using the Y1 receptor antagonist BIBO3304 to improve β-cell function and survival in T2D.. The gene expression of the NPY system in human islets from nondiabetic subjects and subjects with T2D was determined and correlated with the stimulation index. The glucose-lowering and β-cell-protective effects of BIBO3304, a selective orally bioavailable Y1 receptor antagonist, in high-fat diet (HFD)/multiple low-dose streptozotocin (STZ)-induced and genetically obese (db/db) T2D mouse models were assessed.. In this study, we identified a more than 2-fold increase in NPY1R and its ligand, NPY mRNA expression in human islets from subjects with T2D, which was significantly associated with reduced insulin secretion. Consistently, the pharmacological inhibition of Y1 receptors by BIBO3304 significantly protected β cells from dysfunction and death under multiple diabetogenic conditions in islets. In a preclinical study, we demonstrated that the inhibition of Y1 receptors by BIBO3304 led to reduced adiposity and enhanced insulin action in the skeletal muscle. Importantly, the Y1 receptor antagonist BIBO3304 treatment also improved β-cell function and preserved functional β-cell mass, thereby resulting in better glycemic control in both HFD/multiple low-dose STZ-induced and db/db T2D mice.. Our results revealed a novel causal link between increased islet NPY-Y1 receptor gene expression and β-cell dysfunction and failure in human T2D, contributing to the understanding of the pathophysiology of T2D. Furthermore, our results demonstrate that the inhibition of the Y1 receptor by BIBO3304 represents a potential β-cell-protective therapy for improving functional β-cell mass and glycemic control in T2D.

Topics: Animals; Arginine; Diabetes Mellitus, Type 2; Glucose; Glycemic Control; Insulin; Insulin-Secreting Cells; Male; Mice; Mice, Inbred C57BL; Neuropeptide Y; Obesity; Receptors, Neuropeptide Y

Restoring the control of food intake is the key to obesity management and prevention. The arcuate nucleus (ARC) of the hypothalamus is extensively being studied as a potential anti-obesity target. Animal studies showed that neuropeptide FF (NPFF) reduces food intake by its action in neuropeptide Y (NPY) neurons of the hypothalamic ARC, but the detailed mode of action observed in human neurons is missing, due to the lack of a human-neuron-based model for pharmacology testing. Here, we validated and utilized a human-neural-stem-cell-based (hNSC) model of ARC to test the effects of NPFF on cellular pathways and neuronal activity. We found that in the human neurons, decreased cAMP levels by NPFF resulted in a reduced rate of cytoplasmic calcium oscillations, indicating an inhibition of ARC NPY neurons. This suggests the therapeutic potential of NPFFR2 in obesity. In addition, we demonstrate the use of human-stem-cell-derived neurons in pharmacological applications and the potential of this model to address functional aspects of human hypothalamic neurons.

Topics: Animals; Arcuate Nucleus of Hypothalamus; Humans; Neurons; Neuropeptide Y; Obesity; Oligopeptides

Obesity is a serious public health problem associated with excessive food intake. Regulation of food intake in highly organized organisms is under the control of a large number of orexigenic and anorexigenic molecules. Therefore, the main purpose of this study has been to determine the relationship between obesity and some of the circulating orexigenic and anorexigenic peptides that have a role in appetite control and to determine whether the concentrations of these molecules differ according to blood groups.. The study included 400 individuals of whom 100 were obese women, 100 obese men, 100 healthy men and 100 healthy women. Obese women and men were divided into 4 groups, according to their blood groups. In the control group, healthy women and healthy men were similarly divided into 4 blood groups. Each blood group within the groups, therefore, had 25 participants.. When leptin, nesfatin-1, obestatin and neuropeptide-Y, ghrelin and galanin levels of the control group and obese participants were compared, regardless of blood groups, leptin, nesfatin-1, obestatin and neuropeptide-Y were significantly higher, whereas only the ghrelin levels were significantly lower in obese patients. When the amounts of these hormones were measured according to gender, the situation was similar. When leptin, nesfatin-1, obestatin and neuropeptide-Y values of the control and obese participants' blood groups were compared with each other; these hormones were high in all blood groups; however, leptin levels in A blood group, nesfatin-1 levels in AB and O blood group, obestatin levels in AB blood group, neuropeptide-Y levels in A, B, AB blood groups were significantly higher. When the ghrelin levels of the blood groups in the control group and obese participants were compared, it was only significantly lower in the AB blood group. The ghrelin levels in the other blood groups of the obese individuals were again low, but not significantly so. When the distribution of hormones according to gender was evaluated, a situation parallel to the above results was recorded.. Leptin, nesfatin-1, obestatin and neuropeptide-Y and galanin levels of obese individuals were significantly higher than the control values, whereas the ghrelin values were significantly lower regardless of blood groups. Also, these hormones in blood partly varied with ABO blood groups. These different concentrations of hormones in ABO blood groups might be related with stimulation or suppression of appetite in human. However, further studies in other ethnic groups are needed to confirm these results.

Topics: ABO Blood-Group System; Female; Galanin; Ghrelin; Humans; Leptin; Male; Neuropeptide Y; Obesity; Orexins

We previously demonstrated that Npy1r

Topics: Animals; Female; Gonadal Hormones; Male; Mice; Neuroinflammatory Diseases; Neuropeptide Y; Obesity; Prosencephalon; Receptors, Neuropeptide Y

d-allulose, a rare sugar, has sweetness with few calories. d-allulose regulates feeding and glycemia, and ameliorates hyperphagia, obesity and diabetes. All these functions involve the central nervous system. However, central mechanisms underlying these effects of d-allulose remain unknown. We recently reported that d-allulose activates the anorexigenic neurons in the hypothalamic arcuate nucleus (ARC), the neurons that respond to glucagon-like peptide-1 and that express proopiomelanocortin. However, its action on the orexigenic neurons remains unknown. This study investigated the effects of d-allulose on the ARC neurons implicated in hunger, by measuring cytosolic Ca

Topics: Animals; Appetite; Arcuate Nucleus of Hypothalamus; Eating; Fructose; Ghrelin; Glucose; Hyperphagia; Mice; Neurons; Neuropeptide Y; Obesity; Rats; Rats, Sprague-Dawley

Fibroblast growth factor 11 (FGF11) is a member of the intracellular fibroblast growth factor family. Here, we report the central role of FGF11 in the regulation of metabolism. Lentiviral injection of Fgf11 shRNA into the arcuate nucleus of the mouse hypothalamus decreased weight gain and fat mass, increased brown adipose tissue thermogenesis, and improved glucose and insulin intolerances under high-fat diet conditions. Fgf11 was expressed in the NPY-expressing neurons, and Fgf11 knockdown considerably decreased Npy expression and projection, leading to increased expression of tyrosine hydroxylase in the paraventricular nucleus. Mechanistically, FGF11 regulated Npy gene expression through the glycogen synthase kinase 3-cAMP response element-binding protein pathway. Our study defines the physiological significance of hypothalamic FGF11 in the regulation of metabolism in response to overnutrition such as high-fat diet.

Topics: Animals; Arcuate Nucleus of Hypothalamus; Diet, High-Fat; Fibroblast Growth Factors; Hypothalamus; Mice; Neuropeptide Y; Obesity; Paraventricular Hypothalamic Nucleus

High-calorie diets and chronic stress are major contributors to the development of obesity and metabolic disorders. These two risk factors regulate the activity of the sympathetic nervous system (SNS). The present study showed a key role of the cannabinoid type 1 receptor (CB1) in dopamine β-hydroxylase (

Topics: Animals; Cannabinoids; Corticosterone; Diet, High-Fat; Dopamine beta-Hydroxylase; Endocannabinoids; Mice; Neurons; Neuropeptide Y; Norepinephrine; Obesity; Receptor, Cannabinoid, CB1; Weight Gain

The goal of this study was to investigate the importance of central hormone-sensitive lipase (HSL) expression in the regulation of food intake and body weight in mice to clarify whether intracellular lipolysis in the mammalian hypothalamus plays a role in regulating appetite.. Using pharmacological and genetic approaches, we investigated the role of HSL in the rodent brain in the regulation of feeding and energy homeostasis under basal conditions during acute stress and high-fat diet feeding.. We found that HSL, a key enzyme in the catabolism of cellular lipid stores, is expressed in the appetite-regulating centers in the hypothalamus and is activated by acute stress through a mechanism similar to that observed in adipose tissue and skeletal muscle. Inhibition of HSL in rodent models by a synthetic ligand, global knockout, or brain-specific deletion of HSL prevents a decrease in food intake normally seen in response to acute stress and is associated with the increased expression of orexigenic peptides neuropeptide Y (NPY) and agouti-related peptide (AgRP). Increased food intake can be reversed by adeno-associated virus-mediated reintroduction of HSL in neurons of the mediobasal hypothalamus. Importantly, metabolic stress induced by a high-fat diet also enhances the hyperphagic phenotype of HSL-deficient mice. Specific deletion of HSL in the ventromedial hypothalamic nucleus (VMH) or AgRP neurons reveals that HSL in the VMH plays a role in both acute stress-induced food intake and high-fat diet-induced obesity.. Our results indicate that HSL activity in the mediobasal hypothalamus is involved in the acute reduction in food intake during the acute stress response and sensing of a high-fat diet.

Topics: Agouti-Related Protein; Animals; Appetite; Body Weight; Diet, High-Fat; Eating; Energy Metabolism; Female; Homeostasis; Hyperphagia; Hypothalamus; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Neurons; Neuropeptide Y; Obesity; RNA Splicing Factors; Sterol Esterase; Stress, Physiological; Transcriptome

Neuropeptide Y affects several physiological functions, notably appetite regulation. We analysed the association between four single nucleotide polymorphisms (SNP) in the NPY gene (rs5574, rs16147, rs16139, rs17149106) and measures of obesity, dietary intake, physical activity, blood pressure, glucose and lipid metabolism from adolescence to young adulthood.. The sample included both birth cohorts of the Estonian Children Personality Behaviour and Health Study at ages 15 (n = 1075 with available complete data), 18 (n = 913) and 25 (n = 926) years. Linear mixed-effects regression models were used for longitudinal association between NPY SNP-s and variables of interest. Associations at ages 15, 18 and 25 were analysed by ANOVA.. Rs5574 CC-homozygotes had a greater increase per year in waist-to-hip ratio (WHR) and a smaller decrease in daily energy intake and carbohydrate intake from age 15-25 years; fasting glucose and cholesterol were higher in rs5574 CC-homozygotes. Rs16147 TT-homozygotes had higher body weight and a greater increase in sum of 5 skinfolds, waist circumference, WHR and waist-to-height ratio; however, they had lower carbohydrate intake throughout the observation period. Rs16147 TT-homozygotes and both rs16139 and rs17149106 heterozygotes had higher triglyceride levels. All NPY SNP-s were associated with blood pressure: rs5574 TT-and rs16147 CC-homozygotes had a smaller increase in diastolic blood pressure, while rs16139 and rs17149106 heterozygous had lower blood pressure throughout the study.. Variants of the NPY gene were associated with measures of obesity, dietary intake, glucose and lipid metabolism and blood pressure from adolescence to young adulthood.

Topics: Adolescent; Adult; Blood Pressure; Cohort Studies; Energy Intake; Female; Glucose; Humans; Lipid Metabolism; Longitudinal Studies; Male; Neuropeptide Y; Obesity; Polymorphism, Single Nucleotide; Young Adult

Neuropeptide Y (NPY) and peptide YY (PYY) are involved in metabolic regulation. The purpose of the study was to assess the serum levels of NPY and PYY in adolescents with anorexia nervosa (AN) or obesity (OB), as well as in a healthy control group (CG). The effects of potential confounders on their concentrations were also analysed. Eighty-nine adolescents were included in this study (AN = 30, OB = 30, and CG = 29). Anthropometric measurements and psychometric assessment of depressive symptoms, eating behaviours, body attitudes, and fasting serum levels of NPY and PYY were analysed. The AN group presented severe depressive symptoms, while the OB group held different attitudes towards the body. The levels of NPY were lower in the AN and OB groups as compared with the CG. The PYY levels were higher in the OB group than in the AN group and the CG. The severity of eating disorder symptoms predicted fasting serum concentrations of NPY. Lower levels of NPY in AN, as well as in OB suggests the need to look for a common link in the mechanism of this effect. Higher level of PYY in OB may be important in explaining complex etiopathogenesis of the disease. The psychopathological symptoms may have an influence on the neurohormones regulating metabolism.

Topics: Adolescent; Anorexia Nervosa; Blood Glucose; Body Mass Index; Child; Depression; Fasting; Feeding Behavior; Female; Humans; Insulin; Male; Neuropeptide Y; Obesity; Peptide YY

Energy restriction is a first therapy in the treatment of obesity, but the underlying biological mechanisms have not been completely clarified. We analyzed the effects of restriction of high-fat diet (HFD) on weight loss, circulating gut hormone levels and expression of hypothalamic neuropeptides. Ten-week-old male Wistar rats (

Topics: Adiposity; Agouti-Related Protein; Animals; Caloric Restriction; Diet, Fat-Restricted; Diet, High-Fat; Dietary Fats; Disease Models, Animal; Eating; Ghrelin; Hypothalamus; Leptin; Male; Metabolic Diseases; Neuropeptide Y; Neuropeptides; Obesity; Pro-Opiomelanocortin; Rats; Rats, Wistar; Weight Loss

The preclinical multicomponent free-choice high-fat high-sucrose (fcHFHS) diet has strong validity to model diet-induced obesity (DIO) and associated maladaptive molecular changes in the central nervous system. fcHFHS-induced obese rats demonstrate increased sensitivity to intracerebroventricular infusion of the orexigenic Neuropeptide Y (NPY). The brain region-specific effects of NPY signaling on fcHFHS diet component selection are not completely understood. For example, fcHFHS-fed rats have increased intake of chow and fat following intracerebroventricular NPY infusion, whereas NPY administration in the nucleus accumbens, a key hub of the reward circuitry, specifically increases fat intake. Here, we investigated whether NPY infusion in the lateral hypothalamic area (LHA), which is crucially involved in the regulation of intake, regulates fcHFHS component selection, and if LHA NPY receptor subtypes 1 or 5 (NPYR1/5) are involved. Male Wistar rats were fed a chow or fcHFHS diet for at least seven days, and received intra-LHA vehicle or NPY infusions in a cross-over design. Diet component intake was measured two hours later. Separate experimental designs were used to test the efficacy of NPY1R- or NPY5R antagonism to prevent the orexigenic effects of intra-LHA NPY. Intra-LHA NPY increased caloric intake in chow- and fcHFHS-fed rats. This effect was mediated specifically by chow intake in fcHFHS-fed rats. The orexigenic effects of intra-LHA NPY were prevented by NPY1R and NPY5R antagonism in chow-fed rats, but only by NPY5R antagonism in fcHFHS-fed rats. Thus, NPY signaling has brain region-specific effects on fcHFHS component selection and LHA NPYR sensitivity is dysregulated during consumption of a fcHFHS diet.

Topics: Animals; Diet; Dietary Fats; Hypothalamic Area, Lateral; Hypothalamus; Male; Neuropeptide Y; Obesity; Rats; Rats, Wistar

In males, obesity increases sympathetic nerve activity (SNA), but the mechanisms are unclear. Here, we investigate insulin, via an action in the arcuate nucleus (ArcN), and downstream neuropathways, including melanocortin receptor 3/4 (MC3/4R) in the hypothalamic paraventricular nucleus (PVN) and dorsal medial hypothalamus (DMH). We studied conscious and α-chloralose-anesthetized Sprague-Dawley rats fed a high-fat diet, which causes obesity prone (OP) rats to accrue excess fat and obesity-resistant (OR) rats to maintain fat content, similar to rats fed a standard control (CON) diet. Nonspecific blockade of the ArcN with muscimol and specific blockade of ArcN insulin receptors (InsR) decreased lumbar SNA (LSNA), heart rate (HR), and mean arterial pressure (MAP) in OP, but not OR or CON, rats, indicating that insulin supports LSNA in obese males. In conscious rats, intracerebroventricular infusion of insulin increased MAP only in OP rats and also improved HR baroreflex function from subnormal to supranormal. The brain sensitization to insulin may elucidate how insulin can drive central SNA pathways when transport of insulin across the blood-brain barrier may be impaired. Blockade of PVN, but not DMH, MC3/4R with SHU9119 decreased LSNA, HR, and, MAP in OP, but not OR or CON, rats. Interestingly, nanoinjection of the MC3/4R agonist melanotan II (MTII) into the PVN increased LSNA only in OP rats, similar to PVN MTII-induced increases in LSNA in CON rats after blockade of sympathoinhibitory neuropeptide Y Y1 receptors. ArcN InsR expression was not increased in OP rats. Collectively, these data indicate that obesity increases SNA, in part via increased InsR signaling and downstream PVN MC3/4R.

Topics: Animals; Brain; Heart Rate; Insulin; Male; Melanocyte-Stimulating Hormones; Neuropeptide Y; Obesity; Rats; Rats, Sprague-Dawley; Receptor, Melanocortin, Type 4; Receptors, Neuropeptide Y; Sympathetic Nervous System

Obesity-associated low-grade inflammation favors weight gain, whereas systemic infection frequently leads to anorexia. Thus, inflammatory signals can either induce positive or negative energy balance. In this study, we used whole-cell patch-clamp to investigate the acute effects of three important proinflammatory cytokines, tumor necrosis factor α (TNF-α), interleukin-6, and interleukin-1β (IL-1β) on the membrane excitability of agouti-related peptide (AgRP)- or proopiomelanocortin (POMC)-producing neurons. We found that both TNF-α and IL-1β acutely inhibited the activity of 35-42% of AgRP-producing neurons, whereas very few POMC neurons were depolarized by TNF-α. Interleukin-6 induced no acute changes in the activity of AgRP or POMC neurons. Our findings indicate that the effect of TNF-α and IL-1β, especially on the activity of AgRP-producing neurons, may contribute to inflammation-induced anorexia observed during acute inflammatory conditions.

Topics: Agouti-Related Protein; Animals; Anorexia; Arcuate Nucleus of Hypothalamus; Energy Metabolism; Humans; Hypothalamus; Inflammation; Interleukin-1beta; Interleukin-6; Mice; Neurons; Neuropeptide Y; Obesity; Patch-Clamp Techniques; Pro-Opiomelanocortin; Tumor Necrosis Factor-alpha

The orexigenic hormone neuropeptide Y (NPY) plays a pivotal role in the peripheral regulation of fat metabolism. However, the mechanisms underlying the effects of sex on NPY function have not been extensively analyzed. In this study, we examined the effects of NPY deficiency on fat metabolism in male and female mice. Body weight was slightly decreased, whereas white adipose tissue (WAT) mass was significantly decreased as the thermogenic program was upregulated in NPY-/- female mice compared with that in wild-type mice; these factors were not altered in response to NPY deficiency in male mice. Moreover, lack of NPY resulted in an increase in luteinizing hormone (LH) expression in the pituitary gland, with concomitant activation of the estradiol-mediated thermogenic program in inguinal WAT, and alleviated age-related modification of adiposity in female mice. Taken together, these data revealed a novel intracellular mechanism of NPY in the regulation of fat metabolism and highlighted the sexual dimorphism of NPY as a promising target for drug development to reduce postmenopausal adiposity.

Topics: Adipose Tissue, White; Animals; Cell Differentiation; Cell Proliferation; Cells, Cultured; Estradiol; Female; Luteinizing Hormone; Male; Mice; Neuropeptide Y; Obesity; Phenotype; Pituitary Gland; Postmenopause; Sex Characteristics

When it comes to obesity, men exhibit a higher incidence of metabolic syndrome than women in early adult life, but this sex advantage wanes in postmenopausal women. A key diagnostic of the metabolic syndrome is insulin resistance in both peripheral tissues and brain, especially in the hypothalamus. Since the anorexigenic hormone 17β-estradiol (E2) regulates food intake in part by inhibiting the excitability of the hypothalamic neuropeptide Y/agouti-related peptide (NPY/AgRP) neurons, we hypothesized that E2 would protect against insulin resistance in NPY/AgRP neurons with diet-induced obesity (DIO). Therefore, we did whole-cell recordings and single cell quantitative polymerase chain reaction in arcuate NPYGFP neurons from both female and male mice to test the efficacy of insulin with DIO. The resting membrane potential and input resistance of NPY/AgRP neurons were significantly increased in DIO versus control-diet fed males. Most notably, the efficacy of insulin to activate KATP channels in NPY/AgRP neurons was significantly attenuated, although the KATP channel opener diazoxide was fully effective in NPY/AgRP neurons from DIO males, indicating that the KATP channels were expressed and functional. In contrast, insulin was fully efficacious to activate KATP channels in DIO females, and the response was reversed by the KATP channel blocker tolbutamide. However, the ability of insulin to activate KATP channels was abrogated with ovariectomy but fully restored with E2 replacement. Insulin resistance in obese males was likely mediated by an increase in suppressor of cytokine signaling-3 (SOCS-3), protein tyrosine phosphatase B (PTP1B) and T-cell protein tyrosine phosphatase (TCPTP) activity, since the expression of all 3 mRNAs were upregulated in the obese males but not in females. As proof of principle, pre-incubation of hypothalamic slices from DIO males with the PTP1B/TCPTP inhibitor CX08005 completely rescued the effects of insulin. Therefore, E2 protects NPY/AgRP neurons in females against insulin resistance through, at least in part, attenuating phosphatase activity. The neuroprotective effects of E2 may explain sex differences in the expression of metabolic syndrome that disappears with the loss of E2 in aging.

Topics: Agouti-Related Protein; Animals; Estradiol; Female; Insulin Resistance; Male; Mice; Mice, Transgenic; Neurons; Neuropeptide Y; Obesity; Patch-Clamp Techniques; Sex Characteristics

Few studies have assessed the effect of the NPY gene rs16147 variant on metabolic response following a dietary intervention. We evaluated the effect of rs16147 on body weight and biochemical changes after a high-protein/low-carbohydrate hypocaloric diet compared with a standard severe hypocaloric diet over 9 months.. A population of 270 obese individuals was enrolled. At baseline, participants were randomly allocated to one of two hypocaloric diets, high protein (Diet HP) or standard (Diet S), for a period of 9 months.. After both diets, all genotypes showed decreased body mass index, weight, fat mass, waist circumference, and leptin levels. Participants with the minor allele (A) assigned to the HP diet showed decreases in total cholesterol (-6.5 ± 4.8 vs 10.1 ± 4.1 mg/dL; p < 0.05), LDL cholesterol (-5.9 ± 3.8 vs 9.6 ± 2.4 mg/dL; p < 0.05), triglycerides (-1.0 ± 4.8 vs 16.2 ± 4.1 mg/dL; p < 0.05), insulin (-0.5 ± 2.8 vs 1.7 ± 2.1 UI/L; p < 0.05), HOMA-IR (-0.2 ± 2.1 vs 0.5 ± 2.0 units; p < 0.05), and CRP (-0.3 ± 0.4 vs 1.3 ± 0.2 mg/dL; p < 0.05). Participants with the minor allele assigned to diet S also showed decreases in total cholesterol (-6.1 ± 4.1 vs 14.4 ± 3.1 mg/dL; p < 0.05), LDL-cholesterol (-3.1 ± 2.8 vs 15.0 ± 3.1 mg/dL; p < 0.05), triglycerides (-6.9 ± 4.1 vs 13.2 ± 4.0 mg/dL; p < 0.05), insulin (-0.3 ± 2.1 vs. -1.2 ± 0.2 UI/L: p < 0.05), HOMA-IR (-0.3 ± 2.1 vs. -1.6 ± 1.1 units: p < 0.05), and CRP (-0.4 ± 0.1 vs 1.1 ± 0.2 mg/dL; p < 0.05).. In obese Caucasians, the presence of the A allele of the rs16147 genetic variant produces a better metabolic response that is secondary to weight loss with two different hypocaloric diets.

Topics: Diet, High-Protein Low-Carbohydrate; Female; Humans; Insulin Resistance; Male; Middle Aged; Neuropeptide Y; Obesity

Common mutations in the human prohormone convertase (PC)1/3 gene (PCKSI) are linked to increased risk of obesity. Previous work has shown that the rs6232 single-nucleotide polymorphism (N221D) results in slightly decreased activity, although whether this decrease underlies obesity risk is not clear. We observed significantly decreased activity of the N221D PC1/3 enzyme at the pH of the trans-Golgi network; at this pH, the mutant enzyme was less stable than wild-type enzyme. Recombinant N221D PC1/3 also showed enhanced susceptibility to heat stress. Enhanced susceptibility to tunicamycin-induced endoplasmic reticulum stress was observed in AtT-20/PC2 cell clones in which murine PC1/3 was replaced by human N221D PC1/3, as compared with wild-type human PC1/3. However, N221D PC1/3-expressing AtT-20/PC2 clones processed proopiomelanocortin to α-MSH similarly to wild-type PC1/3. We also generated a CRISPR-edited mouse line expressing the N221D mutation in the PCKSI gene. When homozygous N221D mice were fed either a standard or a high-fat diet, we found no increase in body weight compared with their wild-type sibling controls. Sexual dimorphism was observed in pituitary ACTH for both genotypes, with females exhibiting lower levels of pituitary ACTH. In contrast, hypothalamic α-MSH content for both genotypes was higher in females compared with males. Hypothalamic corticotropin-like intermediate peptide content was higher in wild-type females compared with wild-type, but not N221D, males. Taken together, these data suggest that the increased obesity risk linked to the N221D allele in humans may be due in part to PC1/3-induced loss of resilience to stressors rather than strictly to decreased enzymatic activity on peptide precursors.

Topics: alpha-MSH; Animals; Endoplasmic Reticulum Stress; Enzyme Stability; Female; Glucose Intolerance; Humans; Hydrogen-Ion Concentration; Hypothalamus; Male; Mice; Neuropeptide Y; Obesity; Pituitary Gland; Polymorphism, Single Nucleotide; Pro-Opiomelanocortin; Proprotein Convertase 1; Sex Characteristics

Type 2 diabetes mellitus is a major health concern worldwide; however, the molecular mechanism underlying its development is poorly understood. The hormone amylin is postulated to be involved, as human amylin forms amyloid in the pancreases of diabetic patients, and oligomers have been shown to be cytotoxic to β-cells. As rodent amylin is non-amyloidogenic, mice expressing human amylin have been developed to investigate this hypothesis. However, it is not possible to differentiate the effects of amylin overexpression from β-cell loss in these models. We have developed transgenic mice that overexpress [

Topics: Animals; Blood Glucose; Body Weight; Brain; Diabetes Mellitus, Type 2; Disease Models, Animal; Gene Expression Profiling; Gene Expression Regulation; Humans; Insulin; Islet Amyloid Polypeptide; Leptin; Male; Mice; Mice, Transgenic; Nerve Tissue Proteins; Neuropeptide Y; Obesity; Phenotype; Phosphorylation; Pro-Opiomelanocortin; Proto-Oncogene Proteins c-fos; RNA, Messenger; Signal Transduction; STAT3 Transcription Factor; Suppressor of Cytokine Signaling 3 Protein

Excessive food intake and metabolic disorder promote obesity and diabetes. In China, peanut skin is used as a herbal medicine to treat hemophilia, thrombocytopenic purpura, and hepatic hemorrhage. In the present study, we demonstrated that peanut skin extract (PSE) safely reduced appetite, body weight, fat tissue, plasma TG and TC, and blood glucose level in mice with diet-induced obesity (DIO). Moreover, the leptin/leptin receptor/neuropeptide Y (NPY) and adiponectin signaling pathways involved in the antiobesity effects of PSE are confirmed through leptin and adiponectin overexpression and leptin receptor silencing in mice. PSE consisted of oligosaccharide and polyphenol in a mass ratio of 45 : 55, and both parts were important for the antiobesity function of PSE. Our results suggested that PSE can be developed as functional medical food to treat metabolic disorders and obesity.

Topics: Adiponectin; Adipose Tissue; Animals; Anti-Obesity Agents; Arachis; Body Weight; China; Diet, High-Fat; Disease Models, Animal; Humans; Leptin; Mice; Mice, Inbred ICR; Neuropeptide Y; Obesity; Plant Extracts; Receptors, Leptin; Signal Transduction

Neuropeptide Y (NPY) has been shown to have a prominent role in the control of bone formation through the regulation of osteoblast activity. We aimed to investigate the role of hypothalamus-derived NPY in bone metabolism.. Accordingly, adeno-associated virus (AAV)-mediated RNA interference (RNAi) was utilized to downregulate NPY gene expression in rats fed regular chow (RC) or a high-fat diet (HF). The serum concentrations of glucose, insulin, corticosterone, osteocalcin, insulin-like growth factor (IGF-1), triglycerides (TC), and cholesterol (TG) and fat mass and bone mineral density (BMD) were measured to assess the effect of NPY knockdown on basal and obesity-induced BMD. Forkhead transcription factor (FoxO1) and activating transcription factor 4 (ATF4) were measured to explore the molecular mechanism of the effect of dorsomedial nucleus (DMH) NPY knockdown on bone formation.. Our results showed that DMH NPY knockdown enhanced basal and the obesity-induced decrease in BMD and osteocalcin and promoted the phosphorylation of FoxO1 and reduced the expression of ATF4.. Our data suggest that DMH NPY knockdown can alter bone metabolism.

Topics: Animals; Bone Density; Bone Diseases, Metabolic; Dependovirus; Gene Knockdown Techniques; HEK293 Cells; Humans; Hypothalamus; Male; Neuropeptide Y; Obesity; Organ Specificity; Rats; Rats, Sprague-Dawley; Rats, Transgenic; RNA, Small Interfering

The aim of the present study is to investigate the effects of topiramate on the fat mass/obesity-associated protein (FTO) and on the neuropeptide Y (NPY) level in the hypothalamus depending on the recently increased prevalence of obesity.. In this study, twenty-four female rats were divided into four equal groups: Non-obese control, obese control, non-obese topiramate, and obese topiramate. Obese groups were fed with a 40% high-fat diet. At the end of the 9th week, the drug treatment started and the subjects were treated with topiramate once a day for 6 weeks. All animals underwent cardiac perfusion under high-dose anesthesia on the 15th week. Tissues were analyzed using biochemical, histological, and stereological methods.. In terms of neuron number in the arcuate nucleus area, a significant difference was observed among all groups (P < 0.01). The neuron number of the non-obese topiramate group was found to be significantly higher than that of the non-obese control group (P < 0.01). In the examination of the ventromedial nucleus of the entire group, it was observed that the neuron number of the non-obese control group was significantly lower than those of the other groups (P < 0.01). A significant increase in the NPY levels of the obese groups compared to the groups treated with topiramate was observed. Furthermore, the amount of the FTO protein increased in obese rats, while FTO and NPY levels decreased in the groups treated with topiramate.. In conclusion, the mechanism of the effect of topiramate to create a state of obesity is thought to involve the decrease in the levels of NPY and FTO.

Topics: Alpha-Ketoglutarate-Dependent Dioxygenase FTO; Animals; Anti-Obesity Agents; Female; Hypothalamus; Neurons; Neuropeptide Y; Obesity; Rats; Topiramate

Serotonin (5-HT) plays a regulatory role in coordinating the neural circuits regulating energy balance, with differences in both 5-HT availability at the synapse and the activity of 5-HT receptors mediating anorectic (via POMC/CART activation) and orexigenic (via NPY/AgRP activation) responses. In conditions of overweight and obesity the control of energy balance is clearly deregulated, and serotonergic modulation appears to make a significant contribution to weight gain. Fluoxetine (FLX), a selective serotonin reuptake inhibitor (SSRI) that increases 5-HT availability in the synaptic cleft may thus have potential effects on energy balance. Our aim was to use an overfeeding model to investigate the effects of chronic FLX treatment on energy balance-related parameters regulated by hypothalamic neuropeptides. Nursing male Wistar rats were assigned to normofed (9 pups/dam) or overfed (3 pups/dam) groups beginning at 3 days of age and continuing until 21 days of age, when commercial chow and water were made available ad libitum until experimental treatments were begun. From 39 through 59 days of age groups were divided according to pharmacological treatment: 1) NV group, normofed + vehicle solution (NaCl 0.9%, 10 ml/kg b.w.), 2) NF group, normofed + FLX (10 mg/kg b.w., in vehicle solution, 10 ml/kg b.w.) 3), OV, overfed + vehicle solution and 4) OF, overfed + FLX. At 60 days of age, body weight, white and brown adipose tissue content, and food intake were determined, and serum biochemical parameters and hypothalamic neuropeptide gene expression were measured. Results showed that FLX induced reductions in several murinometric indices, improvement of adipose profile, hypophagic behavior, reduction in serum parameters, and positive modulation of hypophagia-related genes. These data suggest that the beneficial effects of FLX-treatment on overfeeding-induced physical and behavioral effects in rats was due to hypothalamic alterations that led to improvement in energy balance in animals with a compromised metabolism.

Topics: Animals; Behavior, Animal; Body Composition; Body Weight; Eating; Energy Metabolism; Fluoxetine; Hypothalamus; Male; Neuropeptide Y; Neuropeptides; Obesity; Rats; Rats, Wistar; Receptors, Serotonin; Selective Serotonin Reuptake Inhibitors; Serotonin

Increased fructose consumption and chronic exposure to stress have been associated with the development of obesity and insulin resistance. In the hypothalamus, a crossroad of stress responses and energy balance, insulin and glucocorticoids regulate the expression of orexigenic neuropeptides, neuropeptide Y (NPY) and agouti-related protein (AgRP), and anorexigenic neuropeptides, proopio-melanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART).. We investigated whether chronic stress and fructose diet disrupt these hormonal signaling pathways and appetite control in the hypothalamus, contributing to the development of insulin resistance and obesity. Potential roles of hypothalamic inflammation and oxidative stress in the development of insulin resistance were also analyzed.. Insulin, glucocorticoid, and leptin signaling, expression of orexigenic and anorexigenic neuropeptides, and antioxidative and inflammatory statuses in the whole hypothalamus of fructose-fed female rats exposed to unpredictable stress for 9 weeks were analyzed using quantitative PCR and Western blotting.. Chronic stress combined with a fructose-enriched diet reduced protein content and stimulatory phosphorylation of Akt kinase, and elevated 11β-hydroxysteroid dehydrogenase 1 and glucocorticoid receptor expression, while alterations in appetite regulation (NPY, AgRP, POMC, CART, leptin receptor, and SOCS3 expression) were not observed. The expression of antioxidative defense enzymes (mitochondrial manganese superoxide dismutase 2, glutathione reductase, and catalase) and proinflammatory cytokines (IL-1β, IL-6, and TNFα) was reduced.. Our results underline the combination of long-term stress exposure and fructose overconsumption as more detrimental for hypothalamic function than for either of the factors separately, as it enhanced glucocorticoid and impaired insulin signaling, antioxidative -defense, and inflammatory responses of this homeostasis- regulating center.

Topics: Animal Feed; Animals; Antioxidants; Appetite Regulation; Diet; Energy Metabolism; Female; Fructose; Hypothalamus; Insulin; Leptin; Neuropeptide Y; Neuropeptides; Obesity; Rats, Wistar; Receptors, Leptin; Stress, Physiological

Intracerebroventricular insulin increased sympathetic nerve activity (SNA) and baroreflex control of SNA and heart rate more dramatically in obese male rats; in obese females, the responses were abolished. In obese males, the enhanced lumbar SNA (LSNA) responses were associated with reduced tonic inhibition of LSNA by neuropeptide Y (NPY) in the PVN. However, PVN NPY injection decreased LSNA similarly in obesity prone/obesity resistant/control rats. Collectively, these results suggest that NPY inputs were decreased. In obese females, NPY inhibition in the PVN was maintained. Moreover, NPY neurons in the arcuate nucleus became resistant to the inhibitory effects of insulin. A high-fat diet did not alter arcuate NPY neuronal InsR expression in males or females. Obesity-induced 'selective sensitization' of the brain to the sympathoexcitatory effects of insulin and leptin may contribute to elevated basal SNA, and therefore hypertension development, in males with obesity. These data may explain in part why obesity increases SNA less in women compared to men.. Obesity increases sympathetic nerve activity (SNA) in men but not women; however, the mechanisms are unknown. We investigated whether intracerebroventricular insulin infusion increases SNA more in obese male than female rats and if sex differences are mediated by changes in tonic inhibition of SNA by neuropeptide Y (NPY) in the paraventricular nucleus (PVN). When consuming a high-fat diet, obesity prone (OP) rats accrued excess fat, whereas obesity resistant (OR) rats maintained adiposity as in rats eating a control (CON) diet. Insulin increased lumbar SNA (LSNA) similarly in CON/OR males and females under urethane anaesthesia. The LSNA response was magnified in OP males but abolished in OP females. In males, blockade of PVN NPY Y1 receptors with BIBO3304 increased LSNA in CON/OR rats but not OP rats. Yet, PVN nanoinjections of NPY decreased LSNA similarly between groups. Thus, tonic PVN NPY inhibition of LSNA may be lost in obese males as a result of a decrease in NPY inputs. By contrast, in females, PVN BIBO3304 increased LSNA similarly in OP, OR and CON rats. After insulin, PVN BIBO3304 failed to increase LSNA in CON/OR females but increased LSNA in OP females, suggesting that with obesity NPY neurons become resistant to the inhibitory effects of insulin. These sex differences were not associated with changes in arcuate NPY neuronal insulin receptor expression. Collectively, these data reveal a marked sex difference in the impact of obesity on the sympathoexcitatory actions of insulin and implicate sexually dimorphic changes in NPY inhibition of SNA in the PVN as one mechanism.

Topics: Animals; Arcuate Nucleus of Hypothalamus; Arginine; Baroreflex; Female; Insulin; Male; Neural Inhibition; Neuropeptide Y; Obesity; Paraventricular Hypothalamic Nucleus; Rats; Rats, Sprague-Dawley; Receptors, Neuropeptide Y; Sex Factors; Sympathetic Nervous System

This study was intended to assess the influence of the rs16147 variant of the NPY gene on liver histology in patients with non-alcoholic fatty liver disease (NAFLD).. Eighty-nine patients with NAFLD were recruited into the study. Serum chemistry tests were done including lipid profile, transaminases, adipokines, and insulin resistance. Genotype of polymorphism (rs161477) of the NPY gene was studied.. Twenty-three patients (25.0%) had the GG genotype (wild type) and sixty-six patients (75%) the GA (n=39) or AA (n=27) (mutant) types. Patients with A allele had a lower percentage of lobular inflammation and steatohepatitis (lobular inflammation plus ballooning) than those with wild genotype. Patients with A allele showed lower SAF (Steatosis, Activity, Fibrosis) scores than non-A allele carriers (5.4±2.7 points vs. 4.1±1.1 points; p=0.01). In the analysis without fibrosis (NAS score), the same differences were detected (4.5±1.8 points vs. 3.4±1.8 points; p=0.01). In the logistic regression analysis A allele carriers showed lower odds for inflammation (OR 0.11, 95% CI 0.02-0.84, p=0.03) and steatohepatitis (OR 0.39, 95% CI 0.14-0.86, p=0.04) after adjusting for age, sex, and body mass index.. A variant of polymorphism rs16147 of the NPY gene is independently associated to a lower percentage of steatohepatitis and lobular inflammation in obese subjects with biopsy-proven NAFLD.

Topics: Adipokines; Adiposity; Adult; Blood Glucose; Body Weight; Comorbidity; Female; Genetic Association Studies; Genotype; Humans; Insulin Resistance; Lipids; Liver; Male; Middle Aged; Neuropeptide Y; Non-alcoholic Fatty Liver Disease; Obesity; Polymorphism, Single Nucleotide

In diet-induced obesity, metformin (MF) has weight-lowering effect and improves glucose homeostasis and insulin sensitivity. However, there is no information on the efficiency of MF and the mechanisms of its action in melanocortin-type obesity. We studied the effect of the 10-day treatment with MF at the doses of 200, 400 and 600 mg/kg/day on the food intake and the metabolic and hormonal parameters in female C57Bl/6J (genotype Ay/a) agouti-mice with melanocortin-type obesity, and the influence of MF on the hypothalamic signaling in obese animals at the most effective metabolic dose (600 mg/kg/day). MF treatment led to a decrease in food intake, the body and fat weights, the plasma levels of glucose, insulin and leptin, all increased in agouti-mice, to an improvement of the lipid profile and glucose sensitivity, and to a reduced fatty liver degeneration. In the hypothalamus of obese agouti-mice, the leptin and insulin content was reduced and the expression of the genes encoding leptin receptor (LepR), MC3- and MC4-melanocortin receptors and pro-opiomelanocortin (POMC), the precursor of anorexigenic melanocortin peptides, was increased. The activities of AMP-activated kinase (AMPK) and the transcriptional factor STAT3 were increased, while Akt-kinase activity did not change from control C57Bl/6J (a/a) mice. In the hypothalamus of MF-treated agouti-mice (10 days, 600 mg/kg/day), the leptin and insulin content was restored, Akt-kinase activity was increased, and the activities of AMPK and STAT3 were reduced and did not differ from control mice. In the hypothalamus of MF-treated agouti-mice, the Pomc gene expression was six times higher than in control, while the gene expression for orexigenic neuropeptide Y was decreased by 39%. Thus, we first showed that MF treatment leads to an improvement of metabolic parameters and a decrease of hyperleptinemia and hyperinsulinaemia in genetically-induced melanocortin obesity, and the specific changes in the hypothalamic signaling makes a significant contribution to this effect of MF.

Topics: Agouti-Related Protein; Animals; Body Weight; Female; Gene Expression Regulation; Hypoglycemic Agents; Hypothalamus; Leptin; Melanocortins; Metformin; Mice; Mice, Inbred C57BL; Mice, Obese; Neuropeptide Y; Obesity; Receptors, Leptin

Topics: Acyl-CoA Dehydrogenase, Long-Chain; Adipocytes; Adipogenesis; Adipose Tissue; Adiposity; Animals; Animals, Newborn; Anorexia; CCAAT-Enhancer-Binding Proteins; Chickens; Female; Gene Expression Regulation; Male; Neuropeptide Y; Obesity; Poultry Diseases; PPAR gamma; Time Factors; Weight Gain

Neuropeptide Y (NPY) exerts a powerful orexigenic effect in the hypothalamus. However, extra-hypothalamic nuclei also produce NPY, but its influence on energy homeostasis is unclear. Here we uncover a previously unknown feeding stimulatory pathway that is activated under conditions of stress in combination with calorie-dense food; NPY neurons in the central amygdala are responsible for an exacerbated response to a combined stress and high-fat-diet intervention. Central amygdala NPY neuron-specific Npy overexpression mimics the obese phenotype seen in a combined stress and high-fat-diet model, which is prevented by the selective ablation of Npy. Using food intake and energy expenditure as readouts, we demonstrate that selective activation of central amygdala NPY neurons results in increased food intake and decreased energy expenditure. Mechanistically, it is the diminished insulin signaling capacity on central amygdala NPY neurons under combined stress and high-fat-diet conditions that leads to the exaggerated development of obesity.

Topics: Amygdala; Animals; Body Temperature; Diet, High-Fat; Eating; Electrophysiology; Energy Metabolism; Hypothalamus; Immunohistochemistry; In Situ Hybridization, Fluorescence; Insulin; Male; Mice; Neurons; Neuropeptide Y; Obesity; Phenotype; Real-Time Polymerase Chain Reaction

During the development of obesity the expansion of white adipose tissue (WAT) leads to a dysregulation and an excessive remodeling of extracellular matrix (ECM), leading to fibrosis formation. These ECM changes have high impact on WAT physiology and may change obesity progression. Blocking WAT fibrosis may have beneficial effects on the efficacy of diet regimen or therapeutical approaches in obesity. Since dipeptidyl peptidase IV (DPP-IV) inhibitors prevent fibrosis in tissues, such as heart, liver and kidney, the objective of this study was to assess whether vildagliptin, a DPP-IV inhibitor, prevents fibrosis in WAT in a mouse model of obesity, and to investigate the mechanisms underlying this effect.. We evaluated the inhibitory effect of vildagliptin on fibrosis markers on WAT of high-fat diet (HFD)-induced obese mice and on 3T3-L1 cell line of mouse adipocytes treated with a fibrosis inducer, transforming growth factor beta 1 (TGFβ1).. Vildagliptin prevents the increase of fibrosis markers in WAT of HFD-fed mice and reduces blood glucose, serum triglycerides, total cholesterol and leptin levels. In the in vitro study, the inhibition of DPP-IV with vildagliptin, neuropeptide Y (NPY) treatment and NPY Y. Vildagliptin prevents fibrosis formation in adipose tissue in obese mice, at least partially through NPY and NPY Y. This study highlights the importance of vildagliptin in the treatment of fibrosis that occur in obesity.

Topics: 3T3-L1 Cells; Adamantane; Adipocytes; Adipose Tissue, White; Animals; Blood Glucose; Collagen; Diet, High-Fat; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Extracellular Matrix; Fibrosis; Hypolipidemic Agents; Leptin; Lipids; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Neuropeptide Y; Nitriles; Obesity; Pyrrolidines; Receptors, Neuropeptide Y; RNA Interference; RNA, Small Interfering; Transforming Growth Factor beta1; Vildagliptin

Slowly digestible starch (SDS), as a functional carbohydrate providing a slow and sustained glucose release, may be able to modulate food intake through activation of the gut-brain axis.. Diet-induced obese rats were used to test the effect on feeding behavior of high-fat (HF) diets containing an SDS, fabricated to digest into the ileum, as compared to rapidly digestible starch (RDS). Ingestion of the HF-SDS diet over an 11-week period reduced daily food intake, through smaller meal size, to the same level as a lean body control group, while the group consuming the HF-RDS diet remained at a high food intake. Expression levels (mRNA) of the hypothalamic orexigenic neuropeptide Y (NPY) and Agouti-related peptide (AgRP) were significantly reduced, and the anorexigenic corticotropin-releasing hormone (CRH) was increased, in the HF-SDS fed group compared to the HF-RDS group, and to the level of the lean control group.. SDS with digestion into the ileum reduced daily food intake and paralleled suppressed expression of appetite-stimulating neuropeptide genes associated with the gut-brain axis. This novel finding suggests further exploration involving a clinical study and potential development of SDS-based functional foods as an approach to obesity control.

Topics: Animals; Behavior, Animal; Brain; Diet, High-Fat; Dietary Carbohydrates; Energy Intake; Feeding Behavior; Functional Food; Gastrointestinal Tract; Male; Microspheres; Neuropeptide Y; Obesity; Rats; Rats, Sprague-Dawley; Starch

Drug discovery and development is commonly schematized as a "pipeline," and, although appreciated by drug developers to be a useful oversimplification, this cartology may perpetuate inaccurate notions of straightforwardness and is of minimal utility for process engineering to improve efficiency. To create a more granular schema, a group of drug developers, researchers, patient advocates, and regulators developed a crowdsourced atlas of the steps involved in translating basic discoveries into health interventions, annotated with the steps that are particularly prone to difficulty or failure. This Drug Discovery, Development, and Deployment Map (4DM), provides a network view of the process, which will be useful for communication and education to those new to the field, orientation and navigation of individual projects, and prioritization of technology development and re-engineering endeavors to improve efficiency and effectiveness. The 4DM is freely available for utilization, modification, and further development by stakeholders across the translational ecosystem.

Topics: Biomedical Technology; Clinical Trials as Topic; Communication; Drug Development; Drug Discovery; Humans; Intersectoral Collaboration; Learning; Myositis Ossificans; National Academies of Science, Engineering, and Medicine, U.S., Health and Medicine Division; Neuropeptide Y; Obesity; Polycystic Kidney, Autosomal Dominant; Pyrazoles; Pyrimidines; Research Design; Translational Research, Biomedical; United States; United States Food and Drug Administration

The adipocyte-derived hormone leptin acts via its receptor (LepRb) on central nervous system neurons to communicate the repletion of long-term energy stores, to decrease food intake, and to promote energy expenditure. We generated mice that express Cre recombinase from the calcitonin receptor (Calcr) locus (Calcrcre mice) to study Calcr-expressing LepRb (LepRbCalcr) neurons, which reside predominantly in the arcuate nucleus (ARC). Calcrcre-mediated ablation of LepRb in LepRbCalcrknockout (KO) mice caused hyperphagic obesity. Because LepRb-mediated transcriptional control plays a crucial role in leptin action, we used translating ribosome affinity purification followed by RNA sequencing to define the transcriptome of hypothalamic Calcr neurons, along with its alteration in LepRbCalcrKO mice. We found that ARC LepRbCalcr cells include neuropeptide Y (NPY)/agouti-related peptide (AgRP)/γ-aminobutyric acid (GABA) ("NAG") cells as well as non-NAG cells that are distinct from pro-opiomelanocortin cells. Furthermore, although LepRbCalcrKO mice exhibited dysregulated expression of several genes involved in energy balance, neither the expression of Agrp and Npy nor the activity of NAG cells was altered in vivo. Thus, although direct leptin action via LepRbCalcr cells plays an important role in leptin action, our data also suggest that leptin indirectly, as well as directly, regulates these cells.

Topics: Agouti-Related Protein; Animals; Eating; Hypothalamus; Leptin; Mice; Mice, Transgenic; Neurons; Neuropeptide Y; Obesity; Pro-Opiomelanocortin; Receptors, Calcitonin; Receptors, Leptin

To determine whether age and neuropeptide Y (NPY) were involved in the skeletal response to extended periods of diet-induced obesity.. Male wild-type (WT) and NPY null (NPYKO) mice were fed a mild (23% fat) high-fat diet for 10 weeks from 6 or 16 weeks of age. Metabolism and bone density were assessed during feeding. Skeletal changes were assessed by microCT and histomorphometry.. High-fat feeding in 6-week-old WT mice led to significantly increased body weight, adiposity and serum leptin levels, accompanied with markedly suppressed cortical bone accrual. NPYKO mice were less susceptible to fat accrual but, importantly, displayed a complete lack of suppression of bone accrual or cortical bone loss. In contrast, when skeletally mature (16 week old) mice underwent 10 weeks of fat feeding, the metabolic response to HFD was similar to younger mice, however bone mass was not affected in either WT or NPYKO. Thus, growing mice are particularly susceptible to the detrimental effects of HFD on bone mass, through suppression of bone accrual involving NPY signalling.. This study provides new insights into the relationship between the opposing processes of a positive weight/bone relationship and the negative 'metabolic' effect of obesity on bone mass. This negative effect is particularly active in growing skeletons, which have heightened sensitivity to changes in obesity. In addition, NPY is identified as a fundamental driver of this negative 'metabolic' pathway to bone.

Topics: Animals; Bone Density; Bone Remodeling; Cortical Bone; Diet, High-Fat; Disease Models, Animal; Mice; Mice, Inbred Strains; Neuropeptide Y; Obesity; Weight Gain

Associated with numerous metabolic and behavioral abnormalities, obesity is classified by metrics reliant on body weight (such as body mass index). However, overnutrition is the common cause of obesity, and may independently contribute to these obesity-related abnormalities. Here, we use dietary challenges to parse apart the relative influence of diet and/or energy balance from body weight on various metabolic and behavioral outcomes.. Seventy male mice (mus musculus) were subjected to the diet switch feeding paradigm, generating groups with various body weights and energetic imbalances. Spontaneous activity patterns, blood metabolite levels, and unbiased gene expression of the nutrient-sensing ventral hypothalamus (using RNA-sequencing) were measured, and these metrics were compared using standardized multivariate linear regression models.. Spontaneous activity patterns were negatively related to body weight (p<0.0001) but not diet/energy balance (p = 0.63). Both body weight and diet/energy balance predicted circulating glucose and insulin levels, while body weight alone predicted plasma leptin levels. Regarding gene expression within the ventral hypothalamus, only two genes responded to diet/energy balance (neuropeptide y [npy] and agouti-related peptide [agrp]), while others were related only to body weight.. Collectively, these results demonstrate that individual components of obesity-specifically obesogenic diets/energy imbalance and elevated body mass-can have independent effects on metabolic and behavioral outcomes. This work highlights the shortcomings of using body mass-based indices to assess metabolic health, and identifies novel associations between blood biomarkers, neural gene expression, and animal behavior following dietary challenges.

Topics: Agouti-Related Protein; Animals; Behavior, Animal; Biomarkers; Body Weight; Circadian Rhythm; Diet; Energy Intake; Energy Metabolism; Gene Expression; Hypothalamus; Leptin; Male; Mice; Mice, Inbred C57BL; Neuropeptide Y; Obesity; Sleep; Wakefulness

Neuropeptide Y (NPY) Y5 receptor plays a key role in the effects of NPY, an important neurotransmitter in the control of energy homeostasis including stimulation of food intake and inhibition of energy expenditure. The NPY-Y5 receptor system has been an attractive drug target for potential use in treating obesity. Here we report the discovery and characterization of two novel Y5 receptor antagonists, S-2367 and S-234462. Both compounds displayed high affinity for the Y5 receptor in the radio-ligand binding assay, while in the cell-based functional assay, S-2367 and S-234462 showed, respectively, surmountable and insurmountable antagonism. In cell-based washout experiments, S-234462 dissociated from the Y5 receptor more slowly than S-2367. In vivo study showed that S-234462 effectively suppressed food intake induced by acute central injection of a selective Y5 receptor agonist. Furthermore, high-fat diet-induced obese (DIO) mice treated with S-234462 for 5 weeks showed a significant decrease in body weight gain and food intake compared to those treated with S-2367. In conclusion, S-234462 exhibits insurmountable antagonism of NPY Y5 receptor in vitro and superior anti-obesity effects to the surmountable NPY Y5 antagonist S-2367 in DIO mice.

Topics: Animals; Diet, High-Fat; Disease Models, Animal; Eating; Energy Metabolism; Injections, Intraventricular; Male; Mice, Inbred C57BL; Mice, Obese; Neuropeptide Y; Obesity; Receptors, Neuropeptide Y

Overweight and obesity are important risk factors for diabetes, cardiovascular diseases, and premature death in modern society. Recently, numerous natural and synthetic compounds have been tested in diet-induced obese animal models, to counteract obesity. Melatonin is a circadian hormone, produced by pineal gland and extra-pineal sources, involved in processes which have in common a rhythmic expression. In teleost, it can control energy balance by activating or inhibiting appetite-related peptides. The study aims at testing effects of melatonin administration to control-fed and overfed zebrafish, in terms of expression levels of orexigenic (Ghrelin, orexin, NPY) and anorexigenic (leptin, POMC) genes expression and morphometry of visceral and subcutaneous fat depots.. Adult male zebrafish (n = 56) were divided into four dietary groups: control, overfed, control + melatonin, overfed + melatonin. The treatment lasted 5 weeks and BMI levels of every fish were measured each week. After this period fishes were sacrificed; morphological and morphometric studies have been carried out on histological sections of adipose tissue and adipocytes. Moreover, whole zebrafish brain and intestine were used for qRT-PCR.. Our results demonstrate that melatonin supplementation may have an effect in mobilizing fat stores, in increasing basal metabolism and thus in preventing further excess fat accumulation. Melatonin stimulates the anorexigenic and inhibit the orexigenic signals.. It seems that adequate melatonin treatment exerts anti-obesity protective effects, also in a diet-induced obesity zebrafish model, that might be the result of the restoration of many factors: the final endpoint reached is weight loss and stabilization of weight gain.

Topics: Adipocytes; Adipose Tissue; Animals; Appetite; Body Mass Index; Brain Chemistry; Cell Count; Cell Size; Diet; Disease Models, Animal; Gene Expression; Male; Melatonin; Neuropeptide Y; Obesity; Orexins; Pro-Opiomelanocortin; RNA, Messenger; Zebrafish

Diabetic retinopathy (DR) is one of the major complications of diabetes, which eventually leads to blindness. Up to date, no animal model has yet shown all the co-morbidities often observed in DR patients. Here, we investigated whether obese 42 weeks old ZSF1 rat, which spontaneously develops diabetes, hypertension and obesity, would be a suitable model to study DR. Although arteriolar tortuosity increased in retinas from obese as compared to lean (hypertensive only) ZSF1 rats, vascular density pericyte coverage, microglia number, vascular morphology and retinal thickness were not affected by diabetes. These results show that, despite high glucose levels, obese ZSF1 rats did not develop DR. Such observations prompted us to investigate whether the expression of genes, possibly able to contain DR development, was affected. Accordingly, mRNA sequencing analysis showed that genes (i.e. Npy and crystallins), known to have a protective role, were upregulated in retinas from obese ZSF1 rats. Lack of retina damage, despite obesity, hypertension and diabetes, makes the 42 weeks of age ZSF1 rats a suitable animal model to identify genes with a protective function in DR. Further characterisation of the identified genes and downstream pathways could provide more therapeutic targets for the treat DR.

Topics: Animals; Blood Glucose; Crystallins; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Diabetic Retinopathy; Disease Models, Animal; Gene Expression Profiling; Hypertension; Male; Metabolic Syndrome; Neuropeptide Y; Obesity; Rats; Retina

Cold exposure is considered to be a form of stress and has various adverse effects on the body. The present study aimed to investigate the effects of chronic daily cold exposure on food intake, body weight, serum glucose levels and the central energy balance regulatory pathway in mice fed with a high‑fat diet (HFD). C57BL/6 mice were divided into two groups, which were fed with a standard chow or with a HFD. Half of the mice in each group were exposed to ice‑cold water for 1 h/day for 7 weeks, while the controls were exposed to room temperature. Chronic daily cold exposure significantly increased energy intake, body weight and serum glucose levels in HFD‑fed mice compared with the control group. In addition, 1 h after the final cold exposure, c‑fos immunoreactivity was significantly increased in the central amygdala of HFD‑fed mice compared with HFD‑fed mice without cold exposure, indicating neuronal activation in this brain region. Notably, 61% of these c‑fos neurons co‑expressed the neuropeptide Y (NPY), and the orexigenic peptide levels were significantly increased in the central amygdala of cold‑exposed mice compared with control mice. Notably, cold exposure significantly decreased the anorexigenic brain‑derived neurotropic factor (BDNF) messenger RNA (mRNA) levels in the ventromedial hypothalamic nucleus and increased growth hormone releasing hormone (GHRH) mRNA in the paraventricular nucleus. NPY‑ergic neurons in the central amygdala were activated by chronic cold exposure in mice on HFD via neuronal pathways to decrease BDNF and increase GHRH mRNA expression, possibly contributing to the development of obesity and impairment of glucose homeostasis.

Topics: Adipose Tissue, Brown; Adipose Tissue, White; Amygdala; Animals; Body Weight; Brain-Derived Neurotrophic Factor; Cold Temperature; Diet, High-Fat; Eating; Glucose; Green Fluorescent Proteins; Growth Hormone-Releasing Hormone; Homeostasis; Mice, Inbred C57BL; Neurons; Neuropeptide Y; Obesity; Proto-Oncogene Proteins c-fos; RNA, Messenger; Stress, Physiological; Ventromedial Hypothalamic Nucleus

Prenatal undernutrition and postnatal overnutrition increase the risk of some peripheral and central metabolic disorders in adulthood. We speculated that disturbances of appetite/metabolic regulatory factors might already have been established in the early stages of life and contribute to obesity later in life. The effects of a high-fat diet on the levels of peripheral and central appetite/metabolic regulatory factors were compared between the offspring of normally nourished dams and those of undernourished dams in the peri-pubertal period. In the offspring of the normally nourished dams (control), the consumption of the high-fat diet resulted in lower hypothalamic mRNA levels of orexigenic factors (neuropeptide Y (NPY) and prepro-orexin (pporexin)), whereas no such changes were seen in the offspring of the undernourished dams (subjected to intrauterine growth restriction). These results indicate that in high-energy conditions either the adaptive response does not function properly or has not been established in the offspring of undernourished dams. Because NPY and pporexin are negatively regulated by leptin, these findings suggest that in the intrauterine growth restriction group, the leptin resistance of hypothalamic functions, which is usually caused by diet-induced obesity in adulthood, had already been established in the peri-pubertal period.

Topics: Animals; Appetite Regulation; Diet, High-Fat; Female; Fetal Development; Fetal Growth Retardation; Gene Expression Regulation, Developmental; Hypothalamus; Intra-Abdominal Fat; Lactation; Leptin; Malnutrition; Maternal Nutritional Physiological Phenomena; Nerve Tissue Proteins; Neurons; Neuropeptide Y; Obesity; Orexins; Protein Precursors; Rats, Sprague-Dawley; Weaning

A gain-of-function polymorphism in human neuropeptide Y (

Topics: Adrenergic Neurons; Animals; Cholesterol; Diabetes Mellitus, Type 2; Energy Intake; Energy Metabolism; Fatty Acids; Fatty Liver; Gene Expression; Glucose; Hypercholesterolemia; Liver; Metabolic Syndrome; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neuropeptide Y; Obesity; Receptors, Neuropeptide Y; Sympathetic Nervous System

Obesity is a multifactorial disorder with high heritability (50-75%), which is probably higher in early-onset and severe cases. Although rare monogenic forms and several genes and regions of susceptibility, including copy number variants (CNVs), have been described, the genetic causes underlying the disease still remain largely unknown. We searched for rare CNVs (>100kb in size, altering genes and present in <1/2000 population controls) in 157 Spanish children with non-syndromic early-onset obesity (EOO: body mass index >3 standard deviations above the mean at <3 years of age) using SNP array molecular karyotypes. We then performed case control studies (480 EOO cases/480 non-obese controls) with the validated CNVs and rare sequence variants (RSVs) detected by targeted resequencing of selected CNV genes (n = 14), and also studied the inheritance patterns in available first-degree relatives. A higher burden of gain-type CNVs was detected in EOO cases versus controls (OR = 1.71, p-value = 0.0358). In addition to a gain of the NPY gene in a familial case with EOO and attention deficit hyperactivity disorder, likely pathogenic CNVs included gains of glutamate receptors (GRIK1, GRM7) and the X-linked gastrin-peptide receptor (GRPR), all inherited from obese parents. Putatively functional RSVs absent in controls were also identified in EOO cases at NPY, GRIK1 and GRPR. A patient with a heterozygous deletion disrupting two contiguous and related genes, SLCO4C1 and SLCO6A1, also had a missense RSV at SLCO4C1 on the other allele, suggestive of a recessive model. The genes identified showed a clear enrichment of shared co-expression partners with known genes strongly related to obesity, reinforcing their role in the pathophysiology of the disease. Our data reveal a higher burden of rare CNVs and RSVs in several related genes in patients with EOO compared to controls, and implicate NPY, GRPR, two glutamate receptors and SLCO4C1 in highly penetrant forms of familial obesity.

Topics: Case-Control Studies; DNA Copy Number Variations; Female; Genetic Loci; Humans; Male; Neuropeptide Y; Obesity; Organic Anion Transporters; Pedigree; Polymorphism, Single Nucleotide; Receptors, Kainic Acid; Receptors, Metabotropic Glutamate

Maternal obesity has been shown to increase the risk of obesity and related disorders in the offspring, which has been partially attributed to changes of appetite regulators in the offspring hypothalamus. On the other hand, endoplasmic reticulum (ER) stress and autophagy have been implicated in hypothalamic neuropeptide dysregulation, thus may also play important roles in such transgenerational effect. In this study, we show that offspring born to high-fat diet-fed dams showed significantly increased body weight and glucose intolerance, adiposity and plasma triglyceride level at weaning. Hypothalamic mRNA level of the orexigenic neuropeptide Y (NPY) was increased, while the levels of the anorexigenic pro-opiomelanocortin (POMC), NPY1 receptor (NPY1R) and melanocortin-4 receptor (MC4R) were significantly downregulated. In association, the expression of unfolded protein response (UPR) markers including glucose-regulated protein (GRP)94 and endoplasmic reticulum DNA J domain-containing protein (Erdj)4 was reduced. By contrast, protein levels of autophagy-related genes Atg5 and Atg7, as well as mitophagy marker Parkin, were slightly increased. The administration of 4-phenyl butyrate (PBA), a chemical chaperone of protein folding and UPR activator, in the offspring from postnatal day 4 significantly reduced their body weight, fat deposition, which were in association with increased activating transcription factor (ATF)4, immunoglobulin-binding protein (BiP) and Erdj4 mRNA as well as reduced Parkin, PTEN-induced putative kinase (PINK)1 and dynamin-related protein (Drp)1 protein expression levels. These results suggest that hypothalamic ER stress and mitophagy are among the regulatory factors of offspring metabolic changes due to maternal obesity.

Topics: Animals; Animals, Newborn; Autophagy-Related Protein 5; Autophagy-Related Protein 7; Diet, High-Fat; Female; Gene Expression Regulation; HSP40 Heat-Shock Proteins; Hypothalamus; Maternal Nutritional Physiological Phenomena; Membrane Glycoproteins; Neuropeptide Y; Obesity; Phenylbutyrates; Pregnancy; Pro-Opiomelanocortin; Rats; Rats, Sprague-Dawley; Receptor, Melanocortin, Type 4; Receptors, Neuropeptide Y; Signal Transduction; Stress, Physiological; Ubiquitin-Protein Ligases; Unfolded Protein Response

Greater than 40% of renal cell carcinoma (RCC) cases in the United States are attributed to excessive body weight. Moreover, obesity also may be linked to RCC prognosis. However, the molecular mechanisms underlying these associations are unclear. In the current study, the authors evaluated the role of promoter methylation in obesity-related genes in RCC tumorigenesis and disease recurrence.. Paired tumors (TU) and normal adjacent (N-Adj) tissues from 240 newly diagnosed and previously untreated white patients with RCC were examined. For the discovery phase, 63 RCC pairs were analyzed. An additional 177 RCC pairs were evaluated for validation. Pyrosequencing was used to determine CpG methylation in 20 candidate obesity-related genes. An independent data set from The Cancer Genome Atlas also was analyzed for functional validation. The association between methylation and disease recurrence was analyzed using multivariate Cox proportional hazards models and Kaplan-Meier survival analysis.. Methylation in neuropeptide Y (NPY), leptin (LEP), and leptin receptor (LEPR) was significantly higher in TU compared with N-Adj tissues (P<.0001) in both the discovery and validation groups. High methylation in LEPR was associated with an increased risk of disease recurrence (hazard ratio, 3.15; 95% confidence interval, 1.23-8.07 [P = .02]). Patients with high methylation in LEPR had a shorter recurrence-free survival compared with patients in the low-methylation group (log-rank P = 2.25 × 10. Somatic alterations of promoter methylation in the NPY, LEP, and LEPR genes are involved in RCC tumorigenesis. Furthermore, LEPR methylation appears to be associated with RCC recurrence. Future research to elucidate the biology underlying this association is warranted. Cancer 2017;123:3617-27. © 2017 American Cancer Society.

Topics: Aged; Carcinoma, Renal Cell; Cohort Studies; CpG Islands; DNA Methylation; Female; Gene Expression Regulation, Neoplastic; Humans; Kaplan-Meier Estimate; Kidney Neoplasms; Leptin; Male; Middle Aged; Neoplasm Invasiveness; Neoplasm Recurrence, Local; Neoplasm Staging; Neuropeptide Y; Obesity; Prognosis; Promoter Regions, Genetic; Proportional Hazards Models; Prospective Studies; Receptors, Leptin; Risk Assessment; Survival Analysis

Obesity increases sympathetic nerve activity (SNA) via activation of proopiomelanocortin neurons in the arcuate nucleus (ArcN), and this action requires simultaneous withdrawal of tonic neuropeptide Y (NPY) sympathoinhibition. However, the sites and neurocircuitry by which NPY decreases SNA are unclear. Here, using designer receptors exclusively activated by designer drugs (DREADDs) to selectively activate or inhibit ArcN NPY neurons expressing agouti-related peptide (AgRP) in mice, we have demonstrated that this neuronal population tonically suppresses splanchnic SNA (SSNA), arterial pressure, and heart rate via projections to the paraventricular nucleus (PVN) and dorsomedial hypothalamus (DMH). First, we found that ArcN NPY/AgRP fibers closely appose PVN and DMH presympathetic neurons. Second, nanoinjections of NPY or an NPY receptor Y1 (NPY1R) antagonist into PVN or DMH decreased or increased SSNA, respectively. Third, blockade of DMH NPY1R reversed the sympathoinhibition elicited by selective, DREADD-mediated activation of ArcN NPY/AgRP neurons. Finally, stimulation of ArcN NPY/AgRP terminal fields in the PVN and DMH decreased SSNA. Considering that chronic obesity decreases ArcN NPY content, we propose that the ArcN NPY neuropathway to the PVN and DMH is pivotal in obesity-induced elevations in SNA.

Topics: Agouti-Related Protein; Animals; Arcuate Nucleus of Hypothalamus; Blood Pressure; Chronic Disease; Gene Expression Regulation; Heart Rate; Mice; Mice, Transgenic; Neuropeptide Y; Obesity; Paraventricular Hypothalamic Nucleus; Receptors, Neuropeptide Y; Sympathetic Nervous System

Beige adipocytes can interconvert between white and brown-like states and switch between energy storage versus expenditure. Here we report that beige adipocyte plasticity is important for feeding-associated changes in energy expenditure and is coordinated by the hypothalamus and the phosphatase TCPTP. A fasting-induced and glucocorticoid-mediated induction of TCPTP, inhibited insulin signaling in AgRP/NPY neurons, repressed the browning of white fat and decreased energy expenditure. Conversely feeding reduced hypothalamic TCPTP, to increase AgRP/NPY neuronal insulin signaling, white adipose tissue browning and energy expenditure. The feeding-induced repression of hypothalamic TCPTP was defective in obesity. Mice lacking TCPTP in AgRP/NPY neurons were resistant to diet-induced obesity and had increased beige fat activity and energy expenditure. The deletion of hypothalamic TCPTP in obesity restored feeding-induced browning and increased energy expenditure to promote weight loss. Our studies define a hypothalamic switch that coordinates energy expenditure with feeding for the maintenance of energy balance.

Topics: Agouti-Related Protein; Animals; Eating; Energy Metabolism; Hypothalamus; Mice; Mice, Transgenic; Neuropeptide Y; Obesity; Protein Tyrosine Phosphatase, Non-Receptor Type 2

Leptin is an adipokine released mainly by adipose tissue, with many functions including regulation of energy balance. However, little is known about the effect of LEPR polymorphism on orexigenic and anorexigenic neuropeptides. Thus, the aim of the present study is to verify the influence of LEPR polymorphism (rs2767485) on serum orexigenic (NPY, MCH and AgRP) and anorexigenic (Leptin and α-MSH) neuropeptides levels among obese adolescents submitted to 1year of multicomponent weight loss therapy.. Seventy-six adolescents with obesity were enrolled in 1year of weight loss therapy including clinical, nutritional, psychological and exercise-related. Blood samples were collected to analyze neuropeptides (NPY, MCH, AgRP and leptin) and LEPR genotyping. Visceral fat was measured by ultrasound and body composition was measured by plethysmography. The parameters were measured at baseline and after one year. Adolescents were grouped according to genotype (TT or CT+CC group). Effect of the weight loss therapy was analyzed through ANOVA and Wilcox, according to normality. Statistic value was set at <0.05.. C-allele carriers have the orexigenic neuropeptides (NPY, AgRP and MCH) levels statistically higher when compared with TT group, at baseline. Furthermore, TT group seems to respond better to the therapy by a greater delta on BMI. Indeed, the data suggest a concomitant increased of AgRP levels in CT+CC genotypes, after weight loss therapy.. Both groups responded to the weight loss intervention, however wildtypes (TT) appear to respond to the intervention most optimally with C carries, where post intervention reduction in BMI was significantly greater in wildtypes. The leptin receptor polymorphism seems to affect neuroendocrine regulation of energy balance among adolescents with obesity.

Topics: Adiposity; Adolescent; Agouti-Related Protein; Brazil; Energy Metabolism; Female; Humans; Leptin; Male; Neuropeptide Y; Obesity; Polymorphism, Single Nucleotide; Receptors, Leptin; Ultrasonography; Weight Loss

We recently reported the in vitro and in vivo antiobesity effects of Tenebrio molitor larvae, a traditional food in many countries, but it remains unknown how the larvae affect appetite regulation in mice with diet-induced obesity. We hypothesized that the extract of T molitor larvae mediates appetite by regulating neuropeptide expression. We investigated T molitor larvae extract's (TME's) effects on anorexigenesis and endoplasmic reticulum (ER) stress-induced orexigenic neuropeptide expression in the hypothalami of obese mice. Intracerebroventricular TME administration suppressed feeding by down-regulating the expression of the orexigenic neuropeptides neuropeptide Y and agouti-related protein. T molitor larvae extract significantly reduced the expression of ER stress response genes. These results suggest that TME and its bioactive components are potential therapeutics for obesity and ER stress-driven disease states.

Topics: Agouti-Related Protein; Animals; Biological Products; Body Weight; Cell Line; Diet; Diet, High-Fat; Disease Models, Animal; Endoplasmic Reticulum Stress; Gene Expression Regulation; Ghrelin; Hypothalamus; Larva; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Mitogen-Activated Protein Kinases; Neuropeptide Y; Obesity; Tenebrio; TOR Serine-Threonine Kinases

Early-life stress (ES) is a risk factor for metabolic disorders (e.g. obesity) with a notoriously higher prevalence in women compared to men. However, mechanisms underlying these effects remain elusive. The development of the hypothalamic feeding and metabolic regulatory circuits occurs mostly in the early sensitive postnatal phase in rodents and is tightly regulated by the metabolic hormones leptin and ghrelin. We have previously demonstrated that chronic ES reduces circulating leptin and alters adipose tissue metabolism early and later in life similarly in both sexes. However, it is unknown whether chronic ES might also affect developmental ghrelin and insulin levels, and if it induces changes in hypothalamic feeding circuits, possibly in a sex-dependent manner. We here show that chronic ES, in the form of exposure to limited nesting and bedding material from postnatal day (P)2 to P9 in mice, affects ghrelin levels differently, depending on the form of ghrelin (acylated vs desacylated), on age (P9 vs P14) and on sex, while insulin levels were similarly increased in both sexes after ES at P9. Even though ghrelin levels were more strongly affected in ES-exposed females, hypothalamic neuropeptide Y (NPY) and agouti-related peptide (AgRP) fiber density at P14 were similarly altered in both sexes by ES. In the paraventricular nucleus of the hypothalamus, both NPY and AgRP fiber density were increased, while in the arcuate nucleus of the hypothalamus, NPY was increased and AgRP unaltered. Additionally, the hypothalamic mRNA expression of ghrelin's receptor (i.e. growth hormone secretagogue receptor) was not affected by ES. Taken together, the specific alterations found in these important regulatory circuits after ES might contribute to an altered energy balance and feeding behavior in adulthood and thereby to an increased vulnerability to develop metabolic disorders.

Topics: Adipose Tissue; Agouti-Related Protein; Animals; Arcuate Nucleus of Hypothalamus; Feeding Behavior; Female; Ghrelin; Hypothalamus; Insulin; Leptin; Male; Mice; Mice, Inbred C57BL; Neuropeptide Y; Obesity; Paraventricular Hypothalamic Nucleus; Sex Factors; Stress, Psychological

The mitochondrial uncoupling agent 2,4-dinitrophenol (DNP), historically used as a treatment for obesity, is known to cross the blood-brain-barrier, but its effects on central neural circuits controlling body weight are largely unknown. As hypothalamic melanocortin neuropeptide Y/agouti-related protein (NPY/AgRP) and pro-opiomelanocortin (POMC) neurons represent key central regulators of food intake and energy expenditure we investigated the effects of DNP on these neurons, food intake and energy expenditure.. C57BL/6 and melanocortin-4 receptor (MC4R) knock-out mice were administered DNP intracerebroventricularly (ICV) and the metabolic changes were characterized. The specific role of NPY and POMC neurons and the ionic mechanisms mediating the effects of uncoupling were examined with in vitro electrophysiology performed on NPY hrGFP or POMC eGFP mice.. Here we show DNP-induced differential effects on melanocortin neurons including inhibiting orexigenic NPY and activating anorexigenic POMC neurons through independent ionic mechanisms coupled to mitochondrial function, consistent with an anorexigenic central effect. Central administration of DNP induced weight-loss, increased BAT thermogenesis and browning of white adipose tissue, and decreased food intake, effects that were absent in MC4R knock-out mice and blocked by the MC4R antagonist, AgRP.. These data show a novel central anti-obesity mechanism of action of DNP and highlight the potential for selective melanocortin mitochondrial uncoupling to target metabolic disorders.

Topics: 2,4-Dinitrophenol; Adipose Tissue, Brown; Animals; Body Weight; Eating; Energy Metabolism; Male; Melanocortins; Mice; Mice, Inbred C57BL; Mice, Knockout; Mitochondria; Neurons; Neuropeptide Y; Obesity; Pro-Opiomelanocortin; Receptor, Melanocortin, Type 4; Receptors, Melanocortin; Thermogenesis; Uncoupling Protein 1; Weight Loss

In visceral obesity, an overactive endocannabinoid/CB. We analyzed the hypothalamic circuitry targeted by leptin following chronic treatment of DIO mice with JD5037.. Leptin treatment or an increase in endogenous leptin following fasting/refeeding induced STAT3 phosphorylation in neurons in the arcuate nucleus (ARC) in lean and JD5037-treated DIO mice, but not in vehicle-treated DIO animals. Co-localization of pSTAT3 in leptin-treated mice was significantly less common with NPY. Peripheral CB

Topics: Animals; Arcuate Nucleus of Hypothalamus; Body Weight; Cannabinoids; Diet, High-Fat; Dietary Fats; Eating; Hypothalamus; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Neuropeptide Y; Obesity; Pro-Opiomelanocortin; Pyrazoles; Receptor, Cannabinoid, CB1; Receptor, Melanocortin, Type 4; Receptors, Cannabinoid; Receptors, Leptin; Signal Transduction; STAT3 Transcription Factor; Sulfonamides

When individuals undergo gestation in an obese dam, they are at increased risk for impairments in the ability of the brain to regulate body weight. In rodents, gestation in an obese dam leads to a number of changes to the development of the hypothalamic neurones that regulate body weight, including reduced neuronal connectivity at birth. In the present study, we aimed to clarify how this neural circuitry develops normally, as well as to explore the mechanism underpinning the deficiency in connectivity seen in foetuses developing in obese dams. First, we developed an in vitro model for observing and manipulating the axonal growth of foetal arcuate nucleus (ARN) neuropeptide (NPY) neurones. We then used this model to test 2 hypotheses: (i) ARN NPY neurones respond to Netrin-1, one of a small number of axon growth and guidance factors that regulate neural circuit formation throughout the developing brain; and (ii) Netrin-1 responsiveness would be lost upon exposure to the inflammatory cytokine interleukin (IL)-6, which is elevated in foetuses developing in obese dams. We observed that ARN NPY neurones responded to Netrin-1 with a significant expansion of their growth cones, comprising the terminal apparatus that neurones use to navigate. Unexpectedly, we found further that NPY neurones from obese pregnancies had a reduced responsiveness to Netrin-1, raising the possibility that ARN NPY neurones from foetuses developing in obese dams were phenotypically different from normal NPY neurones. Finally, we observed that IL-6 treatment of normal NPY neurones in vitro led to a reduced growth cone responsiveness to Netrin-1, essentially causing them to behave similarly to NPY neurones from obese pregnancies. These results support the hypothesis that IL-6 can disrupt the normal process of axon growth from NPY neurones, and suggest one possible mechanism for how the body weight regulating circuitry fails to develop properly in the offspring of obese dams.

Topics: Animals; Arcuate Nucleus of Hypothalamus; Cells, Cultured; Female; Growth Cones; Interleukin-6; Male; Mice, Inbred C57BL; Netrin-1; Neurons; Neuropeptide Y; Obesity; Pregnancy; Pregnancy Complications

Stress increases the risk for major depressive disorder (MDD), overeating, and alcohol dependence (AD). The neuropeptide Y system is one of the best-known modulators of the stress response, and some of its effects are mediated through the neuropeptide Y receptor Y2 (NPY2R). The functional NPY2R variant rs6857715 (C-599T) has been implicated in both obesity and AD, but with opposing alleles. The present study explored whether rs6857715 is also associated with MDD. Analysis of the overall sample (595 MDD cases; 1295 controls) showed an association with the AD risk allele C [P=0.020, odds ratio (OR) (C-allele)=1.18]. The association remained significant after excluding MDD patients with AD/alcohol abuse [P=0.038, OR (C-allele)=1.18]; increased weight/appetite [P=0.006, OR (C-allele)=1.23]; or both [P=0.008, OR (C-allele)=1.25]. The present findings suggest that the NPY2R rs6857715 C-allele makes a genuine contribution toward MDD.

Topics: Adult; Alcoholism; Alleles; Case-Control Studies; Depressive Disorder, Major; Female; Genetic Predisposition to Disease; Germany; Humans; Male; Middle Aged; Neuropeptide Y; Obesity; Odds Ratio; Polymorphism, Single Nucleotide; Promoter Regions, Genetic; Receptors, Neuropeptide Y

The main genetic variant described in NPY gene is rs16147 (G-399A) and it is located within the promoter region upstream of the gene for neropeptide Y (NPY). We evaluate the effects of the rs16147 NPY gene polymorphism on metabolic changes secondary to weight loss after 3 months of a hypocaloric diet in adult obese patients.. A population of 82 obese patients was analysed in an interventional design of one arm. Before and after 3 months on a hypocaloric diet, an anthropometric evaluation, an assessment of nutritional intake and a biochemical analysis were performed. The statistical analysis was performed for combined GA and AA as a group (minor allele group) and GG as second group (major allele group) (dominant model).. In A allele carriers, the mean (SD) decrease in weight was -2.8 (2.2) kg [decrease in non A allele carriers -2.6 (1.1) kg, P > 0.05), body mass index was -1.2 (0.6) kg m. We found that the rs164147 genotype affected the reduction of waist circumference, HOMA-IR, insulin, CRP and IL-6 levels in response to weight loss diet in obese subjects.

Topics: Adipokines; Adult; Biomarkers; Blood Glucose; Body Mass Index; C-Reactive Protein; Caloric Restriction; Cardiovascular Diseases; Diet, Fat-Restricted; Diet, Reducing; Female; Follow-Up Studies; Humans; Insulin Resistance; Male; Middle Aged; Neuropeptide Y; Obesity; Polymorphism, Single Nucleotide; Prospective Studies; Risk Factors; Waist Circumference; Weight Loss

Consumption of dietary fat is one of the key factors leading to obesity. High-fat diet (HFD)-induced obesity is characterized by induction of inflammation in the hypothalamus; however, the temporal regulation of proinflammatory markers and their impact on hypothalamic appetite-regulating neuropeptide Y/agouti-related peptide (NPY/AgRP) neurons remains undefined.. Mice were injected with an acute lipid infusion for 24 h or fed a HFD over 8-20 weeks. Characterized mouse NPY/AgRP hypothalamic cell lines were used for in vitro experimentation. Immunohistochemistry in brain slices or quantitative real-time PCR in cell lines, was performed to determine changes in the expression of key inflammatory markers and neuropeptides.. Hypothalamic inflammation, indicated by tumor necrosis factor (TNF)-α expression and astrocytosis in the arcuate nucleus, was evident following acute lipid infusion. HFD for 8 weeks suppressed TNF-α, while significantly increasing heat-shock protein 70 and ciliary neurotrophic factor, both neuroprotective components. HFD for 20 weeks induced TNF-α expression in NPY/AgRP neurons, suggesting a detrimental temporal regulatory mechanism. Using NPY/AgRP hypothalamic cell lines, we found that palmitate provoked a mixed inflammatory response on a panel of inflammatory and endoplasmic reticulum (ER) stress genes, whereas TNF-α significantly upregulated IκBα, nuclear factor (NF)-κB and interleukin-6 mRNA levels. Palmitate and TNF-α exposure predominantly induced NPY mRNA levels. Utilizing an I kappa B kinase β (IKKβ) inhibitor, we demonstrated that these effects potentially occur via the inflammatory IKKβ/NF-κB pathway.. These findings indicate that acute lipid and chronic HFD feeding in vivo, as well as acute palmitate and TNF-α exposure in vitro, induce markers of inflammation or ER stress in the hypothalamic appetite-stimulating NPY/AgRP neurons over time, which may contribute to a dramatic alteration in NPY/AgRP content or expression. Acute and chronic HFD feeding in vivo temporally regulates arcuate TNF-α expression with reactive astrocytosis, which suggests a time-dependent neurotrophic or neurotoxic role of lipids.

Topics: Animals; Appetite; Arcuate Nucleus of Hypothalamus; Diet, High-Fat; Disease Models, Animal; Gene Expression Regulation; Hypothalamus; Inflammation; Interleukin-6; Male; Mice; Mice, Inbred C57BL; Neurons; Neuropeptide Y; Obesity; Palmitates; Tumor Necrosis Factor-alpha

Recent data suggest that common genetic risks for metabolic disorders such as obesity may be human-specific and exert effects via the central nervous system. To overcome the limitation of human tissue access for study, we have generated induced human pluripotent stem cell (hiPSC)-derived neuronal cultures that recapture many features of hypothalamic neurones within the arcuate nucleus. In the present study, we have comprehensively characterised this model across development, benchmarked these neurones to in vivo events, and demonstrate a link between obesity risk variants and hypothalamic development. The dynamic transcriptome across neuronal maturation was examined using microarray and RNA sequencing methods at nine time points. K-means clustering of the longitudinal data was conducted to identify co-regulation and microRNA control of biological processes. The transcriptomes were compared with those of 103 samples from 13 brain regions reported in the Genotype-Tissue Expression database (GTEx) using principal components analysis. Genes with proximity to body mass index (BMI)-associated genetic variants were mapped to the developmentally expressed genesets, and enrichment significance was assessed with Fisher's exact test. The human neuronal cultures have a transcriptional and physiological profile of neuropeptide Y/agouti-related peptide arcuate nucleus neurones. The neuronal transcriptomes were highly correlated with adult hypothalamus compared to any other brain region from the GTEx. Also, approximately 25% of the transcripts showed substantial changes in expression across neuronal development and potential co-regulation of biological processes that mirror neuronal development in vivo. These developmentally expressed genes were significantly enriched for genes in proximity to BMI-associated variants. We confirmed the utility of this in vitro human model for studying the development of key hypothalamic neurones involved in energy balance and show that genes at loci associated with body weight regulation may share a pattern of developmental regulation. These data support the need to investigate early development to elucidate the human-specific central nervous system pathophysiology underlying obesity susceptibility.

Topics: Agouti-Related Protein; Arcuate Nucleus of Hypothalamus; Body Mass Index; Body Weight; Cells, Cultured; Genetic Loci; Humans; Induced Pluripotent Stem Cells; Neurons; Neuropeptide Y; Obesity; Transcriptome

Diet-induced hypothalamic inflammation is an important mechanism leading to dysfunction of neurons involved in controlling body mass. Studies have shown that polyunsaturated fats can reduce hypothalamic inflammation. Here, we evaluated the presence and function of RvD2, a resolvin produced from docosahexaenoic acid, in the hypothalamus of mice.. Male Swiss mice were fed either chow or a high-fat diet. RvD2 receptor and synthetic enzymes were evaluated by real-time PCR and immunofluorescence. RvD2 was determined by mass spectrometry. Dietary and pharmacological approaches were used to modulate the RvD2 system in the hypothalamus, and metabolic phenotype consequences were determined.. All enzymes involved in the synthesis of RvD2 were detected in the hypothalamus and were modulated in response to the consumption of dietary saturated fats, leading to a reduction of hypothalamic RvD2. GPR18, the receptor for RvD2, which was detected in POMC and NPY neurons, was also modulated by dietary fats. The substitution of saturated by polyunsaturated fats in the diet resulted in increased hypothalamic RvD2, which was accompanied by reduced body mass and improved glucose tolerance. The intracerebroventricular treatment with docosahexaenoic acid resulted in increased expression of the RvD2 synthetic enzymes, increased expression of anti-inflammatory cytokines and improved metabolic phenotype. Finally, intracerebroventricular treatment with RvD2 resulted in reduced adiposity, improved glucose tolerance and increased hypothalamic expression of anti-inflammatory cytokines.. Thus, RvD2 is produced in the hypothalamus, and its receptor and synthetic enzymes are modulated by dietary fats. The improved metabolic outcomes of RvD2 make this substance an attractive approach to treat obesity.

Topics: Animals; Anti-Inflammatory Agents; Calcium-Binding Proteins; Cytokines; Diet, High-Fat; Disease Models, Animal; Docosahexaenoic Acids; Encephalitis; Gene Expression Regulation; Glucose Tolerance Test; Hypothalamus; Male; Mice; Microfilament Proteins; Neurons; Neuropeptide Y; Obesity; Oxygen Consumption; Pro-Opiomelanocortin; Receptors, G-Protein-Coupled

Gastric electrical stimulation (GES) has great potential for the treatment of obesity. We investigated the impact of chronic GES on the alteration of adipose tissue and the regulation of neuropeptide Y (NPY), orexin (OX), α-melanocyte-stimulating hormone (α-MSH) and oxytocin (OXT), and their receptors in several tissues.. Most of the experiments included three groups of diet-induced obesity rats: (1) sham-GES (SGES); (2) GL-6mA (GES with 6 mA, 4 ms, 40 Hz, 2 s on, 3 s off at lesser curvature); and (3) SGES-PF (SGES rats receiving pair feeding to match the consumption of GL-6mA rats). Chronic GES was applied for 2 h every day for 4 weeks. During treatment with GES, food intake and body weight were monitored weekly. The alteration of epididymal fat weight, gastric emptying, and expression of peptides and their receptors in several tissues were determined.. GL-6mA was more potent than SGES-PF in decreasing body weight gain, epididymal fat tissue weight, adipocyte size and gastric emptying. Chronic GES significantly altered NPY, OX, α-MSH and OXT and their receptors in the hypothalamus, adipose tissue and stomach.. Chronic GES effectively leads to weight loss by reducing food intake, fat tissue weight and gastric emptying. NPY, α-MSH, orexin and OXT, and their receptors in the hypothalamus, adipose tissue and stomach appear to be involved in the anti-obesity effects of chronic GES.

Topics: Adipocytes; alpha-MSH; Animals; Disease Models, Animal; Eating; Electric Stimulation Therapy; Electrodes, Implanted; Epididymis; Gastric Emptying; Gastric Mucosa; Ghrelin; Hypothalamus; Intra-Abdominal Fat; Leptin; Male; Neuropeptide Y; Obesity; Orexin Receptors; Orexins; Oxytocin; Pro-Opiomelanocortin; Rats; Rats, Sprague-Dawley; Receptor, Melanocortin, Type 3; Receptors, G-Protein-Coupled; Receptors, Melanocortin; Receptors, Neuropeptide; Receptors, Neuropeptide Y; Receptors, Oxytocin; RNA, Messenger; Weight Loss

Y2 receptors have been implicated in the development of obesity and are a potential target for obesity treatment due to their known role of inhibiting neuropeptide Y (NPY) induced feeding responses. However, the precise neuronal population on which Y2 receptors act to fulfil this role is less clear. Here we utilise a novel inducible, postnatal onset NPY neurons specific deletion model to investigate the functional consequences of loss of Y2 signalling in this population of neurons on feeding and energy homeostasis regulation. While the consequences of lack of Y2 signalling in NPY neurons are confirmed in terms of the uncoupling of suppression/increasing of NPY and pro-opiomelanocortin (POMC) mRNA expression in the arcuate nuclei (Arc), respectively, this lack of Y2 signalling surprisingly does not have any significant effect on spontaneous food intake. Fasting induced food intake, however, is strongly increased but only in the first 1h after re-feeding. Consequently no significant changes in body weight are being observed although body weight gain is increased in male mice after postnatal onset Y2 deletion. Importantly, another known function of central Y2 receptor signalling, the suppression of bone formation is conserved in this conditional model with whole body bone mineral content being decreased. Taken together this model confirms the critical role of Y2 signalling to control NPY and associated POMC expression in the Arc, but also highlights the possibility that others, non-NPY neuronal Y2 receptors, are also involved in controlling feeding and energy homeostasis regulation.

Topics: Animals; Arcuate Nucleus of Hypothalamus; Body Weight; Fasting; Homeostasis; Mice; Neurons; Neuropeptide Y; Obesity; Osteogenesis; Receptors, Neuropeptide Y

We aimed to evaluate the effects of maternal and/or paternal obesity on offspring body mass, leptin signaling, appetite-regulating neurotransmitters and local inflammatory markers. C57BL/6 mice received standard chow (SC, lean groups) or high-fat diet (HF, obese groups) starting from one month of age. At three months, HF mice became obese relative to SC mice. They were then mated as follows: lean mother and lean father, lean mother and obese father, obese mother and lean father, and obese mother and obese father. The offspring received the SC diet from weaning until three months of age, when they were sacrificed. In the offspring, paternal obesity did not lead to changes in the Janus kinase (JAK)/signal transducer and activation of the transcription (STAT) pathway or feeding behavior but did induce hypothalamic inflammation. On the other hand, maternal obesity resulted in increased weight gain, hyperleptinemia, decreased leptin OBRb receptor expression, JAK/STAT pathway impairment, and increased SOCS3 signaling in the offspring. In addition, maternal obesity elevated inflammatory markers and altered NPY and POMC expression in the hypothalamus. Interestingly, combined parental obesity exacerbated the deleterious outcomes compared to single-parent obesity. In conclusion, while maternal obesity is known to program metabolic changes and obesity in offspring, the current study demonstrated that obese fathers induce hypothalamus inflammation in offspring, which may contribute to the development of metabolic syndromes in adulthood.

Topics: Animals; Body Weight; Diet, High-Fat; Energy Intake; Fathers; Female; Hyperphagia; Hypothalamus; Inflammation Mediators; Janus Kinase 1; Leptin; Male; Mice; Mothers; Neuropeptide Y; Obesity; Parents; Pro-Opiomelanocortin; Receptors, Leptin; Signal Transduction; STAT1 Transcription Factor; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins

Ghrelin, the natural ligand of the growth hormone secretagogue receptor type 1a (GHS-R1a), is mainly secreted from the stomach and regulates food intake and energy homeostasis. p27 regulates cell cycle progression in many cell types. Here, we report that rats affected by the multiple endocrine neoplasia syndrome MENX, caused by a p27 mutation, develop pancreatic islet hyperplasia containing elevated numbers of ghrelin-producing ε-cells. The metabolic phenotype of MENX-affected rats featured high endogenous acylated and unacylated plasma ghrelin levels. Supporting increased ghrelin action, MENX rats show increased food intake, enhanced body fat mass, and elevated plasma levels of triglycerides and cholesterol. Ghrelin effect on food intake was confirmed by treating MENX rats with a GHS-R1a antagonist. At 7.5 months, MENX-affected rats show decreased mRNA levels of hypothalamic GHS-R1a, neuropeptide Y (NPY), and agouti-related protein (AgRP), suggesting that prolonged hyperghrelinemia may lead to decreased ghrelin efficacy. In line with ghrelin's proposed role in glucose metabolism, we find decreased glucose-stimulated insulin secretion in MENX rats, while insulin sensitivity is improved. In summary, we provide a novel nontransgenic rat model with high endogenous ghrelin plasma levels and, interestingly, improved glucose tolerance. This model might aid in identifying new therapeutic approaches for obesity and obesity-related diseases, including type 2 diabetes.

Topics: Agouti-Related Protein; Animals; Appetite Regulation; Blood Glucose; Cyclin-Dependent Kinase Inhibitor p27; Ghrelin; Hypothalamus; Insulin Resistance; Multiple Endocrine Neoplasia; Mutation; Neuropeptide Y; Obesity; Rats; Receptors, Ghrelin; RNA, Messenger

Neuropeptide Y (NPY) in the dorsomedial hypothalamus (DMH) plays an important role in the regulation of energy balance. While DMH NPY overexpression causes hyperphagia and obesity in rats, knockdown of NPY in the DMH via adeno-associated virus (AAV)-mediated RNAi (AAVshNPY) ameliorates these alterations. Whether this knockdown has a therapeutic effect on obesity and glycemic disorder has yet to be determined. The present study sought to test this potential using a rat model of high-fat diet (HFD)-induced obesity and insulin resistance, mimicking human obesity with impaired glucose homeostasis. Rats had ad libitum access to rodent regular chow (RC) or HFD. Six weeks later, an oral glucose tolerance test (OGTT) was performed for verifying HFD-induced glucose intolerance. After verification, obese rats received bilateral DMH injections of AAVshNPY or the control vector AAVshCTL, and OGTT and insulin tolerance test (ITT) were performed at 16 and 18 wk after viral injection (23 and 25 wk on HFD), respectively. Rats were killed at 26 wk on HFD. We found that AAVshCTL rats on HFD remained hyperphagic, obese, glucose intolerant, and insulin resistant relative to lean control RC-fed rats receiving DMH injection of AAVshCTL, whereas these alterations were reversed in NPY knockdown rats fed a HFD. NPY knockdown rats exhibited normal food intake, body weight, glucose tolerance, and insulin sensitivity, as seen in lean control rats. Together, these results demonstrate a therapeutic action of DMH NPY knockdown against obesity and impaired glucose homeostasis in rats, providing a potential target for the treatment of obesity and diabetes.

Topics: Adiposity; Animals; Blood Glucose; Body Weight; Dependovirus; Diet, High-Fat; Disease Models, Animal; Down-Regulation; Eating; Energy Metabolism; Gene Knockdown Techniques; Genetic Vectors; Glucose Intolerance; Hypothalamus, Middle; Insulin; Insulin Resistance; Male; Neuropeptide Y; Obesity; Rats, Sprague-Dawley; RNA, Small Interfering; RNAi Therapeutics; Time Factors

Ghrelin's receptor, growth hormone secretagogue receptor (GHSR), is highly expressed in the arcuate nucleus (ARC) and in neuropeptide Y (NPY) neurons. Fasting, diet-induced obesity (DIO), and 17β-estradiol (E2) influence ARC Ghsr expression. It is unknown if these effects occur in NPY neurons. Therefore, we examined the expression of Npy, Agrp, and GHSR signaling pathway genes after fasting, DIO, and E2 replacement in ARC and pools of NPY neurons. In males, fasting increased ARC Ghsr and NPY Foxo1 but decreased NPY Ucp2. In males, DIO decreased ARC and NPY Ghsr and Cpt1c. In fed females, E2 increased Agrp, Ghsr, Cpt1c, and Foxo1 in ARC. In NPY pools, E2 decreased Foxo1 in fed females but increased Foxo1 in fasted females. DIO in females suppressed Agrp and augmented Cpt1c in NPY neurons. In summary, genes involved in GHSR signaling are differentially regulated between the ARC and NPY neurons in a sex-dependent manner.

Topics: Animals; Arcuate Nucleus of Hypothalamus; Estradiol; Fasting; Female; Gene Expression Regulation; Male; Mice; Neurons; Neuropeptide Y; Obesity; Receptors, Ghrelin; Sex Factors; Signal Transduction

Clinical studies indicate alternate-day, intermittent fasting (IMF) protocols result in meaningful weight loss in obese individuals. To further understand the mechanisms sustaining weight loss by IMF, we investigated the metabolic and neural alterations of IMF in obese mice. Male C57/BL6 mice were fed a high-fat diet (HFD; 45% fat) ad libitum for 8 weeks to promote an obese phenotype. Mice were divided into four groups and either maintained on ad libitum HFD, received alternate-day access to HFD (IMF-HFD), and switched to ad libitum low-fat diet (LFD; 10% fat) or received IMF of LFD (IMF-LFD). After 4 weeks, IMF-HFD (∼13%) and IMF-LFD (∼18%) had significantly lower body weights than the HFD. Body fat was also lower (∼40%-52%) in all diet interventions. Lean mass was increased in the IMF-LFD (∼12%-13%) compared with the HFD and IMF-HFD groups. Oral glucose tolerance area under the curve was lower in the IMF-HFD (∼50%), whereas the insulin tolerance area under the curve was reduced in all diet interventions (∼22%-42%). HPLC measurements of hypothalamic tissue homogenates indicated higher (∼55%-60%) norepinephrine (NE) content in the anterior regions of the medial hypothalamus of IMF compared with the ad libitum-fed groups, whereas NE content was higher (∼19%-32%) in posterior regions in the IMF-LFD group only. Relative gene expression of Npy in the arcuate nucleus was increased (∼65%-75%) in IMF groups. Our novel findings indicate that intermittent fasting produces alterations in hypothalamic NE and neuropeptide Y, suggesting the counterregulatory processes of short-term weight loss are associated with an IMF dietary strategy.

Topics: Adipose Tissue; Animals; Anterior Hypothalamic Nucleus; Arcuate Nucleus of Hypothalamus; Body Weight; Chromatography, High Pressure Liquid; Diet, High-Fat; Fasting; Gene Expression; Glucose Tolerance Test; Hypothalamus; Male; Mice; Mice, Inbred C57BL; Neuropeptide Y; Norepinephrine; Obesity; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Weight Loss

High-fat diet (HFD)-induced hypertension in rabbits is neurogenic because of the central sympathoexcitatory actions of leptin. Hypothalamic melanocortin and neuropeptide Y (NPY) neurons are recognized as the major signalling pathways through which leptin exerts its central effects. In this study, we assessed the effects of specific antagonists and agonists to melanocortin and NPY receptors on HFD-induced sympathoexcitation and hypertension.. Rabbits were instrumented with intracerebroventricular cannula, renal sympathetic nerve activity (RSNA) electrode, and blood pressure telemetry transmitter.. After 3 weeks HFD (13.5% fat, n = 12) conscious rabbits had higher RSNA (+3.8  nu, P = 0.02), blood pressure (+8.6  mmHg, P < 0.001) and heart rate (+15  b/min, P = 0.01), and brain-derived neurotrophic factor levels in the hypothalamus compared with rabbits fed a control diet (4.2% fat, n = 11). Intracerebroventricular administration of the melanocortin receptor antagonist SHU9119 reduced RSNA (-2.7  nu) and blood pressure (-8.5  mmHg) in HFD but not control rabbits, thus reversing 100% of the hypertension and 70% of the sympathoexcitation induced by a HFD. By contrast, blocking central NPY Y1 receptors with BVD10 increased RSNA only in HFD rabbits. Intracerebroventricular α-melanocortin stimulating hormone increased RSNA and heart rate (P < 0.001) in HFD rabbits but had no effect in control rabbits.. These findings suggest that obesity-induced hypertension and increased RSNA are dependent on the balance between greater activation of melanocortin signalling through melanocortin receptors and lesser activation of NPY sympathoinhibitory signalling. The amplification of the sympathoexcitatory effects of α-melanocortin stimulating hormone also indicates that the underlying mechanism is related to facilitation of leptin-melanocortin signalling, possibly involving chronic activation of brain-derived neurotrophic factor.

Topics: alpha-MSH; Animals; Blood Pressure; Brain-Derived Neurotrophic Factor; Diet, High-Fat; Heart Rate; Hormones; Hypertension; Hypothalamus; Kidney; Leptin; Male; Melanocyte-Stimulating Hormones; Neuropeptide Y; Obesity; Pro-Opiomelanocortin; Rabbits; Receptors, Corticotropin; Receptors, Melanocortin; Receptors, Neuropeptide Y; Sympathetic Nervous System

Rats raised in small litters (SL) are obese and hyperphagic. In the present study, we evaluated whether obesity is associated with changes in the mesocorticolimbic dopaminergic reward system in these animals at adulthood. We also assessed the anti-obesity effects of dietary calcium supplementation. To induce early overfeeding, litters were adjusted to three pups on postnatal day (PN)3 (SL group). Control litters were kept with 10 pups each until weaning (NL group). On PN120, SL animals were subdivided into two groups: SL (standard diet) and SL-Ca [SL with calcium supplementation (10 g calcium carbonate/kg rat chow) for 60 days]. On PN175, animals were subjected to a food challenge: animals could choose between a high-fat (HFD) or a high-sugar diet (HSD). Food intake was recorded after 30 min and 12 h. Euthanasia occurred on PN180. SL rats had higher food intake, body mass and central adiposity. Sixty days of dietary calcium supplementation (SL-Ca) prevented these changes. Only SL animals preferred the HFD at 12 h. Both SL groups had lower tyrosine hydroxylase content in the ventral tegmental area, lower dopaminergic transporter content in the nucleus accumbens, and higher type 2 dopamine receptor (D2R) content in the hypothalamic arcuate nucleus (ARC). They also had higher neuropeptide Y (NPY) and lower pro-opiomelanocortin contents in the ARC. Calcium treatment normalised only D2R and NPY contents. Precocious obesity induces long-term effects in the brain dopaminergic system, which can be associated with an increased preference for fat at adulthood. Calcium treatment prevents this last alteration, partially through its actions on ARC D2R and NPY proteins.

Topics: Animals; Arcuate Nucleus of Hypothalamus; Brain; Calcium, Dietary; Diet, High-Fat; Dopamine; Eating; Energy Intake; Female; Food Preferences; Male; Neuropeptide Y; Nucleus Accumbens; Obesity; Pro-Opiomelanocortin; Rats, Wistar; Receptors, Dopamine D2; Reward; Tyrosine 3-Monooxygenase; Ventral Tegmental Area

Previously we reported that prenatal undernutrition (UN) leads to a dysregulation of appetite suppression through alterations in hypothalamic neuropeptide gene expression. In the current study, we expand our observations and investigate neuroendocrine transcriptional responses and central leptin sensitivity within the arcuate nucleus of rats exposed to prenatal UN or a postnatal high-fat diet (HF). Pregnant Wistar rats were fed a standard chow diet either ad libitum (AD) or at 30 % of AD intake throughout gestation (UN) resulting in either control or intrauterine growth-restricted female offspring. At weaning, AD offspring were fed either a chow (C) or a HF (30 % fat wt/wt) diet ad libitum for the remainder of the study, whereas UN offspring were fed a chow diet only. At ~142 days, AD and UN offspring received either recombinant rat leptin (L) or saline (S) subcutaneously for 14 days. Prenatal UN had a significant effect on hypothalamic NPY (P < 0.0001), AgRP (P < 0.01) and ObRb (P < 0.02) mRNA expression compared to AD chow-fed offspring. A postnatal HF diet had a significant effect on AgRP mRNA expression (P < 0.001), compared to AD chow-fed offspring, but no effect on NPY and ObRb expression. Leptin treatment, in both UN and HF offspring, was ineffective in reducing NPY and AgRP mRNA expression, and had no effect on ObRb expression. These findings suggest that prenatal UN and a postnatal HF diet lead to differential neuroendocrine gene expression in the hypothalamic arcuate nuclei and reduced sensitivity to leptin's anorexigenic effects.

Topics: Agouti-Related Protein; Animals; Arcuate Nucleus of Hypothalamus; Diet, High-Fat; Female; Gene Expression; Leptin; Male; Malnutrition; Neuropeptide Y; Obesity; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Wistar

Chronic psychosocial stress is a crucial risk factor in the development of many diseases including obesity. Neuropeptide Y (NPY), distributed throughout the peripheral and central nervous system, is believed to pay a role in the pathophysiologic relationship between stress and obesity. Although several animal studies have investigated the impact on obesity of interactions between NPY single nucleotide polymorphisms (SNPs) and stress, the same remains to be analyzed in humans.. To identify NPY gene-by-stress interaction effects on human obesity, we analyzed the interaction between four NPY SNPs and stress with obesity-related traits, including visceral adipose tissue (VAT). A total of 1468 adult subjects were included for this analysis.. In a SNP-only model without interaction with stress, no significant SNPs were found (pSNP>0.05). However, NPY SNPs-by-stress interaction effects were significantly linked to body mass index (BMI), waist circumference, and VAT (pint<0.05), even though a significant interaction effect for rs16135 on BMI was not identified. These significant interaction effects were also detected in interaction results for the binary traits of obesity. Among the obesity traits, mean changes of VAT by increased stress levels in homozygous risk allele carriers were the greatest (range of mean increases for four SNPs (min-max)=12.57cm(2)-29.86cm(2)).. This study suggests that common polymorphisms for NPY were associated with human obesity by interacting with psychosocial stress, emphasizing the need for stress management in obesity prevention.

Topics: Aged; Alleles; Body Mass Index; Female; Gene-Environment Interaction; Genotype; Humans; Intra-Abdominal Fat; Male; Middle Aged; Neuropeptide Y; Obesity; Phenotype; Polymorphism, Single Nucleotide; Republic of Korea; Risk Factors; Stress, Psychological; Waist Circumference

Transthyretin (TTR) is a blood and cerebrospinal fluid transporter of thyroxine and retinol. Gene expression profiling revealed an elevation of Ttr expression in the dorsomedial hypothalamus (DMH) of rats with exercise-induced anorexia, implying that central TTR may also play a functional role in modulating food intake and energy balance. To test this hypothesis, we have examined the effects of brain TTR on food intake and body weight and have further determined hypothalamic signaling that may underlie its feeding effect in rats. We found that intracerebroventricular (icv) administration of TTR in normal growing rats decreased food intake and body weight. This effect was not due to sickness as icv TTR did not cause a conditioned taste aversion. ICV TTR decreased neuropeptide Y (NPY) levels in the DMH and the paraventricular nucleus (P < 0.05). Chronic icv infusion of TTR in Otsuka Long-Evans Tokushima Fatty rats reversed hyperphagia and obesity and reduced DMH NPY levels. Overall, these results demonstrate a previously unknown anorectic action of central TTR in the control of energy balance, providing a potential novel target for treating obesity and its comorbidities.

Topics: Animals; Arcuate Nucleus of Hypothalamus; Blotting, Western; Body Weight; Cells, Cultured; Eating; Gene Expression Profiling; Hyperphagia; Hypothalamus; Infusions, Intraventricular; Male; Neuropeptide Y; Obesity; Oligonucleotide Array Sequence Analysis; Prealbumin; Rats, Inbred OLETF; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction

Electroacupuncture (EA) has been shown to exert beneficial effects on obesity, but the mechanism is unclear. This study investigated the effects of EA on diet-induced obese (DIO) rats. Fifty male Sprague-Dawley rats were randomly divided into low-fat diet (LFD, 10 rats) and high-fat diet (HFD, 40 rats) groups. After the DIO models had been established, successful model rats were randomly divided into HFD, EA, and orlistat (OLST) groups. The EA group received EA at Zusanli (ST36) and Quchi (LI11) for 20 minutes once per day for 28 days. The OLST group was treated with orlistat by gavage. The body weight, homeostasis model assessment-insulin resistance index, adipocyte diameters, and neuroprotein Y/agouti-related protein and protein tyrosine phosphatase 1B levels were significantly lower in the EA group than in the HFD group. The rats of the OLST group showed watery stools and yellow hairs whereas those of the EA group had regular stools and sleek coats. The effect of EA on weight loss may be related to improved insulin resistance caused by changes in the adipocyte size and by reductions in the expressions of neuroprotein Y/agouti-related protein and protein tyrosine phosphatase 1B. This study indicates that EA may be a better method of alternative therapy for treating obesity and other metabolic diseases.

Topics: Agouti-Related Protein; Animals; Blood Glucose; Diet, High-Fat; Electroacupuncture; Female; Humans; Insulin; Insulin Resistance; Male; Neuropeptide Y; Obesity; Protein Tyrosine Phosphatase, Non-Receptor Type 1; Rats; Rats, Sprague-Dawley

This study examined the proteomic profile of the hypothalamus in mice exposed to a high-fat diet (HFD) or with the anorexia of acute illness. This comparison could provide insight on the effects of these two opposite states of energy balance on appetite regulation.. Four to six-week-old male C56BL/6J mice were fed a normal (control 1 group; n=7) or a HFD (HFD group; n=10) for 8 weeks. The control 2 (n=7) and lipopolysaccharide (LPS) groups (n=10) were fed a normal diet for 8 weeks before receiving an injection of saline and LPS, respectively. Hypothalamic regions were analysed using a quantitative proteomics method based on a combination of techniques including iTRAQ stable isotope labeling, orthogonal two-dimensional liquid chromatography hyphenated with nanospray ionization and high-resolution mass spectrometry. Key proteins were validated with quantitative PCR.. Quantitative proteomics of the hypothalamous regions profiled a total of 9249 protein groups (q<0.05). Of these, 7718 protein groups were profiled with a minimum of two unique peptides for each. Hierachical clustering of the differentiated proteome revealed distinct proteomic signatures for the hypothalamus under the HFD and LPS nutritional conditions. Literature research with in silico bioinformatics interpretation of the differentiated proteome identified key biological relevant proteins and implicated pathways. Furthermore, the study identified potential pharmacologic targets. In the LPS groups, the anorexigen pro-opiomelanocortin was downregulated. In mice with obesity, nuclear factor-κB, glycine receptor subunit alpha-4 (GlyR) and neuropeptide Y levels were elevated, whereas serotonin receptor 1B levels decreased.. High-precision quantitative proteomics revealed that under acute systemic inflammation in the hypothalamus as a response to LPS, homeostatic mechanisms mediating loss of appetite take effect. Conversely, under chronic inflammation in the hypothalamus as a response to HFD, mechanisms mediating a sustained 'perpetual cycle' of appetite enhancement were observed. The GlyR protein may constitute a novel treatment target for the reduction of central orexigenic signals in obesity.

Topics: Animals; Anorexia; Appetite Regulation; Computational Biology; Diet, High-Fat; Disease Models, Animal; Down-Regulation; Hypothalamus; Inflammation; Insulin; Insulin Resistance; Lipopolysaccharides; Male; Mice; Mice, Inbred C57BL; Neuropeptide Y; NF-kappa B; Obesity; Pro-Opiomelanocortin; Proteome; Receptor, Serotonin, 5-HT1B; Receptors, Glycine; RNA, Messenger

Ghrelin, a peptide hormone produced by the stomach, is the endogenous ligand for the Growth Hormone Secretagogue Receptor (GHSR). Ghrelin acts on the GHSR to increase food intake, appetitive behaviors, and adiposity. Recently, a rat model with a null mutation to the GHSR gene (FHH-GHSR(m1/Mcwi)) was generated and used in behavioral studies, but the basic metabolic phenotype of this strain as well as that of the background strain (Fawn Hooded Hypertensive, FHH) has not been characterized in detail. Here we compared male FHH-GHSR(m1/Mcwi) rats with their wild-type littermates (FHH-WT) in a number of metabolic parameters. In the 24h of recovery following an acute overnight fast, FHH-GHSR(m1/Mcwi) rats consumed less food than FHH-WT animals, and relative to their body weights, adult FHH-GHSR(m1/Mcwi) rats consumed fewer calories when placed on a high-fat diet. Despite this, FHH-GHSR(m1/Mcwi) rats did not show a difference in diet-induced obesity or weight gain. Fasted FHH-GHSR(m1/Mcwi) rats exhibited increased Agouti-Related Peptide (AgRP) and Neuropeptide Y (NPY) expression in the Arcuate Nucleus (ARC), indicative of altered central regulation of feeding and energy balance. FHH-GHSR(m1/Mcwi) rats exhibited lower levels of home cage locomotor behavior over the entire light/dark cycle, and reduced levels of food anticipatory activity when placed on a restricted feeding schedule. Finally, FHH-GHSR(m1/Mcwi) rats consumed less of a palatable dessert (cookie dough) given after the completion of the scheduled meal. Altogether, our data show that rats lacking a functional GHSR tend to eat less than their wild-type counterparts in the face of acute fasts, chronic high-fat diet exposure, and exposure to a palatable dessert, despite not showing differences in body weight and glucose homeostasis that are characteristic of GHSR null mice. These data indicate that many, but not all responses to GHSR ablation are conserved between rats and mice. The FHH-GHSR(m1/Mcwi) rat thus represents a novel and useful model for studying GHSR function in rats.

Topics: Agouti-Related Protein; Animals; Arcuate Nucleus of Hypothalamus; Body Weight; Diet, High-Fat; Disease Models, Animal; Eating; Fasting; Feeding Behavior; Gene Expression Regulation; Ghrelin; Glucose Tolerance Test; Humans; Locomotion; Male; Mutation; Neuropeptide Y; Obesity; Rats; Rats, Transgenic; Receptors, Ghrelin

High fat diet (HFD)-induced hypertension in rabbits is neurogenic and caused by the central action of leptin, which is thought to be dependent on activation of α-melanocortin-stimulating hormone (α-MSH) and neuropeptide Y-positive neurons projecting to the dorsomedial hypothalamus (DMH) and ventromedial hypothalamus (VMH). However, leptin may act directly in these nuclei. Here, we assessed the contribution of leptin, α-MSH, and neuropeptide Y signaling in the DMH and VMH to diet-induced hypertension. Male New Zealand white rabbits were instrumented with a cannula for drug injections into the DMH or VMH and a renal sympathetic nerve activity (RSNA) electrode. After 3 weeks of an HFD (13.3% fat; n=19), rabbits exhibited higher RSNA, mean arterial pressure (MAP), and heart rate compared with control diet-fed animals (4.2% fat; n=15). Intra-VMH injections of a leptin receptor antagonist or SHU9119, a melanocortin 3/4 receptor antagonist, decreased MAP, heart rate, and RSNA compared with vehicle in HFD rabbits (P<0.05) but not in control diet-fed animals. By contrast, α-MSH or neuropeptide Y injected into the VMH had no effect on MAP but produced sympathoexcitation in HFD rabbits (P<0.05) but not in control diet-fed rabbits. The effects of the leptin antagonist, α-MSH, or neuropeptide Y injections into the DMH on MAP or RSNA of HFD rabbits were not different from those after vehicle injection. α-MSH into the DMH of control diet-fed animals did increase MAP, heart rate, and RSNA. We conclude that the VMH is the likely origin of leptin-mediated sympathoexcitation and α-MSH hypersensitivity that contribute to obesity-related hypertension.

Topics: alpha-MSH; Animals; Blood Pressure; Diet, High-Fat; Dorsomedial Hypothalamic Nucleus; Hypertension; Leptin; Male; Melanocyte-Stimulating Hormones; Neuropeptide Y; Obesity; Rabbits; Receptors, Leptin; Receptors, Melanocortin; Signal Transduction; Sympathetic Nervous System; Ventromedial Hypothalamic Nucleus

Over the past decades, life-styles changing have led to exacerbated food and caloric intake and a reduction in energy expenditure. Obesity, main outcome of these changes, increases the risk for developing type 2 diabetes, cardiovascular disease and metabolic syndrome, the leading cause of death in adult and middle age population. Body weight and energy homeostasis are maintained via complex interactions between orexigenic and anorexigenic neuropeptides that take place predominantly in the hypothalamus. Overeating may disrupt the mechanisms of feeding control, by decreasing the expression of proopiomelanocortin (POMC) and α-melanocyte stimulating hormone (α-MSH) and increasing orexigenic neuropeptide Y (NPY) and agouti-related peptide (AgRP), which leads to a disturbance in appetite control and energy balance. Studies have shown that regular physical exercise might decrease body-weight, food intake and improve the metabolic profile, however until the currently there is no consensus about its effects on the expression of orexigenic/anorexigenic neuropeptides expression. Therefore, we propose that the type and length of physical exercise affect POMC/αMSH and NPY/AgRP systems differently and plays an important role in feeding behavior. Moreover, based on the present reports, we hypothesize that increased POMC/αMSH overcome NPY/AgRP expression decreasing food intake in long term physical exercise and that results in amelioration of several conditions related to overweight and obesity.

Topics: Agouti-Related Protein; alpha-MSH; Animals; Appetite Regulation; Body Weight; Eating; Energy Metabolism; Exercise; Feeding Behavior; Humans; Hypothalamus; Models, Theoretical; Neuropeptide Y; Neuropeptides; Obesity; Overweight; Pro-Opiomelanocortin

Neuropeptide Y, a widely circulating neurotransmitter, plays a pivotal role in energy balance, immunomodulation and asthma, and several NPY polymorphisms are promising genetic risk factors for asthma and obesity. We explored the associations of candidate NPY gene polymorphisms with prevalent asthma and its relationship with obesity in young adult asthma patients free of other chronic medical morbidity.. Five common gene variants of NPY (rs16147 (-399T/C), rs17149106 (-602G/T), rs16140 (+1000C/G), rs5573 (+1201A/G), rs5574 (+5327C/T)) previously validated to account for most of the NPY expression in vitro and in vivo were investigated in 126 physician-diagnosed asthma patients without other chronic medical morbidity and 182 healthy controls (21-35years). Plasma levels of NPY, adiponectin, and CRP were determined using ELISA, and IL-6 was measured by Luminex in a subgroup of 70 patients and 69 age- and sex-matched healthy controls.. In logistic regression models controlling for gender and obesity, the CT genotype of rs5574 (OR=0.54, 95%CI: 0.30-0.89) and the GT genotype of rs17149106 (OR=5.58, 95%CI: 1.09-28.54) were significantly associated with asthma. No significant interaction between NPY SNP polymorphisms and obesity were detected. Plasma NPY level was correlated with adiponectin levels (p<0.05). Compared with the healthy controls, patients with asthma had higher BMI (p<0.001), adiponectin (p<0.05), IL-6 (p=0.001) and CRP (p<0.001), and lower NPY levels (p<0.01).. The CT genotype of rs5574 and the GT genotype of rs17149106 are significantly associated with prevalent asthma.

Topics: Adiponectin; Adiposity; Adult; Asthma; C-Reactive Protein; Comorbidity; Female; Genetic Association Studies; Genetic Predisposition to Disease; Genotype; Humans; Male; Neuropeptide Y; Obesity; Polymorphism, Single Nucleotide; Prevalence; Young Adult

Kisspeptin controls reproduction by stimulating gonadotrophin-releasing hormone neurones via its receptor Kiss1r. Kiss1r is also expressed other brain areas and in peripheral tissues, suggesting additional nonreproductive roles. We recently determined that Kiss1r knockout (KO) mice develop an obese and diabetic phenotype. In the present study, we investigated whether Kiss1r KOs develop this metabolic phenotype as a result of alterations in the expression of metabolic genes involved in the appetite regulating system of the hypothalamus, including neuropeptide Y (Npy) and pro-opiomelanocortin (Pomc), as well as leptin receptor (Lepr), ghrelin receptor (Ghsr), and melanocortin receptors 3 and 4 (Mc3r, Mc4r). Body weights, leptin levels and hypothalamic gene expression were measured in both gonad-intact and gonadectomised (GNX) mice at 8 and 20 weeks of age that had received either normal chow or a high-fat diet. We detected significant increases in Pomc expression in gonad-intact Kiss1r KO mice at 8 and 20 weeks, although there were no alterations in the other metabolic-related genes. However, the Pomc increases appeared to reflect genotype differences in circulating sex steroids, because GNX wild-type and Kiss1r KO mice exhibited similar Pomc levels, along with similar Npy levels. The altered Pomc gene expression in gonad-intact Kiss1r KO mice is consistent with previous reports of reduced food intake in these mice and may serve to increase the anorexigenic drive, perhaps compensating for the obese state. However, the surprising overall lack of changes in any of the hypothalamic metabolic genes in GNX KO mice suggests that the aetiology of obesity in the absence of kisspeptin signalling may reflect peripheral rather than central metabolic impairments.

Topics: Animals; Appetite; Body Weight; Energy Metabolism; Female; Gene Expression; Gonads; Hypothalamus; Leptin; Male; Mice; Mice, Knockout; Neuropeptide Y; Obesity; Pro-Opiomelanocortin; Receptor, Melanocortin, Type 3; Receptor, Melanocortin, Type 4; Receptors, Ghrelin; Receptors, Kisspeptin-1

The NPY gene has 4 exons, and it is located at 7p15.1. The main genetic variant described in this gene is rs16147. The aim of this study was to investigate the relationship of NPY rs16147 with body weight, insulin resistance, serum adipokine levels, and risk of metabolic syndrome (MetS).. A population of 1,005 obese patients was analyzed in a cross-sectional survey. Weight, fat mass, waist circumference, blood pressure, basal glucose, C-reactive protein, insulin, insulin resistance (homeostasis model assessment of insulin resistance [HOMA-IR]), lipid profile, and adipocytokine (leptin, adiponectin, and resistin) levels were measured. The genotype of the NPY gene polymorphism (rs16147) was studied.. Body mass index (1.0 ± 0.1; p < 0.05), weight (2.8 ± 0.4 kg; p < 0.05), fat mass (1.8 ± 0.3 kg; p < 0.05), waist circumference (1.9 ± 0.2 cm; p < 0.05), leptin level (15.4 ± 8.2 ng/mL; p < 0.05), insulin level (5.1 ± 1.3 mIU/L; p < 0.05), and HOMA-IR (1.4 ± 0.1 units; p < 0.05) were lower in A allele carriers than in non-A allele carriers in males. Males with an A allele had a lower percentage of MetS (54.8 vs. 69.1%; p < 0.05), central obesity (94.5 vs. 100%; p < 0.05), and hyperglycemia (24.7 vs. 33.8%; p < 0.05) than non-A allele carriers. Logistic regression analysis indicated that male non-A allele carriers had an increased risk of MetS (odds ratio [OR] = 1.26, 95% confidence interval [CI] = 1.17-1.83; p = 0.034), an increased risk of central obesity (OR = 1.08, 95% CI = 1.02-1.11; p = 0.044), and an increased risk of hyperglycemia (OR = 1.20, 95% CI = 1.09-1.79; p = 0.028) after adjusting for age.. In obese males, the rs164147 polymorphism of the NPY gene is associated with leptin, insulin level, HOMA-IR, and an increased risk of MetS and its related phenotypes, such as central obesity and hyperglycemia.

Topics: Adipokines; Adult; Cardiovascular Diseases; Cross-Sectional Studies; Female; Genetic Association Studies; Humans; Hyperglycemia; Insulin Resistance; Male; Metabolic Syndrome; Middle Aged; Neuropeptide Y; Obesity; Polymorphism, Single Nucleotide; Risk Factors

Neurons that co-express agouti-related peptide (AgRP) and neuropeptide Y (NPY) are indispensable for normal feeding behavior. Firing activities of AgRP/NPY neurons are dynamically regulated by energy status and coordinate appropriate feeding behavior to meet nutritional demands. However, intrinsic mechanisms that regulate AgRP/NPY neural activities during the fed-to-fasted transition are not fully understood. We found that AgRP/NPY neurons in satiated mice express high levels of the small-conductance calcium-activated potassium channel 3 (SK3) and are inhibited by SK3-mediated potassium currents; on the other hand, food deprivation suppresses SK3 expression in AgRP/NPY neurons, and the decreased SK3-mediated currents contribute to fasting-induced activation of these neurons. Genetic mutation of SK3 specifically in AgRP/NPY neurons leads to increased sensitivity to diet-induced obesity, associated with chronic hyperphagia and decreased energy expenditure. Our results identify SK3 as a key intrinsic mediator that coordinates nutritional status with AgRP/NPY neural activities and animals' feeding behavior and energy metabolism.

Topics: Action Potentials; Agouti-Related Protein; Animals; Circadian Rhythm; Diet, High-Fat; Energy Metabolism; Fasting; Feeding Behavior; Hyperphagia; Ion Channel Gating; Mice, Inbred C57BL; Mutation; N-Methylaspartate; Neurons; Neuropeptide Y; Obesity; Small-Conductance Calcium-Activated Potassium Channels

Peripheral blood mononuclear cells (PBMC) constitute an easily obtainable blood cell fraction useful in nutrition and obesity studies. Our aim was to study the potential use of PBMC to reflect metabolic recovery associated with weight loss in rats.. By real-time PCR, the fasting response of key energy homeostatic genes in PBMC samples of control and cafeteria-obese rats and of rats fed a control diet after the intake of a cafeteria diet (post-cafeteria model) was analyzed.. Fasting caused decreased mRNA expression of lipogenic (Fasn and Srebp1a) and adipogenic (Pparγ) genes in PBMC, whereas it increased the expression of the key beta-oxidation gene Cpt1a and the orexigenic gene Npy. Fasting response of the genes studied was impaired in cafeteria-obese animals but was recovered in post-cafeteria rats, which showed a significant body weight decrease and normalization of adipose and metabolic parameters. Npy expression analyzed in PBMC has been revealed to be especially useful as a marker of fasting sensitivity, as its fasting response is not affected by the age of the animals and it is recovered even after shorter time of exposure to a balanced diet.. PBMC reflect homeostatic balance recovery associated with weight loss in obese animals, when reverting from a hyperlipidic to a control balanced diet.

Topics: Adipogenesis; Adiposity; Animals; Biomarkers; Energy Metabolism; Leukocytes, Mononuclear; Lipogenesis; Male; Neuropeptide Y; Obesity; PPAR gamma; Prognosis; Rats; Rats, Wistar; Sterol Regulatory Element Binding Protein 1; Treatment Outcome; Weight Loss; Weight Reduction Programs

We have identified female sheep that have either high (HR) or low (LR) cortisol responses to adrenocorticotrophin. On a high-energy diet, HR have greater propensity to weight gain and obesity, although the underlying mechanisms remain to be determined. Hypothalamic appetite-regulating peptides (ARP) exert reciprocal effects on food intake and energy expenditure. We aimed to quantify the expression and function of ARP in LR and HR ewes (n = 4 per group). Gene expression for neuropeptide Y (NPY), agouti-related peptide (AgRP) pro-opiomelanocortin (POMC), melanin-concentrating hormone (MCH), orexin and the melanocortin receptors (MC3R and MC4R) was measured by in situ hybridisation. Expression of NPY, AgRP and POMC was similar in HR and LR, although expression of orexin, MCH, MC3R and MC4R was higher (P < 0.05) in LR. Intracerebroventricular infusions of a low dose (50 μg/h) of NPY, α-melanocyte-stimulating hormone (αMSH), orexin and MCH were performed between 10.00 h and 16.00 h in meal-fed ewes (n = 6-7 per group). Skeletal muscle and retroperitoneal (RP) fat temperatures were recorded using dataloggers. Post-prandial thermogenesis in muscle was higher (P < 0.05) in LR. There was little effect of ARP infusion on muscle or fat temperature in either group. Infusion of these doses of NPY, MCH or orexin did not stimulate food intake in meal-fed ewes, although αMSH reduced (P < 0.01) food intake in LR only. Using 24-h ARP infusions with ad lib. feeding, NPY increased (P < 0.001) food intake in both groups but αMSH was only effective in LR (P < 0.05). In summary, we show that HR are resistant to the satiety effects of αMSH and this coincides with a reduced expression of both the MC3R and MC4R in the paraventricular nucleus of the hypothalamus. We conclude that an increased propensity to obesity in HR female sheep is associated with reduced melanocortin signalling.

Topics: Adrenocorticotropic Hormone; Agouti-Related Protein; Animals; Arcuate Nucleus of Hypothalamus; Body Composition; Feeding Behavior; Female; Hydrocortisone; In Situ Hybridization; Melanocortins; Neuropeptide Y; Obesity; Postprandial Period; Pro-Opiomelanocortin; RNA, Messenger; Sheep; Signal Transduction; Thermogenesis

Neuropeptide Y (NPY) co-localized with noradrenaline in central and sympathetic nervous systems seems to play a role in the control of energy metabolism. In this study, the aim was to elucidate the effects and pathophysiological mechanisms of increased NPY in catecholaminergic neurones on accumulation of body adiposity.. Transgenic mice overexpressing NPY under the dopamine-beta-hydroxylase promoter (OE-NPY(DβH) ) and wild-type control mice were followed for body weight gain and body fat content. Food intake, energy expenditure, physical activity, body temperature, serum lipid content and markers of glucose homoeostasis were monitored. Thermogenic and lipolytic responses in adipose tissues, and urine catecholamine and tissue catecholamine synthesizing enzyme levels were analysed as indices of sympathetic tone.. Homozygous OE-NPY(DβH) mice showed significant obesity accompanied with impaired glucose tolerance and insulin resistance. Increased adiposity was explained by neither increased food intake or fat absorption nor by decreased total energy expenditure or physical activity. Adipocyte hypertrophy and decreased circulating lipid levels suggested decreased lipolysis and increased lipid uptake. Brown adipose tissue thermogenic capacity was decreased and brown adipocytes filled with lipids. Enhanced response to adrenergic stimuli, downregulation of catecholamine synthesizing enzyme expressions in the brainstem and lower adrenaline excretion supported the notion of low basal catecholaminergic activity.. Increased NPY in catecholaminergic neurones induces obesity that seems to be a result of preferential fat storage. These results support the role of NPY as a direct effector in peripheral tissues and an inhibitor of sympathetic activity in the pathogenesis of obesity.

Topics: Adipose Tissue, Brown; Adrenergic Neurons; Animals; Energy Metabolism; Gene Expression Regulation; Hypothalamus; Mice; Mice, Transgenic; Neuropeptide Y; Obesity; RNA, Messenger; Sympathetic Nervous System

The skeleton acts as an endocrine organ that regulates energy metabolism and calcium and phosphorous homeostasis through the secretion of osteocalcin (Oc) and fibroblast growth factor 23 (FGF23). However, evidence suggests that osteoblasts secrete additional unknown factors that contribute to the endocrine function of bone. To search for these additional factors, we generated mice with a conditional osteoblast-specific deletion of p38α MAPK known to display profound defects in bone homeostasis. Herein, we show that impaired osteoblast function is associated with a strong decrease in body weight and adiposity (P < 0.01). The differences in adiposity were not associated with diminished caloric intake, but rather reflected 20% increased energy expenditure and the up-regulation of uncoupling protein-1 (Ucp1) in white adipose tissue (WAT) and brown adipose tissue (BAT) (P < 0.05). These alterations in lipid metabolism and energy expenditure were correlated with a decrease in the blood levels of neuropeptide Y (NPY) (40% lower) rather than changes in the serum levels of insulin, Oc, or FGF23. Among all Npy-expressing tissues, only bone and primary osteoblasts showed a decline in Npy expression (P < 0.01). Moreover, the intraperitoneal administration of recombinant NPY partially restored the WAT weight and adipocyte size of p38α-deficient mice (P < 0.05). Altogether, these results further suggest that, in addition to Oc, other bone-derived signals affect WAT and energy expenditure contributing to the regulation of energy metabolism.

Topics: Adipocytes; Adipose Tissue; Adipose Tissue, Brown; Adipose Tissue, White; Adiposity; Animals; Body Weight; Bone Development; Cell Size; Energy Metabolism; Female; Fibroblast Growth Factor-23; Gene Expression Regulation; Homeostasis; Ion Channels; Lipid Metabolism; Male; Mice; Mice, Knockout; Mitochondrial Proteins; Mitogen-Activated Protein Kinase 14; Neuropeptide Y; Obesity; Osteoblasts; Osteocalcin; Pregnancy; Signal Transduction; Uncoupling Protein 1; Up-Regulation

The hypothalamic arcuate nucleus (ARC) contains 2 key neural populations, neuropeptide Y (NPY) and proopiomelanocortin (POMC), and, together with orexin neurons in the lateral hypothalamus, plays an integral role in energy homeostasis. However, no studies have examined total neuronal number and volume after high-fat diet (HFD) exposure using sophisticated stereology. We used design-based stereology to estimate NPY and POMC neuronal number and volume, as well as glial fibrillary acidic protein (astrocyte marker) and ionized calcium-binding adapter molecule 1 (microglia marker) cell number in the ARC; as well as orexin neurons in the lateral hypothalamus. Stereological analysis indicated approximately 8000 NPY and approximately 9000 POMC neurons in the ARC, and approximately 7500 orexin neurons in the lateral hypothalamus. HFD exposure did not affect total neuronal number in any population. However, HFD significantly increased average NPY cell volume and affected NPY and POMC cell volume distribution. HFD reduced orexin cell volume but had a bimodal effect on volume distribution with increased cells at relatively small volumes and decreased cells with relatively large volumes. ARC glial fibrillary acidic protein cells increased after 2 months on a HFD, although no significant difference after 6 months on chow diet or HFD was observed. No differences in ARC ionized calcium-binding adapter molecule 1 cell number were observed in any group. Thus, HFD affects ARC NPY or POMC neuronal cell volume number not cell number. Our results demonstrate the importance of stereology to perform robust unbiased analysis of cell number and volume. These data should be an empirical baseline reference to which future studies are compared.

Topics: Animals; Arcuate Nucleus of Hypothalamus; Astrocytes; Calcium-Binding Proteins; Cell Count; Cell Size; Diet, High-Fat; Glial Fibrillary Acidic Protein; Intracellular Signaling Peptides and Proteins; Male; Mice; Microfilament Proteins; Microglia; Nerve Tissue Proteins; Neurons; Neuropeptide Y; Neuropeptides; Obesity; Orexins; Pro-Opiomelanocortin

The prevalence of obesity among child-bearing women has increased significantly. The adverse consequences of maternal obesity on the descendants have been well accepted, although few studies have examined the underlying mechanisms. We investigated whether neonatal overfeeding in female mice alters metabolic phenotypes in the offspring and whether hypothalamic leptin signalling is involved. Neonatal overfeeding was induced by reducing the litter size to three pups per litter, in contrast to normal litter size of 10 pups per litter. Normal and neonatally overfed female mice were bred with normal male mice, and offspring of overfeeding mothers (OOM) and control mothers (OCM) were generated. We examined body weight, daily food intake, leptin responsiveness and the number of positive neurones for phosphorylated-signal transducer and activator of transcription 3 (pSTAT3) along with neuropeptide Y (NPY) in the arcuate nucleus of the hypothalamus (ARH) and NPY in the nucleus tractus solitarius (NTS) of the brain stem. The body weight and daily food intake of OOM were significantly higher than those of OCM. Leptin significantly reduced food intake and increased the number of pSTAT3 positive neurones in the ARH of OCM mice, whereas no significant changes in food intake and pSTAT3 neurones were found in leptin-treated OOM mice. The number of NPY neurones in the ARH and NTS of the OOM mice was significantly higher than that of OCM mice. The results of the present study indicate that the obese phenotype from mothers can be passed onto the subsequent generation, which is possibly associated with hypothalamic leptin resistance.

Topics: Animals; Animals, Newborn; Arcuate Nucleus of Hypothalamus; Eating; Female; Leptin; Male; Mice; Mice, Inbred ICR; Neuropeptide Y; Obesity; Signal Transduction; Solitary Nucleus; STAT3 Transcription Factor

The IfitmDel mouse lacks all five of the Ifitm genes via LoxP deletion. This animal breeds normally with no obvious defect in development. The IfitmDel animals exhibit a steady and significantly enhanced weight gain relative to wild-type controls beginning about three months of age and under normal feeding conditions. The increased weight corresponds with elevated fat mass, and in tolerance tests they are hyporesponsive to insulin but respond normally to glucose. Both young (4 mo) and older (12 mo) IfitmDel mice have enhanced levels of serum leptin suggesting a defect in leptin/leptin receptor signaling. Analysis of the gene expression profiles in the hypothalamus of IfitmDel animals, compared to WT, demonstrated an altered ratio of Pomc and Npy neuropeptide expression, which likely impairs the satiation response of the IfitmDel animal leading to an increased eating behavior. Also elevated in hypothalamus of IfitmDel mice were pro-inflammatory cytokine expression and reduced IL-10. Anatomical analysis of the hypothalamus using immunohistochemistry revealed that microglia exhibit an abnormal morphology in IfitmDel animals and respond abnormally to Poly:IC challenge. These abnormalities extend the phenotype of the IfitmDel mouse beyond abnormal responses to viral challenge to include a metabolic phenotype and weight gain. Further, this novel phenotype for the IfitmDel mouse could be related to abnormal neuropeptide production, inflammatory status and microglia status in the hypothalamus.

Topics: Age of Onset; Animals; Antigens, Differentiation; Cytokines; Gene Deletion; Gene Expression Profiling; Hypothalamus; Immunohistochemistry; Leptin; Metabolic Networks and Pathways; Mice; Microglia; Multigene Family; Neuropeptide Y; Obesity; Pro-Opiomelanocortin

Intracerebroventricular injection and overexpression of Neuropeptide Y (NPY) in the paraventricular nucleus (PVN) has been shown to induce obesity and glucose metabolism disorder in rodents; however, the underlying mechanisms are still unclear. The aim of this study was to investigate the mechanism contributing to glucose metabolic disturbance induced by NPY. Recombinant lentiviral NPY vectors were injected into the PVN of rats fed a high fat (HFD) or low-fat diet. 8 weeks later, in vivo intravenous glucose tolerance tests and euglycemic-hyperinsulinemic clamp revealed that insulin resistance of adipose tissue were induced by NPY overexpression with or without HFD. NPY increased food intake, but did not change blood glucose, glycated hemoglobin A1c (HbA1c) or lipid levels. However, NPY decreased the expression of pGSK3β, PI3K p85 and pAKTSer473 in adipose tissue of rats. In vitro, 3T3-L1 adipocytes were treated with NPY, NPY Y1 and Y5 receptor antagonists. Glucose consumption and 2-deoxy-D-[3H] glucose uptake were partly inhibited by NPY, while a decrease in PI3K-AKT pathway signaling and a decreased expression of pGSK3α and pGSK3β were observed. Nevertheless, a Y5 receptor antagonist (L-152,804) reversed the effects of NPY on glucose uptake and consumption. These data suggest that long-term over-expression of NPY in PVN contributes to the establishment of adipose tissue insulin resistance, at least partly via the Y5 Receptor.

Topics: 3T3-L1 Cells; Adipose Tissue; Animals; Diet, Fat-Restricted; Diet, High-Fat; Eating; Glucose; Insulin Resistance; Male; Mice; Neuropeptide Y; Obesity; Paraventricular Hypothalamic Nucleus; Rats; Rats, Sprague-Dawley; Rats, Transgenic; Receptors, Neuropeptide Y; Recombinant Proteins; Signal Transduction; Up-Regulation

Human studies have suggested that early undernutrition increases the risk of obesity, thereby explaining the increase in overweight among individuals from developing countries who have been undernourished as children. However, this conclusion is controversial, given that other studies do not concur. This study sought to determine whether rehabilitation after undernutrition increases the risk of obesity and metabolic disorders. We employed a published experimental food-restriction model. Wistar female rats subjected to severe food restriction since fetal stage and controls were transferred to a moderately high-fat diet (cafeteria) provided at 70 days of life to 6.5 months. Another group of undernourished rats were rehabilitated with chow. The energy intake of undernourished animals transferred to cafeteria formula exceeded that of the controls under this regime and was probably driven by hypothalamic disorders in insulin and leptin signal transduction. The cafeteria diet resulted in greater relative increases in both fat and lean body mass in the undernourished rats when compared with controls, enabling the former group to completely catch up in length and body mass index. White adipose tissues of undernourished rats transferred to the high-lipid regime developed a browning which, probably, contributed to avoid the obesigenic effect observed in controls. Nevertheless, the restricted group rehabilitated with cafeteria formula had greater accretion of visceral than subcutaneous fat, showed increased signs of macrophage infiltration and inflammation in visceral pad, dyslipidemia, and ectopic fat accumulation. The data indicate that early long-term undernutrition is associated with increased susceptibility to the harmful effects of nutritional rehabilitation, without causing obesity.

Topics: Adipose Tissue, White; Adiposity; Animals; Diet, High-Fat; Energy Intake; Female; Hyperphagia; Hypothalamus; Insulin Resistance; Leptin; Liver; Male; Malnutrition; Muscle, Skeletal; Neuropeptide Y; Obesity; Oxidation-Reduction; Pregnancy; Prenatal Exposure Delayed Effects; Pro-Opiomelanocortin; Rats, Wistar; Risk Factors

Obesity is associated with asthma risk and severity, but the underlying biological mechanisms are poorly understood. We hypothesized that cytokine markers of systemic inflammation, and adiponectin and neuropeptide Y (NPY) markers of immuno-modulating and neurohormonal regulation are involved in the obesity-asthma association.. We explored the relationships between body mass index (BMI), C-reactive protein (CRP), IL-6, TNF-α, adiponectin and NPY with asthma prevalence and IL-4 levels in 70 youth with asthma and 69 age- and gender-matched healthy controls using cross-sectional and longitudinal data.. Mean BMI level was higher among patients with asthma than healthy controls (p < 0.001). In logistic regression models controlling for potential confounders, independent associations with asthma prevalence were found for obesity (p = 0.001), increasing tertiles of CRP (linear trend p < 0.001), IL-6 (linear trend p < 0.001) and lowest and highest tertiles of TNF-α (quadratic trend p < 0.05), increasing adiponectin (linear p = 0.022) and decreasing tertiles of NPY (linear trend p = 0.001). Among patients with asthma, NPY level was positively correlated with adiponectin (p < 0.05) and TNF-α (p < 0.05), and levels of NPY and IL-6 were significantly associated with IL-4 level at baseline and 1-year follow-up.. The obesity-asthma association was not explained by systemic inflammation. Specifically, CRP, TNF-a, IL-6, NPY and adiponectin were independently associated with asthma prevalence. NPY and IL-6 were associated with IL-4 marker of allergic airway inflammation in asthma and should be further investigated as prognostic markers of asthma outcomes.

Topics: Adiponectin; Adult; Asthma; Biomarkers; Body Mass Index; Case-Control Studies; Chi-Square Distribution; Cross-Sectional Studies; Female; Humans; Inflammation Mediators; Interleukin-4; Linear Models; Logistic Models; Longitudinal Studies; Male; Neuropeptide Y; Obesity; Prevalence; Risk Factors; Singapore; Time Factors; Young Adult

Diet-induced weight loss varies considerably between individuals, but the mechanisms driving these individual differences remain largely unknown. Here we investigated whether key neuropeptides involved in the regulation of energy balance or reward systems were differentially expressed in mice that were prone or resistant to caloric restriction (CR) induced weight loss. Mice (n=30 males and n=34 females) were fed 70% of their own baseline ad libitum intake for 25days, after which their brains were collected and expression of various neuropeptides were investigated and compared between the 10 male and 10 female mice that showed the greatest (high weight loss, HWL) or lowest weight loss (LWL) (n=40 in total). HWL mice showed a differential neuropeptide profile to LWL in both sexes, characterised by increased expression of neuropeptide Y (NPY), agouti-related peptide (AgRP), leptin receptor (ObRb), and melanocortin 3 receptor (MC3R) in the arcuate nucleus. No changes in the expression of fat mass and obesity related gene (FTO) or suppressor of cytokine signalling 3 (Socs3) were observed. Levels of dopamine D2 receptor were decreased in the nucleus accumbens in HWL compared to LWL mice. HWL mice showed a stronger increase in food anticipatory activity (FAA) in response to CR than LWL mice. These results indicate that the mice prone to diet-induced weight loss experienced greater hunger, potentially driving their elevated FAA.

Topics: Animals; Anticipation, Psychological; Arcuate Nucleus of Hypothalamus; Caloric Restriction; Diet, Reducing; Energy Metabolism; Female; Food; Gene Expression; Humans; Male; Mice; Mice, Obese; Neuropeptide Y; Obesity; Receptor, Melanocortin, Type 3; Receptors, Dopamine D2; Receptors, Leptin; Treatment Failure; Weight Loss

The pathogenesis of polycystic ovary syndrome (PCOS) and obesity is not clarified yet. But some parameters such as neuropeptide Y (NPY), angiopoietin-like protein (Angptl-4), omentin-1 are thought to be involved in this pathogenesis. In this study, we aimed to show possible effects of NPY, Angptl-4, omentin-1 throughout clinical parameters and hormones. Patients were divided into three groups. Group I; healthy volunteers, Group II; non-obese women with PCOS and group III; obese women with PCOS. Serum NPY, Angptl-4, free testosterone, total testosterone, luteinize hormone, sex hormone binding globulin, estradiol, dehydroepiandrosterone sulfate, androstenedione, triglycerides and low density lipoprotein cholesterol levels and HOMA-IR, Ferriman-Galwey scores were significantly higher in group II when compared with group I and similarly in group III when compared with group II (p < 0.005). While comparing all PCOS patients (obese + non-obese) with healthy volunteers, omentin-1 and high density lipoprotein cholesterol levels were significantly low in PCOS group (p < 0.005). As a result of this study, both in the obese and non-obese PCOS patients, there was a significant increase in levels of NPY and Angptl-4 and a significant decline in omentin-1 when compared to healthy subjects. In conclusion, insulin resistance in PCOS patients may be related to the differences of NPY, Angptl-4 and omentin-1 levels and the effects of these differences on metabolic pathways.

Topics: Adult; Androstenedione; Angiopoietin-Like Protein 4; Angiopoietins; Case-Control Studies; Cholesterol, HDL; Cholesterol, LDL; Cytokines; Dehydroepiandrosterone Sulfate; Estradiol; Female; GPI-Linked Proteins; Humans; Insulin Resistance; Lectins; Luteinizing Hormone; Neuropeptide Y; Obesity; Polycystic Ovary Syndrome; Sex Hormone-Binding Globulin; Testosterone; Triglycerides

Mice lacking the RIIβ regulatory subunit of cyclic AMP-dependent protein kinase A (PKA) display reduced adiposity and resistance to diet-induced obesity. Here we show that RIIβ knockout (KO) mice have enhanced sensitivity to leptin's effects on both feeding and energy metabolism. After administration of a low dose of leptin, the duration of hypothalamic JAK/STAT3 signalling is increased, resulting in enhanced POMC mRNA induction. Consistent with the extended JAK/STAT3 activation, we find that the negative feedback regulator of leptin receptor signalling, Socs3, is inhibited in the hypothalamus of RIIβ KO mice. During fasting, RIIβ-PKA is activated and this correlates with an increase in CREB phosphorylation. The increase in CREB phosphorylation is absent in the fasted RIIβ KO hypothalamus. Selective inhibition of PKA activity in AgRP neurons partially recapitulates the leanness and resistance to diet-induced obesity of RIIβ KO mice. Our findings suggest that RIIβ-PKA modulates the duration of leptin receptor signalling and therefore the magnitude of the catabolic response to leptin.

Topics: Adiposity; Agouti-Related Protein; Animals; Cyclic AMP Response Element-Binding Protein; Cyclic AMP-Dependent Protein Kinase RIIbeta Subunit; Cyclic AMP-Dependent Protein Kinases; Diet, High-Fat; Feedback, Physiological; Hypothalamus; Janus Kinases; Leptin; Mice; Mice, Knockout; Neurons; Neuropeptide Y; Obesity; Phosphorylation; Pro-Opiomelanocortin; Receptors, Leptin; RNA, Messenger; Signal Transduction; STAT3 Transcription Factor; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins

Some animals and humans fed a high-energy diet (HED) are diet-resistant (DR), remaining as lean as individuals who were naïve to HED. Other individuals become obese during HED exposure and subsequently defend the obese weight (Diet-Induced Obesity- Defenders, DIO-D) even when subsequently maintained on a low-energy diet. We hypothesized that the body weight setpoint of the DIO-D phenotype resides in the hypothalamic paraventricular nucleus (PVN), where anorexigenic melanocortins, including melanotan II (MTII), increase presynaptic GABA release, and the orexigenic neuropeptide Y (NPY) inhibits it. After prolonged return to low-energy diet, GABA inputs to PVN neurons from DIO-D rats exhibited highly attenuated responses to MTII compared with those from DR and HED-naïve rats. In DIO-D rats, melanocortin-4 receptor expression was significantly reduced in dorsomedial hypothalamus, a major source of GABA input to PVN. Unlike melanocortin responses, NPY actions in PVN of DIO-D rats were unchanged, but were reduced in neurons of the ventromedial hypothalamic nucleus; in PVN of DR rats, NPY responses were paradoxically increased. MTII-sensitivity was restored in DIO-D rats by several weeks' refeeding with HED. The loss of melanocortin sensitivity restricted to PVN of DIO-D animals, and its restoration upon prolonged refeeding with HED suggest that their melanocortin systems retain the ability to up- and downregulate around their elevated body weight setpoint in response to longer-term changes in dietary energy density. These properties are consistent with a mechanism of body weight setpoint.

Topics: alpha-MSH; Animals; Arcuate Nucleus of Hypothalamus; Body Weight; Caloric Restriction; Diet; Dietary Fats; gamma-Aminobutyric Acid; Leptin; Melanocortins; Neuropeptide Y; Obesity; Paraventricular Hypothalamic Nucleus; Peptides, Cyclic; Rats; Rats, Sprague-Dawley; Receptor, Melanocortin, Type 4; Ventromedial Hypothalamic Nucleus

This study first investigated the effects of corn gluten hydrolysate (CGH) (1.5 g/day) administration for 7 days on appetite-responsive genes in lean Sprague-Dawley (SD) rats. In a second set of experiments, the metabolic changes occurring at multiple time points over 8 weeks in response to CGH (35.33% wt/wt) were observed in high-fat (HF, 60% of energy as fat) diet-fed SD rats. In lean rats, the hypothalamus neuropeptide-Y and proopiomelanocortin mRNA levels of the CGH group were significantly changed in response to CGH administration. In the second part of the study, CGH treatment was found to reduce body weight and perirenal and epididymal fat weight. CGH also prevented an increase in food intake at 2 weeks and lowered plasma leptin and insulin levels in comparison with the HF group. This reduction in the plasma and hepatic lipid levels was followed by improved insulin resistance, and the beneficial metabolic effects of CGH were also partly related to increases in plasma adiponectin levels. The Homeostasis Model of Assessment - Insulin Resistance (HOMA-IR), an index of insulin resistance, was markedly improved in the HF-CGH group compared with the HF group at 6 weeks. According to the microarray results, adipose tissue mRNA expression related to G-protein coupled receptor protein signaling pathway and sensory perception was significantly improved after 8 weeks of CGH administration. In conclusion, the present findings suggest that dietary CGH may be effective for improving hyperglycemia, dyslipidemia and insulin resistance in diet-induced obese rats as well as appetite control in lean rats.

Topics: Adipose Tissue; Animals; Body Weight; Diet, High-Fat; Eating; Glutens; Insulin; Leptin; Neuropeptide Y; Obesity; Rats; Rats, Sprague-Dawley; Zea mays

Crude extracts from ginseng demonstrated anti-obesity properties. Ginsenoside Rb1 is the main component of ginseng, however, there are only few studies examining its effects in obesity. In the present study, we evaluated its potential anti-obesity effects in the murine model of diet-induced obesity. Seventy male C57BL/6 mice were randomly divided to consume for 12 weeks either chow diet (N = 8) or high-fat (HF) diet (N = 62). The latter mice were then divided into four groups: diet-induced obesity group (DIO; N = 10), obesity-resistant group (OR; N = 10), HF group (N = 5), and the group whose diet was changed from HF to normal diet (DC; N = 5). Intraperitoneal injections of Rb-1 were administered daily to mice in the DIO and OR groups for 3 weeks. Body weight and energy intake were monitored, and fasting blood glucose, lipids, neuropeptide Y, Y2 receptor, and peptide YY were quantified. Compared with HF group, weight gain and food intake of DIO mice with Rb-1 injection was significantly decreased (p < 0.05). Further, levels of blood glucose and some lipids were also decreased in DIO-Rb1 group compared with HF group. Furthermore, Rb1 was also found to modulate serum levels of PYY and NPY, and mRNA expression of NPY, Y2 receptor and PYY in tissue samples of DIO mice. Taken together, ginsenoside Rb1 may be useful in the treatment of obesity via modifying the serum content and mRNA expression of NPY, Y2 receptor and PYY.

Topics: Animals; Blood Glucose; Body Weight; Diet; Diet, High-Fat; Drug Administration Schedule; Ginsenosides; Injections, Intraperitoneal; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Neuropeptide Y; Obesity; Panax; Peptide YY; Receptors, Neuropeptide Y

We hypothesised that hypothalamic feeding-related neuropeptides are differentially expressed in obese-prone and lean-prone rats and trigger overeating-induced obesity. To test this hypothesis, in the present study, we measured energy balance and hypothalamic neuropeptide Y (NPY) and pro-opiomelanocortin (POMC) mRNA expressions in male JCR:LA-cp rats. We compared, in independent cohorts, free-feeding obese-prone (Obese-FF) and lean-prone (Lean-FF) rats at pre-weaning (10 d old), weaning (21-25 d old) and early adulthood (8-12 weeks). A group of Obese-pair-feeding (PF) rats pair-fed to the Lean-FF rats was included in the adult cohort. The body weights of 10-d-old Obese-FF and Lean-FF pups were not significantly different. However, when the pups were shifted from dams' milk to solid food (weaning), the obese-prone rats exhibited more energy intake over the days than the lean-prone rats and higher body and fat pad weights and fasting plasma glucose, leptin, insulin and lipid levels. These differences were consistent with higher energy consumption and lower energy expenditure. In the young adult cohort, the differences between the Obese-FF and Lean-FF rats became more pronounced, yielding significant age effects on most of the parameters of the metabolic syndrome, which were reduced in the Obese-PF rats. The obese-prone rats displayed higher NPY expression than the lean-prone rats at pre-weaning and weaning, and the expression levels did not differ by age. In contrast, POMC expression exhibited significant age-by-genotype differences. At pre-weaning, there was no genotype difference in POMC expression, but in the weanling cohort, obese-prone pups exhibited lower POMC expression than the lean-prone rats. This genotype difference became more pronounced at adulthood. Overall, the development of hyperphagia-induced obesity in obese-prone JCR rats is related to POMC expression down-regulation in the presence of established NPY overexpression.

Topics: Adiposity; Animals; Arcuate Nucleus of Hypothalamus; Behavior, Animal; Caloric Restriction; Down-Regulation; Energy Intake; Energy Metabolism; Gene Expression Regulation, Developmental; Hyperphagia; Male; Metabolic Syndrome; Neurons; Neuropeptide Y; Obesity; Pro-Opiomelanocortin; Random Allocation; Rats; Rats, Mutant Strains; Receptors, Leptin; RNA, Messenger; Weaning

Hypothalamic appetite regulators neuropeptide Y (NPY) and pro-opiomelanocortin (POMC) are modulated by glucose. This study investigated how maternal obesity disturbs glucose regulation of NPY and POMC, and whether this deregulation is linked to abnormal hypothalamic glucose uptake-lactate conversion. As post-natal high-fat diet (HFD) can exaggerate the effects of maternal obesity, its additional impact was also investigated. Female Sprague Dawley rats were fed a HFD (20 kJ/g) to model maternal obesity. At weaning, male pups were fed chow or HFD. At 9 weeks, in vivo hypothalamic NPY and POMC mRNA responses to acute hyperglycemia were measured; while hypothalami were glucose challenged in vitro to assess glucose uptake-lactate release and related gene expression. Maternal obesity dampened in vivo hypothalamic NPY response to acute hyperglycemia, and lowered in vitro hypothalamic glucose uptake and lactate release. When challenged with 20 mM glucose, hypothalamic glucose transporter 1, monocarboxylate transporters, lactate dehydrogenase-b, NPY and POMC mRNA expression were down-regulated in offspring exposed to maternal obesity. Post-natal HFD consumption reduced in vitro lactate release and monocarboxylate transporter 2 mRNA, but increased POMC mRNA levels when challenged with 20 mM glucose. Overall, maternal obesity produced stronger effects than post-natal HFD consumption to impair hypothalamic glucose metabolism. However, they both disturbed NPY response to hyperglycemia, potentially leading to hyperphagia.

Topics: Adiposity; Animals; Brain Chemistry; Cohort Studies; Female; Glucose; Glucose Transporter Type 1; Growth; Hyperglycemia; Hypothalamus; Male; Neuropeptide Y; Obesity; Pregnancy; Prenatal Exposure Delayed Effects; Pro-Opiomelanocortin; Rats; Rats, Sprague-Dawley; RNA, Messenger; TOR Serine-Threonine Kinases; Triglycerides

Peripheral action of irisin improves glucose homeostasis and increases energy expenditure, with no data on a central role of irisin in metabolism. These studies sought to examine 1) presence of irisin in human cerebrospinal fluid (CSF) and banked human hypothalamic tissue, 2) serum irisin in maternal subjects across varying adiposities with or without gestational diabetes (GDM), and 3) their respective neonate offspring. CSF, serum, and neonatal cord serum were collected from 91 pregnant women with and without GDM attending for an elective cesarean section [body mass index (BMI): 37.7 ± 7.6 kg/m(2); age: 32 ± 8.3 yr]. Irisin was assessed by ELISA and correlated with biochemical and anthropometric data. Irisin expression was examined in human hypothalamus by immunohistochemical staining. Serum irisin in pregnant women was significantly lower in nonobese compared with obese and GDM subjects, after adjusting for BMI, lipids, and glucose. Irisin was present in neonatal cord serum (237 ± 8 ng/ml) and maternal CSF (32 ± 1.5 ng/ml). CSF irisin correlated positively with serum irisin levels from nonobese and obese pregnant women (P < 0.01), with CSF irisin significantly raised in GDM subjects (P < 0.05). Irisin was present in human hypothalamic sections in the paraventricular neurons, colocalized with neuropeptide Y. Irisin was detectable in CSF and in paraventricular neurons. Maternal serum irisin was lower in nonobese pregnant women after adjusting for BMI and a number of metabolic parameters. These studies indicate that irisin may have a central role in metabolism in addition to the known peripheral role. Further studies investigating the central action of irisin in human metabolic disease are required.

Topics: Adiposity; Adult; Biomarkers; Diabetes, Gestational; Female; Fibronectins; Humans; Hypothalamus; Neurons; Neuropeptide Y; Obesity; Pregnancy

We sought to identify mechanisms of beta cell failure in genetically obese mice. Little is known about the role of pancreatic innervation in the progression of beta cell failure. In this work we studied adrenergic innervation, in view of its potent inhibitory effect on insulin secretion. We analyzed genetically obese ob/ob and db/db mice at different ages (6- and 15-week-old), corresponding to different compensatory stages in the course of beta cell dysfunction. 15 week-old HFD mice were also studied.. All mice were characterized by measures of plasma glucose, insulin, and HOMA. After perfusion, pancreata were dissected and studied by light microscopy, electron microscopy, and morphometry. Insulin, Tyrosine Hydroxylase-positive fibers and cells and Neuropeptide Y-positive cells were scored by immunohistochemistry. Islets of obese mice showed increased noradrenergic fiber innervation, with significant increases of synaptoid structures contacting beta cells compared to controls. Noradrenergic innervation of the endocrine area in obese db/db mice tended to increase with age, as diabetes progressed. In ob/ob mice, we also detected an age-dependent trend toward increased noradrenergic innervation that, unlike in db/db mice, was unrelated to glucose levels. We also observed a progressive increase in Neuropeptide Y-immunoreactive elements localized to the islet core.. Our data show increased numbers of sympathetic nerve fibers with a potential to convey inhibitory signals on insulin secretion in pancreatic islets of genetically obese animals, regardless of their diabetic state. The findings suggest an alternative interpretation of the pathogenesis of beta cell failure, as well as novel strategies to reverse abnormalities in insulin secretion.

Topics: Adrenergic Neurons; Age Factors; Animals; Blood Glucose; Diet, High-Fat; Disease Models, Animal; Female; Hypertrophy; Insulin; Insulin-Secreting Cells; Islets of Langerhans; Mice; Neural Inhibition; Neuropeptide Y; Obesity; Tyrosine 3-Monooxygenase

To investigate the expression pattern of adapter protein with a Src-homology 2 domain (SH2B1), the suppressor of cytokine signaling-3 (SOCS3), protein-tyrosine phosphatase 1B (PTP1B) and neturopetide Y (NPY) in obese and normal mice hypothalamus and its relation with serum leptin and insulin levels.. The obesity animal model was prepared with healthy C57/bl6 mice. Lee's index and Homeostasis model assessment-insulin resistance (HOMA-IR) were calculated. The mRNA levels of SH2B1, SOCS3, PTP1B and NPY were measured by fluorescent quantitation RT-PCR. The SH2B1 and NPY protein expressions were detected by Western blot.. Compared with the normal mice of the same age, SH2B1 mRNA expression in the obese mice hypothalamus decreased. SOCS3 and PTP1B mRNA expression increased. Western blot showed that SH2B1 protein expression decreased, while NPY protein expression increased in the obese mice. Linear correlation analysis showed that the serum leptin and fasting insulin levels were negatively correlated with SH2B1mRNA expression and positively correlated with SOCS3 and PTP1B mRNA expression.. SH2B1, SOCS3, PTP1B and NPY are key factors for obesity development.

Topics: Adaptor Proteins, Signal Transducing; Animals; Hypothalamus; Insulin; Insulin Resistance; Leptin; Mice; Mice, Inbred C57BL; Neuropeptide Y; Obesity; Protein Tyrosine Phosphatase, Non-Receptor Type 1; RNA, Messenger; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins

Transcription factor forkhead box O1 (FoxO1) regulates energy expenditure (EE), food intake, and hepatic glucose production. These activities have been mapped to specific hypothalamic neuronal populations using cell type-specific knockout experiments in mice. To parse out the integrated output of FoxO1-dependent transcription from different neuronal populations and multiple hypothalamic regions, we used transgenic mice expressing Cre recombinase from the Nkx2.1 promoter to ablate loxP-flanked Foxo1 alleles from a majority of hypothalamic neurons (Foxo1KO(Nkx2.1) mice). This strategy resulted in the expected inhibition of FoxO1 expression, but only produced a transient reduction of body weight as well as a decreased body length. The transient decrease of body weight in male mice was accompanied by decreased fat mass. Male Foxo1KO(Nkx2.1) mice show food intake similar to that in wild-type controls, and, although female knockout mice eat less, they do so in proportion to a reduced body size. EE is unaffected in Foxo1KO(Nkx2.1) mice, although small increases in body temperature are present. Unlike other neuron-specific Foxo1 knockout mice, Foxo1KO(Nkx2.1) mice are not protected from diet-induced obesity. These studies indicate that, unlike the metabolic effects of highly restricted neuronal subsets (proopiomelanocortin, neuropeptide Y/agouti-related peptide, and steroidogenic factor 1), those of neurons derived from the Nkx2.1 lineage either occur in a FoxO1-independent fashion or are compensated for through developmental plasticity.

Topics: Agouti-Related Protein; Animals; Body Weight; Cell Lineage; Eating; Energy Metabolism; Female; Forkhead Box Protein O1; Forkhead Transcription Factors; Hypothalamus; Male; Mice; Mice, Transgenic; Neurons; Neuropeptide Y; Nuclear Proteins; Obesity; Pro-Opiomelanocortin; Promoter Regions, Genetic; Signal Transduction; Thyroid Nuclear Factor 1; Transcription Factors

Orexigenic neuropeptide Y (NPY) and dynorphin (DYN) regulate energy homeostasis. Single NPY or dynorphin deletion reduces food intake or increases fat loss. Future developments of obesity therapeutics involve targeting multiple pathways. We hypothesised that NPY and dynorphin regulate energy homeostasis independently, thus double NPY and dynorphin ablation would result in greater weight and/or fat loss than the absence of NPY or dynorphin alone.. We generated single and double NPY and dynorphin knockout mice (NPYΔ, DYNΔ, NPYDYNΔ) and compared body weight, adiposity, feeding behaviour, glucose homeostasis and brown adipose tissue uncoupling protein-1 (UCP-1) expression to wildtype counterparts.. Body weight and adiposity were significantly increased in NPYDYNΔ, but not in NPYΔ or DYNΔ. This was not due to increased food intake or altered UCP-1 expression, which were not significantly altered in double knockouts. NPYDYNΔ mice demonstrated increased body weight loss after a 24-h fast, with no effect on serum glucose levels after glucose injection.. Contrary to the predicted phenotype delineated from single knockouts, double NPY and dynorphin deletion resulted in heavier mice, with increased adiposity, despite no significant changes in food intake or UCP-1 activity. This indicates that combining long-term opioid antagonism with blockade of NPY-ergic systems may not produce anti-obesity effects.

Topics: Adipose Tissue; Animals; Appetite Regulation; Body Weight; Dynorphins; Energy Metabolism; Female; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Neuropeptide Y; Obesity

Topics: Agouti-Related Protein; Animals; Anorexia; Appetite; Arcuate Nucleus of Hypothalamus; Calcitonin Gene-Related Peptide; Feeding Behavior; gamma-Aminobutyric Acid; Humans; Hunger; Mice; Neurons; Neuropeptide Y; Obesity; Paraventricular Hypothalamic Nucleus; Prader-Willi Syndrome; Pro-Opiomelanocortin; Time Factors

The hypothalamic arcuate nucleus (ARH) is a brain region critical for regulation of food intake and a primary area for the action of leptin in the CNS. In lean mice, the adipokine leptin inhibits neuropeptide Y (NPY) and agouti-related peptide (AgRP) neuronal activity, resulting in decreased food intake. Here we show that diet-induced obesity in mice is associated with persistent activation of NPY neurons and a failure of leptin to reduce the firing rate or hyperpolarize the resting membrane potential. However, the molecular mechanism whereby diet uncouples leptin's effect on neuronal excitability remains to be fully elucidated. In NPY neurons from lean mice, the Kv channel blocker 4-aminopyridine inhibited leptin-induced changes in input resistance and spike rate. Consistent with this, we found that ARH NPY neurons have a large, leptin-sensitive delayed rectifier K(+) current and that leptin sensitivity of this current is blunted in neurons from diet-induced obese mice. This current is primarily carried by Kv2-containing channels, as the Kv2 channel inhibitor stromatoxin-1 significantly increased the spontaneous firing rate in NPY neurons from lean mice. In HEK cells, leptin induced a significant hyperpolarizing shift in the voltage dependence of Kv2.1 but had no effect on the function of the closely related channel Kv2.2 when these channels were coexpressed with the long isoform of the leptin receptor LepRb. Our results suggest that dynamic modulation of somatic Kv2.1 channels regulates the intrinsic excitability of NPY neurons to modulate the spontaneous activity and the integration of synaptic input onto these neurons in the ARH.

Topics: Action Potentials; Agouti-Related Protein; Animals; Arcuate Nucleus of Hypothalamus; Female; Green Fluorescent Proteins; HEK293 Cells; Humans; In Vitro Techniques; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Nerve Net; Neurons; Neuropeptide Y; Obesity; Potassium Channel Blockers; Shab Potassium Channels

High-fat diet (HFD) feeding causes ghrelin resistance in arcuate neuropeptide Y (NPY)/Agouti-related peptide neurons. In the current study, we investigated the time course over which this occurs and the mechanisms responsible for ghrelin resistance. After 3 weeks of HFD feeding, neither peripheral nor central ghrelin increased food intake and or activated NPY neurons as demonstrated by a lack of Fos immunoreactivity or whole-cell patch-clamp electrophysiology. Pair-feeding studies that matched HFD calorie intake with chow calorie intake show that HFD exposure does not cause ghrelin resistance independent of body weight gain. We observed increased plasma leptin in mice fed a HFD for 3 weeks and show that leptin-deficient obese ob/ob mice are still ghrelin sensitive but become ghrelin resistant when central leptin is coadministered. Moreover, ob/ob mice fed a HFD for 3 weeks remain ghrelin sensitive, and the ability of ghrelin to induce action potential firing in NPY neurons was blocked by leptin. We also examined hypothalamic gliosis in mice fed a chow diet or HFD, as well as in ob/ob mice fed a chow diet or HFD and lean controls. HFD-fed mice exhibited increased glial fibrillary acidic protein-positive cells compared with chow-fed mice, suggesting that hypothalamic gliosis may underlie ghrelin resistance. However, we also observed an increase in hypothalamic gliosis in ob/ob mice fed a HFD compared with chow-fed ob/ob and lean control mice. Because ob/ob mice fed a HFD remain ghrelin sensitive, our results suggest that hypothalamic gliosis does not underlie ghrelin resistance. Further, pair-feeding a HFD to match the calorie intake of chow-fed controls did not increase body weight gain or cause central ghrelin resistance; thus, our evidence suggests that diet-induced hyperleptinemia, rather than diet-induced hypothalamic gliosis or HFD exposure, causes ghrelin resistance.

Topics: Action Potentials; Agouti-Related Protein; Animals; Arcuate Nucleus of Hypothalamus; Diet, High-Fat; Drug Resistance; Ghrelin; Glial Fibrillary Acidic Protein; Gliosis; Green Fluorescent Proteins; Hypothalamus; Immunohistochemistry; In Vitro Techniques; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Mice, Transgenic; Microscopy, Fluorescence; Neurons; Neuropeptide Y; Obesity

Maternal obesity during pregnancy increases the risk of obesity in the offspring. Several observations have pointed to a causative role for the proinflammatory cytokine IL-6, but whether it is present in the fetal circulation and how it acts on the developing fetus are unclear. We first observed that postnatal day 0 offspring from obese mothers had significantly reduced neuropeptide Y (NPY) innervation of the paraventricular nucleus (PVN) compared with that for offspring of normal-weight controls. Thus, the growth of NPY neurites from the arcuate nucleus (ARC) was impaired in the fetal brain by maternal obesity. The neurite growth regulator, Netrin-1, was expressed in the ARC and PVN and along the pathway between the two at gestational day (GD) 17.5 in normal animals, making it likely to be involved in the development of NPY ARC-PVN projections. In addition, the expression of Dcc and Unc5d, receptors for Netrin-1, were altered in the GD17.5 ARC in obese but not normal weight pregnancies. Thus, this important developmental pathway is perturbed by maternal obesity and may explain the defect in NPY innervation of the PVN that occurs in fetuses developing in obese mothers. To investigate whether IL-6 may play a role in these developmental changes, we found first that IL-6 was significantly elevated in the fetal and maternal circulation in pregnancies of obese mice compared with those of normal-weight mice. In addition, treatment of GD17.5 ARC tissue with IL-6 in vitro significantly reduced ARC neurite outgrowth and altered developmental gene expression similar to maternal obesity in vivo. These findings demonstrate that maternal obesity may alter the way in which fetal ARC NPY neurons respond to key developmental signals that regulate normal prenatal neural connectivity and suggest a causative role for elevated IL-6 in these changes.

Topics: Animals; Arcuate Nucleus of Hypothalamus; Cells, Cultured; Diet, High-Fat; Dose-Response Relationship, Drug; Female; Gene Expression Regulation, Developmental; Immunohistochemistry; In Situ Hybridization; Interleukin-6; Mice, Inbred C57BL; Nerve Growth Factors; Netrin-1; Neurites; Neuropeptide Y; Obesity; Paraventricular Hypothalamic Nucleus; Pregnancy; Pregnancy Complications; Reverse Transcriptase Polymerase Chain Reaction; Tumor Suppressor Proteins

Repeated administration of the long-acting glucagon-like peptide 1 receptor agonist exendin-4 (EX-4) has been shown to reduce food intake and body weight and do so without a rebound increase in food intake after treatment termination. The current study examines the neural mechanisms underlying these actions. After 6 weeks of maintenance on a standard chow or a high-fat (HF) diet, male Sprague Dawley rats were treated with EX-4 (3.2 μg/kg, i.p., twice a day) or vehicle for 9 consecutive days. Food intake and body weight (BW) were monitored daily. Expression of the genes for the hypothalamic arcuate nucleus (ARC) peptides proopiomelanocortin (POMC), neuropeptide Y (NPY), and agouti gene-related protein was determined. Expression of the dopamine precursor tyrosine hydroxylase (TH) gene in the ventral tegmental area and genes for dopamine receptors 1 (D1R) and dopamine receptor 2 in the nucleus accumbens were also determined. Pair-fed groups were included to control for the effects of reduced food intake and BW. Treatment with EX-4 significantly decreased food intake and BW over the 9-day period in both the standard chow and HF groups. HF feeding decreased POMC without changing NPY/agouti gene-related protein gene expression in the ARC. Treatment with EX-4 increased POMC and decreased NPY expression independent of the reduction of food intake and BW. Mesolimbic TH and D1R gene expression were decreased significantly in chronic HF diet-fed rats, and these changes were reversed in both EX-4 and pair-fed conditions. These results suggest a role for increased POMC and decreased NPY expression in the ARC in the effects of EX-4 on food intake and BW. Our findings also suggest that EX-4 induced the recovery of mesolimbic TH and D1R expression in HF diet-fed rats may be secondary to HF intake reduction and/or weight loss.

Topics: Animals; Biomarkers; Body Weight; Brain; Eating; Exenatide; Homeostasis; Humans; Male; Neuropeptide Y; Obesity; Peptides; Pro-Opiomelanocortin; Rats; Rats, Sprague-Dawley; Venoms

It has been suggested that obesity triggered by consuming a high-fat diet (HF) can account for oxidative damage and mitochondrial dysfunction. Thus, we aim to explore the oxidative stress and mitochondrial dysfunction detected in the brain of diet-induced obese (DIO) rats.. Sprague-Dawley (SD) rats were fed either a HF diet or a normal-fat (NF) diet for 10weeks to obtain the control (CON), DIO and diet-resistant (DR) rats. d-Galactose was injected subcutaneously for 10weeks to establish oxidative stress model (MOD) rats. Then, the levels of total antioxidant capacity (T-AOC), lipid peroxidation (LPO), malondialdehyde (MDA), both in plasma and brain tissue, and catalase (CAT) in plasma were measured using enzymic assay kits and the levels of ghrelin, neuropeptide Y (NPY) and leptin in both plasma and brain tissue were measured by using enzyme-linked immunosorbent assay (ELISA) kits. Mitochondrial reactive oxygen species (ROS) formation in brain tissues was detected with 2, 7-dichlorofluorescein diacetate (DCFH2-DA) dyeing. The mitochondrial membrane potential (MMP) was measured with tetrachloro-tetraethyl benzimidazol carbocyanine iodide (JC-1) by a flow cytometer.. HF diet leads to an obese or DR state characterized by increased or decreased adiposity. The HF diet increased brain LPO, which was accompanied by lower ghrelin levels in DIO rats compared with DR rats. In addition, the increased mitochondrial ROS and lower MMP were detected in DIO rat comparing with DR rats.. The current results demonstrated that mitochondrial dysfunction and oxidative damage in the brains of DIO rats, induced by HF diets, might be measurable.

Topics: Animals; Antioxidants; Brain; Catalase; Diet, High-Fat; Enzyme-Linked Immunosorbent Assay; Ghrelin; Lipid Peroxidation; Male; Malondialdehyde; Mitochondrial Diseases; Neuropeptide Y; Obesity; Oxidative Stress; Rats; Rats, Sprague-Dawley

The role of neuronal noncoding RNAs in energy control of the body is not fully understood. The arcuate nucleus (ARC) of the hypothalamus comprises neurons regulating food intake and body weight. Here we show that Dicer-dependent loss of microRNAs in these neurons of adult (DicerCKO) mice causes chronic overactivation of the signaling pathways involving phosphatidylinositol-3-kinase (PI3K), Akt, and mammalian target of rapamycin (mTOR) and an imbalance in the levels of neuropeptides, resulting in severe hyperphagic obesity. Similarly, the activation of PI3K-Akt-mTOR pathway due to Pten deletion in the adult forebrain leads to comparable weight increase. Conversely, the mTORC1 inhibitor rapamycin normalizes obesity in mice with an inactivated Dicer1 or Pten gene. Importantly, the continuous delivery of oligonucleotides mimicking microRNAs, which are predicted to target PI3K-Akt-mTOR pathway components, to the hypothalamus attenuates adiposity in DicerCKO mice. Furthermore, loss of miR-103 causes strong upregulation of the PI3K-Akt-mTOR pathway in vitro and its application into the ARC of the Dicer-deficient mice both reverses upregulation of Pik3cg, the mRNA encoding the catalytic subunit p110γ of the PI3K complex, and attenuates the hyperphagic obesity. Our data demonstrate in vivo the crucial role of neuronal microRNAs in the control of energy homeostasis.

Topics: Absorptiometry, Photon; Agouti-Related Protein; Animals; DEAD-box RNA Helicases; HeLa Cells; Humans; Hyperphagia; Hypothalamus; Luminescent Proteins; Mice; Mice, Inbred C57BL; MicroRNAs; Neuropeptide Y; Obesity; Oncogene Protein v-akt; Phosphatidylinositol 3-Kinases; PTEN Phosphohydrolase; Ribonuclease III; TOR Serine-Threonine Kinases; Transduction, Genetic

Tributyltin (TBT) is a largely diffused environmental pollutant. Several studies have demonstrated that TBT is involved in the development of obesity. However, few studies addressing the effects of TBT on the brain neuropeptides involved in appetite and body weight homeostasis have been published.. Experiments were carried out on female and male Sprague-Dawley rats. Animals were exposed to TBT (0.5 μg/kg body weight) for 54 days. The hepatic triglyceride and total cholesterol were determined using commercial enzyme kits. The NPY, AgRP, POMC and CART mRNA expression in brains were quantified by real-time PCR.. TBT exposure resulted in significant increases in the hepatic total cholesterol and triglyceride concentration of both male and female rats. Interestingly, increases in body weight and fat mass were only found in the TBT-treated male rats. TBT exposure also led to a significant increase in food intake by the female rats, while no change was observed in the male rats. Moreover, the neuropeptides expression was different between males and females after TBT exposure. TBT induced brain NPY expression in the female rats, and depressed brain POMC, AgRP and CART expression in the males.. TBT can increase food intake in female rats, which is associated with the disturbance of NPY in brains. TBT had sex-different effects on brain NPY, AgRP, POMC and CART mRNA expression, which indicates a complex neuroendocrine mechanism of TBT.

Topics: Agouti-Related Protein; Animals; Eating; Female; Male; Nerve Tissue Proteins; Neuropeptide Y; Obesity; Peptide Fragments; Pro-Opiomelanocortin; Rats; Rats, Sprague-Dawley; Real-Time Polymerase Chain Reaction; RNA, Messenger; Trialkyltin Compounds

We showed that early weaned rats developed obesity, hyperleptinemia, leptin and insulin resistance at adulthood. Here, we studied the potential beneficial effects of Ilex paraguariensis aqueous solution upon body composition, glycemia, lipid and hormonal profiles, leptin signaling and NPY content.. To induce early weaning, lactating rats' teats were blocked with a bandage to interrupt lactation during the last 3 days (EW group), while control offspring had free access to milk throughout lactation (C group). In postnatal day (PN) 150, EW offspring were subdivided into: EW and EW+ mate groups treated, respectively, with water or yerba mate aqueous solution (1 g/kg BW/day, gavage) during 30 days. C offspring received water for gavage. In PN180, offspring were killed.. EW+ mate group presented lower body weight (-10 %), adipose mass (retroperitoneal:-40 % and epididymal:-44 %), total body fat (-43 %), subcutaneous fat (-46 %), visceral adipocyte area (-21 %), triglyceridemia (-31 %) and hypothalamic NPY content (-37 %) compared to EW group. However, hyperglycemia and lower HDL-c levels observed in EW group were not reverted with mate treatment. Although the hyperleptinemia, lower hypothalamic JAK2 and pSTAT3 content of EW group were not corrected by mate treatment, the hyperphagia and higher hypothalamic SOCS-3 content were normalized in EW+ mate group, indicating that the central leptin resistance could be restored.. Thus, the therapy with yerba mate solution was capable to reverse abdominal obesity, leptin resistance and hypertriglyceridemia, suggesting an important role of this bioactive component in the management of obesity in this programming model.

Topics: Animals; Blood Glucose; Body Composition; Body Weight; Cholesterol, HDL; Cholesterol, LDL; Disease Models, Animal; Dyslipidemias; Female; Hyperglycemia; Hypothalamus; Ilex paraguariensis; Insulin Resistance; Janus Kinase 2; Lactation; Leptin; Neuropeptide Y; Obesity; Plant Extracts; Rats; STAT3 Transcription Factor; Subcutaneous Fat; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins; Weaning

Neuropeptide Y (NPY) is induced in peripheral tissues such as adipose tissue with obesity. The mechanism and function of NPY induction in fat are unclear. Given the evidence that NPY can modulate inflammation, we examined the hypothesis that NPY regulates the function of adipose tissue macrophages (ATMs) in response to dietary obesity in mice. NPY was induced by dietary obesity in the stromal vascular cells of visceral fat depots from mice. Surprisingly, the induction of Npy was limited to purified ATMs from obese mice. Significant basal production of NPY was observed in cultured bone marrow derived macrophage and dendritic cells (DCs) and was increased with LPS stimulation. In vitro, addition of NPY to myeloid cells had minimal effects on their activation profiles. NPY receptor inhibition promoted DC maturation and the production of IL-6 and TNFα suggesting an anti-inflammatory function for NPY signaling in DCs. Consistent with this, NPY injection into lean mice decreased the quantity of M1-like CD11c(+) ATMs and suppressed Ly6c(hi) monocytes. BM chimeras generated from Npy(-/-) donors demonstrated that hematopoietic NPY contributes to the obesity-induced induction of Npy in fat. In addition, loss of Npy expression from hematopoietic cells led to an increase in CD11c(+) ATMs in visceral fat with high fat diet feeding. Overall, our studies suggest that NPY is produced by a range of myeloid cells and that obesity activates the production of NPY in adipose tissue macrophages with autocrine and paracrine effects.

Topics: Adipose Tissue; Animals; Dendritic Cells; Gene Expression Regulation; Hematopoietic Stem Cells; Inflammation; Insulin Resistance; Interleukin-6; Macrophages; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Monocytes; Neuropeptide Y; Obesity; Receptors, Neuropeptide Y; Triglycerides; Tumor Necrosis Factor-alpha

We sought to determine a role for NPY overexpression in the dorsomedial hypothalamus (DMH) in obesity etiology using the rat model of adeno-associated virus (AAV)-mediated expression of NPY (AAVNPY) in the DMH. Rats received bilateral DMH injections of AAVNPY or control vector and were fed on regular chow. Five-week postviral injection, half the rats from each group were switched to access to a high-fat diet for another 11 weeks. We examined variables including body weight, food intake, energy efficiency, meal patterns, glucose tolerance, fat mass, plasma insulin, plasma leptin, and hypothalamic gene expression. Rats with DMH NPY overexpression had increased food intake and body weight and lowered metabolic efficiency. The hyperphagia was mediated through increased meal size during the dark. Although these rats had normal blood glucose, their plasma insulin levels were increased in both basal and glucose challenge conditions. While high-fat diet induced hyperphagia, obesity, and hyperinsulinemia, these effects were amplified in rats with DMH NPY overexpression. Arcuate Npy, agouti-related protein and proopiomelanocortin expression was appropriately regulated in response to positive energy balance. These results indicate that DMH NPY overexpression can cause hyperphagia and obesity and DMH NPY may have actions in glucose homeostasis.

Topics: Agouti-Related Protein; Animals; Body Weight; Dependovirus; Diet, High-Fat; Disease Models, Animal; Energy Metabolism; Gene Expression Regulation; Glucose; Glucose Tolerance Test; Homeostasis; Hyperphagia; Hypothalamus; Leptin; Male; Neuropeptide Y; Obesity; Pro-Opiomelanocortin; Rats; Rats, Sprague-Dawley

Obesity is currently a worldwide pandemic. Leptin resistance is a main mechanism of obese human and rodents. The downregulation of the long form of the leptin receptor (Lrb) was involved in leptin resistance in diet-induced obese rats. In the studies, we investigated whether arcuate nucleus (ARC) silencing of Lrb would promote diet-induced obesity in rats. Lentiviral vectors expressing Lrb-shRNA were administered to 5-week-old male rats by ARC injection. Following viral delivery, the rats were provided with a high-fat diet (HFD) or a chow diet (CD). After 8 weeks of the diet, serum leptin, and insulin concentrations were measured by RIA, gene expression of Lrb in the ARC was detected by a real-time RT-PCR, and leptin signaling was examined by western blot. The Lrb-shRNA knocked down the expression of Lrb mRNA in infected regions by 54% for the HFD rats and 47% for the CD rats respectively. The Lrb knockdown reduced Stats3 activation and increased expression of Npy mRNA. The rats with reduced Lrb in the ARC showed a significant increase in energy intake and body weight (BW) again when fed with a HFD. By contrast, there were no effects of Lrb reduction on energy intake or BW when rats maintained on a low-fat chow. Our results provide evidence that Lrb knockdown selectively in the ARC promotes diet-induced obesity and associated metabolic complications in rats.

Topics: Animals; Arcuate Nucleus of Hypothalamus; Diet, High-Fat; Disease Models, Animal; Gene Expression Regulation; Gene Knockdown Techniques; Genetic Vectors; Lentivirus; Leptin; Male; Neuropeptide Y; Obesity; Rats; Receptors, Leptin; RNA Interference; RNA, Small Interfering; Signal Transduction; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins

A role for the kinin B1 receptor in energy-homeostatic processes was implicated in previous studies; notably, the studies where kinin B1 receptor knockout mice (B1-/-) were shown to have impaired adiposity, impaired leptin and insulin production, lower feed efficiency, protection from liver steatosis and diet-induced obesity when fed a high fat diet (HFD). In particular, in a model where the B1 receptor is expressed exclusively in the adipose tissue, it rescues the plasma insulin concentration and the weight gain seen in wild type mice. Taking into consideration that leptin participates in the formation of hypothalamic nuclei, which modulate energy expenditure, and feeding behavior, we hypothesized that these brain regions could also be altered in B1-/- mice. We observed for the first time a difference in the gene expression pattern of cocaine and amphetamine related transcript (CART) in the (lateral hypothalamic area (LHA) resulting from the deletion of the kinin B1 receptor gene. The correlation between CART expression in the LHA and the thwarting of diet-induced obesity corroborates independent correlations between CART and obesity. Furthermore, it seems to indicate that the mechanism underlying the 'lean' phenotype of B1-/- mice does not stem solely from changes in peripheral tissues but may also receive contributions from changes in the hypothalamic machinery involved in energy homeostasis processes.

Topics: Animals; Body Weight; Energy Intake; Hypothalamic Area, Lateral; Immunohistochemistry; In Situ Hybridization; Kinins; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Nerve Tissue Proteins; Neuropeptide Y; Obesity; RNA, Messenger

Variants in the neuropeptide Y (NPY) gene have been associated with obesity and its traits. The objective of the present study was to evaluate the association of single nucleotide polymorphisms (SNPs) in the NPY gene with obesity, metabolic syndrome features, and inflammatory and cardiovascular disease (CVD) risk biomarkers in Spanish children. We recruited 292 obese children and 242 normal-body mass index (BMI) children. Height, weight, BMI, waist circumference, clinical and metabolic markers, adipokines, and inflammatory (PCR, IL-6, IL-8 and TNF-α) and CVD risk biomarkers (MPO, MMP-9, sE-selectin, sVCAM, sICAM, and PAI-1) were analyzed. Seven SNPs in the NPY gene were genotyped. The results of our study indicate that anthropometric measurements, clinical and metabolic markers, adipokines (leptin and resistin), and inflammatory and CVD risk biomarkers were generally elevated in the obese group. The exceptions to this finding included cholesterol, HDL-c, and adiponectin, which were lower in the obese group, and glucose, LDL-c, and MMP-9, which did not differ between the groups. Both rs16147 and rs16131 were associated with the risk of obesity, and the latter was also associated with insulin resistance, triacylglycerols, leptin, and HDL-c. Thus, we confirm the association of rs16147 with obesity, and we demonstrate for the first time the association of rs16131 with obesity and its possible impact on the early onset of metabolic syndrome features, mainly triacylglycerols, in children.

Topics: Adolescent; Biomarkers; Body Mass Index; Cardiovascular Diseases; Case-Control Studies; Child; Child, Preschool; Cytokines; Female; Genotyping Techniques; Humans; Leptin; Male; Metabolic Syndrome; Neuropeptide Y; Obesity; Polymorphism, Single Nucleotide; Resistin; Risk Factors; Spain; Triglycerides; Waist Circumference

Acute or chronic alterations in energy status alter the balance between excitatory and inhibitory synaptic transmission and associated synaptic plasticity to allow for the adaptation of energy metabolism to new homeostatic requirements. The impact of such changes on endocannabinoid and cannabinoid receptor type 1 (CB1)-mediated modulation of synaptic transmission and strength is not known, despite the fact that this signaling system is an important target for the development of new drugs against obesity. We investigated whether CB1-expressing excitatory vs. inhibitory inputs to orexin-A-containing neurons in the lateral hypothalamus are altered in obesity and how this modifies endocannabinoid control of these neurons. In lean mice, these inputs are mostly excitatory. By confocal and ultrastructural microscopic analyses, we observed that in leptin-knockout (ob/ob) obese mice, and in mice with diet-induced obesity, orexinergic neurons receive predominantly inhibitory CB1-expressing inputs and overexpress the biosynthetic enzyme for the endocannabinoid 2-arachidonoylglycerol, which retrogradely inhibits synaptic transmission at CB1-expressing axon terminals. Patch-clamp recordings also showed increased CB1-sensitive inhibitory innervation of orexinergic neurons in ob/ob mice. These alterations are reversed by leptin administration, partly through activation of the mammalian target of rapamycin pathway in neuropeptide-Y-ergic neurons of the arcuate nucleus, and are accompanied by CB1-mediated enhancement of orexinergic innervation of target brain areas. We propose that enhanced inhibitory control of orexin-A neurons, and their CB1-mediated disinhibition, are a consequence of leptin signaling impairment in the arcuate nucleus. We also provide initial evidence of the participation of this phenomenon in hyperphagia and hormonal dysregulation in obesity.

Topics: Animals; Arachidonic Acids; Arcuate Nucleus of Hypothalamus; Endocannabinoids; Glycerides; Hypothalamus; Intracellular Signaling Peptides and Proteins; Leptin; Male; Membrane Potentials; Mice; Mice, Inbred C57BL; Mice, Obese; Microscopy, Confocal; Microscopy, Electron; Neurons; Neuropeptide Y; Neuropeptides; Obesity; Orexins; Receptor, Cannabinoid, CB1; Signal Transduction; Synaptic Transmission; TOR Serine-Threonine Kinases

It has been reported that plasma NPY levels were increased in obesity, type 2 diabetes mellitus and hypertension. The symptoms of metabolic syndrome frequently appear in patients with acute ischemic stroke. The association between plasma NPY levels and metabolic markers in women with acute ischemic stroke was investigated in the current study.. Plasma NPY concentrations were determined using radioimmunoassay in 58 women aged 60-85 (mean age: 76.5±0.8) with acute ischemic stroke and in 24 women aged 63-67 (mean age: 65.6±0.6) of the control group. Stroke was defined according to the NIHSS (National Institute of Health Stroke Scale) and was confirmed using CT or MR scan.. The prevalence of type 2 diabetes, hypertension and insulin resistance was higher in the group of patients with stroke. Plasma NPY levels measured during the 1st day and 10 days after the acute phase of stroke were significantly lower (p<0.001) compared to the control group.. In women with acute ischemic stroke plasma NPY concentrations were decreased in spite of higher frequency of the occurrence of the symptoms of metabolic syndrome.

Topics: Aged; Aged, 80 and over; Biomarkers; Brain Ischemia; Diabetes Mellitus, Type 2; Female; Humans; Hypertension; Middle Aged; Neuropeptide Y; Obesity; Radioimmunoassay; Stroke

The neuropeptide-Y (NP-Y) gene is a strong candidate gene in the pathophysiology of obesity-linked behavior, and several single-nucleotide polymorphisms of NP-Y have already been linked to body weight and appetite. However, the results from current studies remain inconclusive. The aim of the present study was to test whether a certain functional genetic variant (SNP rs16147) in the NP-Y promoter gene is associated with serum leptin levels and body fat distribution.. We genotyped and measured the serum leptin levels of the NP-Y rs16147 polymorphism in 1,097 Caucasian subjects in the context of a population-based, case-control multicenter study. We measured weight, height and waist circumference, from which we then calculated BMI and waist-to-hip ratio (WHR).. We found the CT-genotype of the SNP rs16147 to be significantly associated with lower WHRs and higher serum leptin levels in women, compared to homozygote gene carriers. No association between rs16147, WHR and serum leptin levels was found in men.. Our results provide evidence that the functionally relevant SNP in the NP-Y promoter gene affects body fat distribution and serum leptin levels in women, pointing towards possible behavioral effects of NPY in obesity.

Topics: Adult; Case-Control Studies; Female; Genotype; Humans; Leptin; Male; Middle Aged; Neuropeptide Y; Obesity; Polymorphism, Single Nucleotide; Sex Factors; Statistics, Nonparametric; Waist-Hip Ratio; White People

The regulation of energy balance is influenced by physical exercise. Although some studies show a stimulation of hormones related to food intake, others show that exercise provides satiety.. The aim of this study was to compare the effects of aerobic training (AT) and aerobic plus resistance training (AT+RT) on anorexigenic and orexigenic factors in obese adolescents undergoing interdisciplinary weight loss therapy.. A total of 26 obese adolescents, aged 15-19 years with BMI≥P95 were submitted to 12 months of interdisciplinary intervention (clinical support, nutrition, psychology and physical exercise) and divided into two groups, aerobic training (AT) (n=13) or aerobic plus resistance training (AT+RT) (n=13), which were matched according to gender and body mass. Blood samples were collected to analyze orexigenic factors (AgRP, NPY, MCH) and the anorexigenic factor alpha-MSH.. The AT and AT+RT groups significantly reduced body mass, body mass index and body fat mass (kg) during the therapy. The AT group showed no significant changes in body lean mass (kg), whereas the AT+RT group showed an increase in body lean mass (kg) during the interdisciplinary intervention. There was an increase in AgRP levels (ng/ml) only in the AT+RT group after 6 months of interdisciplinary intervention compared with baseline condition. Conversely, α-MSH levels (ng/ml) increased only in the AT group after 12 months of interdisciplinary intervention compared with baseline condition.. Aerobic training (AT) as part of an interdisciplinary therapy is more effective than aerobic plus resistance training (AT+RT) to improve secretion of anorexigenic/orexigenic factors in obese adolescents.

Topics: Adolescent; Agouti-Related Protein; alpha-MSH; Body Composition; Body Mass Index; Eating; Energy Metabolism; Exercise; Female; Humans; Hypothalamic Hormones; Male; Melanins; Neuropeptide Y; Obesity; Pituitary Hormones; Resistance Training; Satiation; Weight Loss; Young Adult

Specific methylation of appetite-related genes in leukocytes could serve as a useful biomarker to predict weight regain after an energy restriction program. We aimed to evaluate whether the pre-intervention DNA methylation patterns involved in the epigenetic control of appetite-regulatory genes in leukocytes are associated with the weight regain process. Eighteen men who lost ≥5% of body weight after an 8-week nutritional intervention were categorized as "regainers" (≥10% weight regain) and "non-regainers" (<10% weight regain) 32weeks after stopping dieting. At baseline, leukocytes were isolated and DNA was analyzed for epigenetic methylation patterns of appetite-related gene promoters by MALDI-TOF mass spectrometry. Regainers showed higher methylation levels than non-regainers in proopiomelanocortin (POMC) CpG sites +136bp and +138bp (fold change from non-regainers=26%; p=0.020) and lower methylation of the whole analyzed region of neuropeptide Y (NPY; fold change from non-regainers=-22%; p=0.033), as well as of several individual NPY-promoter CpG sites. Importantly, total baseline NPY methylation was associated with weight-loss regain (r=-0.76; p<0.001), baseline plasma ghrelin levels (r=0.60; p=0.011) and leptin/ghrelin ratio (r=-0.52; p=0.046). Lower methylation levels of POMC CpG sites +136bp and +138bp were associated with success in weight-loss maintenance (odds ratio=0.042 [95% CI 0.01-0.57]; p=0.018), whereas lower total methylation levels in NPY promoter were associated with higher risk of weight regain (odds ratio=14.0 [95% CI 1.13-172]; p=0.039). Therefore, the study of leukocyte methylation levels reflects a putative epigenetic regulation of NPY and POMC, which might be implicated in the weight regain process and be used as biomarkers for predicting weight regain after dieting.

Topics: CpG Islands; DNA Methylation; Ghrelin; Humans; Leptin; Leukocytes; Male; Neuropeptide Y; Obesity; Pro-Opiomelanocortin; Promoter Regions, Genetic; Receptors, Leptin; Weight Gain

Recently, neuropeptide Y (NPY) and Y1 receptor (Y1R) were found to be expressed and synthesized in adipose tissue. This study aimed to compare NPY and Y1R mRNA expressions in subcutaneous and visceral fat tissues as well as serum NPY in normal weight and obese humans and their correlations with clinical parameters and peripheral metabolic factors. We demonstrated that NPY mRNA expression was higher in obese than in normal weight humans (p<0.05) in both subcutaneous and visceral adipose tissues and was significantly greater in visceral when compared with subcutaneous fat in overall (p<0.01), obese (p<0.05) and normal weight humans (p<0.05). Y1R mRNA expression was higher in obese than normal weight subjects in visceral (p<0.01) but not in subcutaneous adipose tissue and was statistically greater in subcutaneous when compared to visceral adipose tissue in obese (p<0.05) and overall subjects (p<0.05). Serum NPY was higher in obese than normal weight groups (p<0.05). Obese subjects showed significantly greater levels of systolic blood pressure (SBP) (p<0.01), diastolic blood pressure (DBP) (p<0.05), plasma insulin (p<0.05), and HOMA-IR (p<0.05) when compared with normal weight subjects. Additionally, Y1R mRNA expression in visceral adipose tissue was positively correlated with body weight (R=0.586), BMI (R=0.611), waist (R=0.474) and hip (R=0.483) circumferences, insulin levels (R=0.539), and HOMA-IR (R=0.480). As the result, Y1R expression in visceral adipose tissue might be an indicator of increased risk of metabolic syndrome. Further studies about blocking specific Y1R may propose strategies for risk reduction in metabolic syndrome and prevention or treatment of obesity.

Topics: Adult; Female; Gene Expression; Humans; Intra-Abdominal Fat; Metabolic Syndrome; Middle Aged; Multivariate Analysis; Neuropeptide Y; Obesity; Receptors, Neuropeptide Y; Risk Factors; Subcutaneous Fat

Two types of fat, white adipose tissue (WAT) and brown adipose tissue (BAT), exist in mammals including adult humans. While WAT stores excess calories and an excessive accumulation of fat causes obesity, BAT dissipates energy to produce heat through nonshivering thermogenesis for protection against cold environments and provides the potential for the development of novel anti-obesity treatments. The hypothalamus plays a central role in the control of energy balance. Specifically, recent observations indicate the importance of the dorsomedial hypothalamus (DMH) in thermoregulation. We have found that the orexigenic neuropeptide Y (NPY) in the DMH has distinct actions in modulating adiposity and BAT thermogenesis. Knockdown of NPY in the DMH elevates the thermogenic activity of classic BAT and promotes the development of brown adipocytes in WAT, leading to increased thermogenesis. These findings identify a novel potential target for combating obesity.

Topics: Adipose Tissue, Brown; Adipose Tissue, White; Adult; Animals; Cell Transdifferentiation; Gene Knockdown Techniques; Genetic Therapy; Humans; Hypothalamus; Neuropeptide Y; Obesity; Signal Transduction; Thermogenesis

Neuropeptide Y (NPY) neurons in both the arcuate nucleus of the hypothalamus (ARH) and the dorsomedial hypothalamus (DMH) have been implicated in food intake and obesity. However, while ARH NPY is highly expressed in the lean animal, DMH NPY mRNA expression is observed only after diet-induced obesity (DIO). Furthermore, while ARH NPY neurons are inhibited by leptin, the effect of this adipokine on DMH NPY neurons is unknown. In this study we show that in contrast to the consistent expression in the ARH, DMH NPY mRNA expression was undetectable until after 10 weeks in mice fed a high-fat diet, and peaked at 20 weeks. Surprisingly, electrophysiological experiments demonstrated that leptin directly depolarized and increased the firing rate of DMH NPY neurons in DIO mice. To further differentiate the regulation of DMH and ARH NPY populations, fasting decreased expression of DMH NPY expression, while it increased ARH NPY expression. However, treatment with a leptin receptor antagonist failed to alter DMH NPY expression, indicating that leptin may not be the critical factor regulating mRNA expression. Importantly, we also demonstrated that DMH NPY neurons coexpress cocaine amphetamine-regulated transcript (CART); however, CART mRNA expression in the DMH peaked earlier in the progression of DIO. This study demonstrates novel and important findings. First, NPY and CART are coexpressed in the same neurons within the DMH, and second, leptin stimulates DMH NPY neurons. These studies suggest that during the progression of DIO, there is an unknown signal that drives the expression of the orexigenic NPY signal within the DMH, and that the chronic hyperleptinemia increases the activity of these NPY/CART neurons.

Topics: Action Potentials; Analysis of Variance; Animals; Diet; Disease Models, Animal; Dose-Response Relationship, Drug; Gene Expression Regulation; Green Fluorescent Proteins; Hypothalamus; In Vitro Techniques; Insulin; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Nerve Tissue Proteins; Neurons; Neuropeptide Y; Obesity; Patch-Clamp Techniques; Proto-Oncogene Proteins c-fos; Radioimmunoassay; RNA, Messenger; STAT3 Transcription Factor; Time Factors

Maternal obesity increases the risk of obesity in offspring, and obesity is accompanied by an increase in blood leptin levels. The "yellow" mutation at the mouse agouti locus (A(y)) increases blood leptin levels in C57BL preobese pregnant mice without affecting other metabolic characteristics. We investigated the influence of the A(y) mutation or leptin injection at the end of pregnancy in C57BL mice on metabolic phenotypes and the susceptibility to diet-induced obesity (DIO) in offspring. In both C57BL-A(y) and leptin-treated mice, the maternal effect was more pronounced in male offspring. Compared with males born to control mothers, males born to A(y) mothers displayed equal food intake (FI) but decreased body weight (BW) gain after weaning, equal glucose tolerance, and enhanced FI-to-BW ratios on the standard diet but the same FI and BW on the high-fat diet. Males born to A(y) mothers were less responsive to the anorectic effect of exogenous leptin and less resistant to fasting (were not hyperphagic and gained less weight during refeeding after food deprivation) compared with males born to control mothers. However, all progeny displayed equal hypothalamic expression of Agouti gene-related protein (AgRP), neuropeptide Y (NPY), and proopiomelanocortin (POMC) and equal plasma leptin and glucose levels after food deprivation. Leptin injections in C57BL mice on day 17 of pregnancy decreased BW in both male and female offspring but inhibited FI and DIO only in male offspring. Our results show that hyperleptinemia during pregnancy has sex-specific long-term effects on energy balance regulation in progeny and does not predispose offspring to developing obesity.

Topics: Agouti-Related Protein; Animals; Body Composition; Body Weight; Eating; Energy Metabolism; Female; Hypothalamus; Leptin; Mice; Mice, Inbred C57BL; Neuropeptide Y; Obesity; Phenotype; Pregnancy; Pregnancy Complications; Pro-Opiomelanocortin; Sex Factors; Weight Gain

We examined the thermal stability of yeast hydrolysates before and after ultrafiltration (UF) in vitro, and the anti-obesity activity of yeast hydrolysates before and after heat treatment in vivo. Yeast hydrolysate after UF showed significantly higher thermal stability than before UF. Yeast hydrolysates before and after UF showed 3 and 4 thermal transition peaks in their thermograms, respectively, and the total thermal denaturation enthalpies of yeast hydrolysates before and after UF were 69.5 and 36.5 J/g, respectively. For the anti-obesity activity study, yeast hydrolysates before and after heating were administered ad libitum with water to 7-week-old male SD rats. The administration of yeast hydrolysate (YH-control; no heat treatment, YH-1; heat treatment at 140°C, and YH-2; heat treatment at 160°C) significantly increased mRNA expression of cocaine- and amphetamine-regulated transcript (CART) compared with control rats (saline administration). However, there was no significant difference between the heat-treated groups and YH-control and there was no significant difference in neuropeptide Y expression between the heat-treated groups and YH-control. These results suggest that yeast hydrolysate can be use an anti-obesity material after heat treatment.

Topics: Animals; Anti-Obesity Agents; Drug Stability; Fungal Proteins; Hot Temperature; Humans; Hydrolysis; Male; Nerve Tissue Proteins; Neuropeptide Y; Obesity; Protein Hydrolysates; Rats; Rats, Sprague-Dawley; Saccharomyces cerevisiae

The dorsomedial hypothalamus (DMH) has long been implicated in feeding behavior and thermogenesis. The DMH contains orexigenic neuropeptide Y (NPY) neurons, but the role of these neurons in the control of energy homeostasis is not well understood. NPY expression in the DMH is low under normal conditions in adult rodents but is significantly increased during chronic hyperphagic conditions such as lactation and diet-induced obesity (DIO). To understand better the role of DMH-NPY neurons, we characterized the efferent projections of DMH-NPY neurons using the anterograde tracer biotinylated dextran amine (BDA) in lactating rats and DIO mice. In both models, BDA- and NPY-colabeled fibers were limited mainly to the hypothalamus, including the paraventricular nucleus of the hypothalamus (PVH), lateral hypothalamus/perifornical area (LH/PFA), and anteroventral periventricular nucleus (AVPV). Specifically in lactating rats, BDA-and NPY-colabeled axonal swellings were in close apposition to cocaine- and amphetamine-regulated transcript (CART)-expressing neurons in the PVH and AVPV. Although the DMH neurons project to the rostral raphe pallidus (rRPa), these projections did not contain NPY immunoreactivity in either the lactating rat or the DIO mouse. Instead, the majority of BDA-labeled fibers in the rRPa were orexin positive. Furthermore, DMH-NPY projections were not observed within the nucleus of the solitary tract (NTS), another brainstem site critical for the regulation of sympathetic outflow. The present data suggest that NPY expression in the DMH during chronic hyperphagic conditions plays important roles in feeding behavior and thermogenesis by modulating neuronal functions within the hypothalamus, but not in the brainstem.

Topics: Age Factors; Animals; Animals, Newborn; Biotin; Chronic Disease; Dextrans; Disease Models, Animal; Efferent Pathways; Female; Gonadotropin-Releasing Hormone; Hyperphagia; Hypothalamic Hormones; Hypothalamus; Intracellular Signaling Peptides and Proteins; Lactic Acid; Male; Melanins; Mice; Mice, Inbred C57BL; Nerve Tissue Proteins; Neurons; Neuropeptide Y; Neuropeptides; Obesity; Orexins; Peptide Fragments; Pituitary Hormones; Pregnancy; Rats; Rats, Wistar; Tryptophan Hydroxylase

Twelve weeks of high-fat diet feeding causes ghrelin resistance in arcuate neuropeptide Y (NPY)/agouti-related protein (AgRP) neurons. In the current study, we investigated whether diet-induced weight loss could restore NPY/AgRP neuronal responsiveness to ghrelin and whether ghrelin mediates rebound weight gain after calorie-restricted (CR) weight loss. Diet-induced obese (DIO) mice were allocated to one of two dietary interventions until they reached the weight of age-matched lean controls. DIO mice received chow diet ad libitum or chow diet with 40% CR. Chow-fed and high-fat-fed mice served as controls. Both dietary interventions normalized body weight, glucose tolerance, and plasma insulin. We show that diet-induced weight loss with CR increases total plasma ghrelin, restores ghrelin sensitivity, and increases hypothalamic NPY and AgRP mRNA expression. We propose that long-term DIO creates a higher body weight set-point and that weight loss induced by CR, as seen in the high-fat CR group, provokes the brain to protect the new higher set-point. This adaptation to weight loss likely contributes to rebound weight gain by increasing peripheral ghrelin concentrations and restoring the function of ghrelin-responsive neuronal populations in the hypothalamic arcuate nucleus. Indeed, we also show that DIO ghrelin-knockout mice exhibit reduced body weight regain after CR weight loss compared with ghrelin wild-type mice, suggesting ghrelin mediates rebound weight gain after CR weight loss.

Topics: Agouti-Related Protein; Animals; Arcuate Nucleus of Hypothalamus; Caloric Restriction; Diet, High-Fat; Diet, Reducing; Drug Resistance; Ghrelin; Male; Mice; Neuropeptide Y; Obesity; RNA, Messenger; Weight Gain; Weight Loss

Taurine is an important nutrient in intrauterine life, being required for fetal organ development and cellular renewal of syncytiotrophoblast (STB), the nutrient transport epithelium of the placenta. As taurine is conditionally essential in human pregnancy, the fetal and placental demand for taurine is met by uptake from maternal blood into STB through the activity of TauT. Pre-eclampsia (PE) and maternal obesity are serious complications of pregnancy, associated with fetal growth restriction (FGR) and abnormal renewal of STB, and maternal obesity is a major risk factor for PE. Here we test the hypothesis that STB TauT activity is reduced in maternal obesity and PE compared to normal pregnancy.STB TauT activity, measured in fragments of placental tissue, was negatively related to maternal BMI over the range 18-46 kg/m(2) in both the first trimester (7-12 weeks gestation) and at term (p < 0.01; linear regression). Neither TauT activity nor expression in the first trimester differed to normal pregnancy at term. STB TauT activity was significantly lower in PE than normal pregnancy (p < 0.01). Neuropeptide Y (NPY), a protein kinase C (PKC) activator which is elevated in PE and obesity, reduced STB TauT activity by 20% (50 pM-50 nM: 2 h) (p < 0.03). Activation of PKC by phorbol 12-myristate-13-acetate (1 μM) reduced TauT activity by 18% (p < 0.05). As TauT activity is inhibited by phosphorylation, we propose that NPY activates PKC in the STB which phosphorylates TauT in PE and maternal obesity.Reduced TauT activity could contribute to dysregulated renewal of STB and FGR that are common to PE and maternal obesity.

Topics: Body Mass Index; Female; Humans; Membrane Glycoproteins; Membrane Transport Proteins; Neuropeptide Y; Obesity; Placenta; Pre-Eclampsia; Pregnancy; Pregnancy Trimester, First; Tetradecanoylphorbol Acetate; Trophoblasts

Five to ten percent of women of reproductive age suffer from polycystic ovary syndrome (PCOS). Leptin, NPY, galanin, cholecystokinin (CCK) are involved in the regulation of eating behavior. PPARγ are receptors that are probably involved in hyperandrogenism. This study was designed to assess associations between the Pro12Ala PPARγ2 gene polymorphism and satiety factors in PCOS. Fifty-four PCOS women and 51 healthy women were studied. Leptin, NPY, galanin, CCK levels, and genetic studies to detect Pro12Ala PPARγ2 gene polymorphism were assessed. The leptin levels in the PCOS women carrying Pro12Ala genotype were higher than in those with Pro12Pro and Ala12Ala. The PCOS women had higher leptin and NPY levels and lower galanin levels. Obese PCOS patients had lower CCK levels.. In the PCOS women, a single Ala allele may have a protective role as far as hyperleptinemia is concerned. The PCOS women may reveal a disrupted central leptin/NPY feedback loop with some shifts in food intake.

Topics: Adult; Body Mass Index; Cholecystokinin; Female; Galanin; Genotype; Humans; Hyperandrogenism; Insulin Resistance; Leptin; Neuropeptide Y; Obesity; Polycystic Ovary Syndrome; Polymorphism, Genetic; PPAR gamma; Satiation

Pups of normally nourished dams that are cross-fostered after birth to dams fed a low-protein (8% by weight) diet (postnatal low protein (PLP)) grow slower during the suckling period and remain small and lean throughout adulthood. At weaning, they have increased expression in the arcuate nucleus (ARC) of the hypothalamus of the orexigenic neuropeptide Y (NPY) and decreased expression of pro-opiomelanocortin, the precursor of anorexigenic melanocortins.. We investigated, using third ventricle administration, whether 3-month-old male PLP rats display altered sensitivity to leptin with respect to food intake, NPY and the melanocortin 3/4-receptor agonist MTII, and using in situ hybridization or laser capture microdissection of the ARC followed by RT-PCR, whether the differences observed were associated with changes in the hypothalamic expression of NPY or the leptin receptor, NPY receptors and melanocortin receptors.. PLP rats were smaller and had reduced percentage body fat content and plasma leptin concentration compared with control rats. Leptin (5 μg) reduced food intake over 0-48 h more in PLP than control rats (P<0.05). Submaximal doses of NPY increased the food intake less in PLP rats than in controls, whereas submaximal doses of MTII reduced the food intake more in PLP rats. Maximal responses did not differ between PLP and control rats. Leptin and melanocortin-3 receptor (MC3R) expression were increased in both ARC and ventromedial hypothalamic nuclei in PLP animals compared with the controls. MC4R, NPY Y1R, Y5R and NPY expression were unchanged.. Postnatal undernourishment results in food intake in adult rats being more sensitive to reduction by leptin and melanocortins, and less sensitive to stimulation by NPY. We propose that this contributes to increased leptin sensitivity and resistance to obesity. Increased expression of ObRb and MC3R may partly explain these findings but other downstream mechanisms must also be involved.

Topics: Animals; Animals, Newborn; Arcuate Nucleus of Hypothalamus; Body Weight; Disease Susceptibility; Eating; Gene Expression Regulation; Leptin; Male; Neuropeptide Y; Obesity; Rats; Rats, Wistar; Receptor, Melanocortin, Type 3; Thinness; Time Factors; Weight Gain

Resistance to brain-mediated effects of leptin is a characteristic feature of obesity, resulting from alterations in leptin receptor signaling in hypothalamic neurons and/or transport across the blood-brain-barrier. We have shown previously, that the latter can be circumvented by intranasal (i.n.) application of leptin in lean rats. This prompted us to test i.n. leptin in animals with diet-induced obesity (DIO) as a basis for future human administration. DIO was induced in male Wistar rats by feeding a cafeteria diet for 25 or 32 wk, respectively. Consecutively, these DIO animals (seven to eight per treatment) and standard diet rats (lean) (14-15 per treatment, matched for age and diet duration) were treated with 0.1, 0.2 mg/kg leptin, or control solution i.n. daily for 4 wk before onset of dark period. Energy intake and body weight were measured daily; blood glucose, serum insulin, and leptin were measured before and after treatment. Expression of hypothalamic neuropeptides was assessed by quantitative real-time PCR. We demonstrate, for the first time, that i.n. leptin reduces appetite and induces weight loss in DIO to the same extent as in lean rats. Our findings are supported accordingly by an altered expression pattern of anorexigenic and orexigenic neuropeptides in the hypothalamus, e.g. proopiomelanocortin, cocaine and amphetamine-related transcript, neuropeptide Y, agouti-related protein. It now appears clear that i.n. leptin is effectively acting in obese animals in the same fashion as in their lean counterparts. These findings now clearly warrant studies in humans and may open new perspectives in the treatment of obesity.

Topics: Adipose Tissue; Administration, Intranasal; Agouti-Related Protein; Animals; Appetite; Blood Glucose; Blood-Brain Barrier; Corticotropin-Releasing Hormone; Diet; Energy Intake; Gene Expression; Humans; Hypothalamus; Leptin; Male; Nerve Tissue Proteins; Neuropeptide Y; Obesity; Pro-Opiomelanocortin; Rats; Rats, Wistar; Receptors, Leptin; RNA, Messenger; Signal Transduction; Weight Loss

Obesity can be associated with systemic low-grade inflammation that contributes to obesity-related metabolic disorders. Recent studies raise the possibility that hypothalamic inflammation contributes to the pathogenesis of diet-induced obesity (DIO), while another study reported that obesity decreases the expression of pro-inflammatory cytokines in spleen. The following study examines the hypothesis that obesity suppresses the splenic synthesis of the anti-inflammatory cytokine, interleukin (IL)-10, thereby resulting in chronic hypothalamic inflammation. The results showed that due to oxidative stress or apoptosis, the synthesis of splenic IL-10 was decreased in DIO when compared with non-obesity rats. Splenectomy (SPX) accelerated DIO-induced inflammatory responses in the hypothalamus. Interestingly, SPX suppressed the DIO-induced increases in food intake and body weight and led to a hypothalamic pro-inflammatory state that was similar to that produced by DIO, indicating that hypothalamic inflammation exerts a dual effect on energy metabolism. These SPX-induced changes were inhibited by the systemic administration of IL-10. Moreover, SPX had no effect on hypothalamic inflammatory responses in IL-10-deficient mice. These data suggest that spleen-derived IL-10 plays an important role in the prevention of hypothalamic inflammation and may be a therapeutic target for the treatment of obesity and hypothalamic inflammation.

Topics: Aldehydes; alpha-MSH; Animals; Apoptosis; Area Under Curve; Body Weight; Cytokines; Diet, High-Fat; Disease Models, Animal; Eating; Encephalitis; Hypothalamus; In Situ Nick-End Labeling; Interleukin-10; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Neurons; Neuropeptide Y; Obesity; Oxidative Stress; Oxygen Consumption; Rats; Rats, Sprague-Dawley; Spleen; Splenectomy

We have shown that intrauterine fetal growth restriction (IUGR) newborn rats exhibit hyperphagia, reduced satiety, and adult obesity. Adenosine monophosphate (AMP)-activated protein kinase (AMPK) is a principal metabolic regulator that specifically regulates appetite in the hypothalamic arcuate nucleus (ARC). In response to fasting, upregulated AMPK activity increases the expression of orexigenic (neuropeptide Y [NPY] and agouti-related protein [AgRP]) and decreases anorexigenic (proopiomelanocortin [POMC]) peptides. We hypothesized that IUGR offspring would exhibit upregulated hypothalamic AMPK, contributing to hyperphagia and obesity. We determined AMPK activity and appetite-modulating peptides (NPY and POMC) during fasting and fed conditions in the ARC of adult IUGR and control females. Pregnant rats were fed ad libitum diet (control) or were 50% food restricted from gestation day 10 to 21 to produce IUGR newborns. At 10 months of age, hypothalamic ARC was dissected from fasted (48 hours) and fed control and IUGR females. Arcuate nucleus messenger RNA ([mRNA] NPY, AgRP, and POMC) and protein expression (total and phosphorylated AMPK, Akt) was determined by quantitative reverse transcriptase-polymerase chain reaction and Western Blot, respectively. In the fed state, IUGR adult females demonstrated evidence of persistent appetite stimulation with significantly upregulated phospho (Thr(172))-AMPKα/AMPK (1.3-fold), NPY/AgRP (2.3/1.8-fold) and decreased pAkt/Akt (0.6-fold) and POMC (0.7-fold) as compared to fed controls. In controls though not IUGR adult females, fasting significantly increased pAMPK/AMPK, NPY, and AgRP and decreased pAkt/Akt and POMC. Despite obesity, fed IUGR adult females exhibit upregulated AMPK activity and appetite stimulatory factors, similar to that exhibited by fasting controls. These results suggest that an enhanced appetite drive in both fed and fasting states contributes to hyperphagia and obesity in IUGR offspring.

Topics: Adenylate Kinase; Agouti-Related Protein; Animals; Appetite Regulation; Arcuate Nucleus of Hypothalamus; Blotting, Western; Female; Fetal Growth Retardation; Immunohistochemistry; Neuropeptide Y; Obesity; Pregnancy; Pro-Opiomelanocortin; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

Neuropeptide Y (NPY) is an important neuronal element involved in cardiovascular regulation. Since elevated plasma levels of NPY have been observed in numerous pathological situations, this study aimed to determine whether long-term elevated plasma concentrations of NPY could result in aberrant baroreflex sensitivity. Mini-osmotic pump containing NPY (85 μg per 30 days) was subcutaneously implanted between scapulae in male rats for 4 months. The rats treated with NPY showed the following characters compared with control group: (1) attenuated heart rate responding to the increases in mean arterial blood pressure (MABP) induced by phenylephrine, but enhanced heart rate responding to the decreases in MABP induced by sodium nitroprusside; (2) decreased protein levels of substance P (SP) and GluR2, while increased the expression of γ-aminobutyric acid A receptor (GABA(A)R) in brainstem; (3) abdominal obesity indicated by increased body weight and accumulated fat mass in peritoneal cavity; (4) significant increases in total cholesterol, triglycerides, and low density lipoprotein levels in the periphery. These findings indicate that long-term NPY administration in the periphery leads to abnormal baroreflex sensitivity due, at least in part, to the down-regulated expression of SP/GluR2 and elevated expression of GABA(A)R in both protein and RNA levels, which indicate the alternations in glutamate function and GABA action in the nucleus tractus solitarii in NPY-treated rats. Furthermore, long-term NPY administration results in abdominal obesity and dyslipidemia.

Topics: Animals; Baroreflex; Blood Pressure; Cholesterol; Heart Rate; Lipoproteins, LDL; Male; Neuropeptide Y; Nitroprusside; Obesity; Rats; Rats, Wistar; Receptors, AMPA; Receptors, GABA-A; Substance P; Triglycerides; Weight Gain

AMPK not only acts as a sensor of cellular energy status but also plays a critical role in the energy balance of the body. In this study, LKB1-AMPK signaling was investigated in diet-induced obese (DIO) and diet resistant (DR) rats. In hypothalamus, DIO rats had lower level of LKB1, AMPKα and pAMPKα than chow-fed or DR rats. Both orexigenic peptide NPY and anorexigenic peptide POMC expression were reduced in hypothalamus of DIO rats. i.c.v. injection of AICAR, an activator of AMPK, increased NPY expression but did not alter POMC expression in DIO rats. In periphery, LKB1 protein content and pAMPKα level were lower in the adipose tissue of DIO rats compared to chow-fed and DR rats. Moreover, pAMPKα and LKB1 protein levels obtained from epididymal fat pad were inversely correlated with epididymal fat mass. LKB1 protein content and pAMPKα in skeletal muscle of DIO rats were not different from those in the muscles of chow-fed and DR rats. In summary, DIO rats, but not DR rats, have impaired LKB1-AMPK signaling in hypothalamus and adipose tissue, suggesting the disturbed energy balance observed in DIO rats is related with abnormalities of AMPK signaling in a tissue specific manner.

Topics: Adenylate Kinase; AMP-Activated Protein Kinase Kinases; Animals; Body Fat Distribution; Cell Size; Diet, High-Fat; Epididymis; Gene Expression; Hypothalamus; Intra-Abdominal Fat; Lipid Metabolism; Male; Muscle, Skeletal; Neuropeptide Y; Obesity; Organ Specificity; Protein Serine-Threonine Kinases; Rats; Rats, Sprague-Dawley; Signal Transduction

Prenatal stress, psychologically and metabolically, increases the risk of obesity and diabetes in the progeny. However, the mechanisms of the pathogenesis remain unknown. In adult mice, stress activates NPY and its Y2R in a glucocorticoid-dependent manner in the abdominal fat. This increased adipogenesis and angiogenesis, leading to abdominal obesity and metabolic syndrome which were inhibited by intra-fat Y2R inactivation. To determine whether stress elevates NPY system and accelerates adipogenic potential of embryo, here we "stressed" murine embryonic stem cells (mESCs) in vitro with epinephrine (EPI) during their adipogenic differentiation. EPI was added during the commitment stage together with insulin, and followed by dexamethasone in the standard adipogenic differentiation medium. Undifferentiated embryonic bodies (EBs) showed no detectable expression of NPY. EPI markedly up-regulated the expression NPY and the Y1R at the commitment stage, followed by increased Y2R mRNA at the late of the commitment stage and the differentiation stage. EPI significantly increased EB cells proliferation and expression of the preadipocyte marker Pref-1 at the commitment stage. EPI also accelerated and amplified adipogenic differentiation detected by increasing the adipocyte markers FABP4 and PPARγ mRNAs and Oil-red O-staining at the end of the differentiation stage. EPI-induced adipogenesis was completely prevented by antagonists of the NPY receptors (Y1R+Y2R+Y5R), indicating that it was mediated by the NPY system in mESC's. Taken together, these data suggest that stress may play an important role in programming ESCs for accelerated adipogenesis by altering the stress induced hormonal regulation of the NPY system.

Topics: Adipocytes; Adipogenesis; Animals; Cell Differentiation; Cell Line; Embryonic Stem Cells; Epinephrine; Gene Expression Regulation; Insulin; Mice; Neuropeptide Y; Obesity; Receptors, Neuropeptide Y; Stress, Physiological; Up-Regulation

Neuropeptide Y (NPY) acting in the hypothalamus is one of the most powerful orexigenic agents known. Of the five known Y receptors, hypothalamic Y1 and Y5 have been most strongly implicated in mediating hyperphagic effects. However, knockout of individual Y1 or Y5 receptors induces late-onset obesity--and Y5 receptor knockout also induces hyperphagia, possibly due to redundancy in functions of these genes. Here we show that food intake in mice requires the combined actions of both Y1 and Y5 receptors. Germline Y1Y5 ablation in Y1Y5(-/-) mice results in hypophagia, an effect that is at least partially mediated by the hypothalamus, since mice with adult-onset Y1Y5 receptor dual ablation targeted to the paraventricular nucleus (PVN) of the hypothalamus (Y1Y5(Hyp/Hyp)) also exhibit reduced spontaneous or fasting-induced food intake when fed a high fat diet. Interestingly, despite hypophagia, mice with germline or hypothalamus-specific Y1Y5 deficiency exhibited increased body weight and/or increased adiposity, possibly due to compensatory responses to gene deletion, such as the decreased energy expenditure observed in male Y1Y5(-/-) animals relative to wildtype values. While Y1 and Y5 receptors expressed in other hypothalamic areas besides the PVN--such as the dorsomedial nucleus and the ventromedial hypothalamus--cannot be excluded from having a role in the regulation of food intake, these studies demonstrate the pivotal, combined role of both Y1 and Y5 receptors in the mediation of food intake.

Topics: Adiposity; Aging; Animals; Diet, High-Fat; Energy Metabolism; Fasting; Feeding Behavior; Gene Deletion; Germ Cells; Glucose; Homeostasis; Hypothalamus; Insulin; Mice; Mice, Knockout; Neuropeptide Y; Obesity; Organ Specificity; Receptors, Neuropeptide Y; Signal Transduction; Weight Gain

Dercum's disease (adiposis dolorosa) is characterised by adiposity and chronic pain in the adipose tissue. It has been proposed that conditions encompassing chronic pain have altered concentrations of neuropeptides involved in pain transmission. The aim of this investigation was to examine whether patients with Dercum's disease have abnormal concentrations of different neuropeptides. In cerebrospinal fluid (CSF) and in plasma (P) from 53 patients with Dercum's disease substance P-like immunoreactivity (SP-LI), neuropeptide Y-like immunoreactivity (NPY-LI), β-endorphin-like immunoreactivity (β-END-LI), calcitonin gene-related peptidelike immunoreactivity (CGRP-LI), met-enkephalin-like immunoreactivity (m-ENK-LI), vasoactive intestinal polypeptide-like immunoreactivity (VIP-LI), somatostatin (SOM-LI), γ2-melanocyte-stimulating hormone-like immunoreactivity (γ2-MSH-LI), and dynorphin-like immunoreactivity (DYN-LI) were measured. Three of the substances were also measured in a control group. The CSF concentration of SP was statistically significantly lower in the Dercum group than in the control group, whereas NPY-LI and b-END-LI were borderline statistically significantly lower and higher, respectively, in Dercum patients compared to controls. Compared with reference values, CSF-MSH-LI levels were slightly elevated and CSF-NPY-LI levels were slightly lowered in the Dercum group. The other substances in both CSF and plasma were within the reference values with a high degree of statistical significance. In conclusion, altered levels of neuropeptides that have previously been seen in different pain conditions cannot clearly be demonstrated in Dercum's disease.

Topics: Adiposis Dolorosa; Humans; Neuropeptide Y; Neuropeptides; Obesity; Substance P; Vasoactive Intestinal Peptide

The function of small intestinal monoacylglycerol lipase (MGL) is unknown. Its expression in this tissue is surprising because one of the primary functions of the small intestine is to convert diet-derived MGs to triacylglycerol (TG), and not to degrade them. To elucidate the function of intestinal MGL, we generated transgenic mice that over-express MGL specifically in small intestine (iMGL mice). After only 3 weeks of high fat feeding, iMGL mice showed an obese phenotype; body weight gain and body fat mass were markedly higher in iMGL mice, along with increased hepatic and plasma TG levels compared to wild type littermates. The iMGL mice were hyperphagic and displayed reduced energy expenditure despite unchanged lean body mass, suggesting that the increased adiposity was due to both increased caloric intake and systemic effects resulting in a hypometabolic rate. The presence of the transgene resulted in lower levels of most MG species in intestinal mucosa, including the endocannabinoid 2-arachidonoyl glycerol (2-AG). The results therefore suggest a role for intestinal MGL, and intestinal 2-AG and perhaps other MG species, in whole body energy balance via regulation of food intake as well as metabolic rate.

Topics: Adiposity; Agouti-Related Protein; Animals; Appetite; Arachidonic Acids; Basal Metabolism; Brain; Eating; Endocannabinoids; Energy Metabolism; Glycerides; Intestine, Small; Mice; Mice, Transgenic; Monoacylglycerol Lipases; Neuropeptide Y; Obesity; Polyunsaturated Alkamides; Pro-Opiomelanocortin; Receptor, Cannabinoid, CB1; Triglycerides

Disturbances in the prenatal period are linked to metabolic disorders in adulthood, implying the hypothalamic systems of appetite and energy balance regulation. In order to analyze the central effects of a high-fat-sucrose (HFS) diet in prenatally stressed (PNS) female adult rats, Wistar dams were exposed to chronic-mild-stress during the third week of gestation and were then compared with unstressed controls. Adult female offspring were fed a chow or HFS diet for 10 weeks. Changes in body weight, adiposity as well as expression and methylation levels of selected hypothalamic genes were analyzed. PNS induced lower birthweight and body length with no changes in body fat mass. After the HFS diet, the expected overweight model was observed accompanied by higher adiposity and insulin resistance, which was worsened by PNS. The stress model induced higher energy intake in adulthood. Hypothalamic gene expression analysis revealed that the HFS diet decreased Slc6a3 (dopamine active transporter), NPY (neuropeptide Y) and IR (insulin receptor) and increased POMC (pro-opiomelanocortin). Hypothalamic DNA methylation levels in the promoter region of Slc6a3 revealed that Slc6a3 was hypermethylated by the HFS diet in CpG site -53 bp to the transcription start site. HFS diet also hypermethylated CpG site -167 bp of the POMC promoter only in nonstressed animals. No correlations were found between gene expression and DNA methylation levels. These results imply that early-life stress in females increased predisposition to diet-induced obesity in adulthood.

Topics: Animals; Body Weight; Diet, High-Fat; Disease Susceptibility; Dopamine Plasma Membrane Transport Proteins; Energy Metabolism; Epigenomics; Female; Hypothalamus; Neuropeptide Y; Obesity; Pregnancy; Prenatal Nutritional Physiological Phenomena; Pro-Opiomelanocortin; Rats; Rats, Wistar; Stress, Physiological; Sucrose; Transcriptome

Elevated plasma triglyceride (TG) levels contribute to an atherogenic dyslipidemia that is associated with obesity, diabetes, and metabolic syndrome. Numerous models of obesity are characterized by increased central nervous system (CNS) neuropeptide Y (NPY) tone that contributes to excess food intake and obesity. Previously, we demonstrated that intracerebroventricular (icv) administration of NPY in lean fasted rats also elevates hepatic production of very low-density lipoprotein (VLDL)-TG. Thus, we hypothesize that elevated CNS NPY action contributes to not only the pathogenesis of obesity but also dyslipidemia. Here, we sought to determine whether the effects of NPY on feeding and/or obesity are dissociable from effects on hepatic VLDL-TG secretion. Pair-fed, icv NPY-treated, chow-fed Long-Evans rats develop hypertriglyceridemia in the absence of increased food intake and body fat accumulation compared with vehicle-treated controls. We then modulated CNS NPY signaling by icv injection of selective NPY receptor agonists and found that Y1, Y2, Y4, and Y5 receptor agonists all induced hyperphagia in lean, ad libitum chow-fed Long-Evans rats, with the Y2 receptor agonist having the most pronounced effect. Next, we found that at equipotent doses for food intake NPY Y1 receptor agonist had the most robust effect on VLDL-TG secretion, a Y2 receptor agonist had a modest effect, and no effect was observed for Y4 and Y5 receptor agonists. These findings, using selective agonists, suggest the possibility that the effect of CNS NPY signaling on hepatic VLDL-TG secretion may be relatively dissociable from effects on feeding behavior via the Y1 receptor.

Topics: Animals; Appetite Regulation; Behavior, Animal; Central Nervous System; Humans; Hyperphagia; Infusions, Intraventricular; Lipoproteins, VLDL; Liver; Male; Nerve Tissue Proteins; Neurons; Neuropeptide Y; Obesity; Protein Isoforms; Rats; Rats, Long-Evans; Receptors, Neuropeptide Y; Recombinant Proteins; Signal Transduction; Triglycerides

Maternal deprivation (MD) during neonatal life has diverse long-term effects, including affectation of metabolism. Indeed, MD for 24 hours during the neonatal period reduces body weight throughout life when the animals are maintained on a normal diet. However, little information is available regarding how this early stress affects the response to increased metabolic challenges during postnatal life. We hypothesized that MD modifies the response to a high fat diet (HFD) and that this response differs between males and females. To address this question, both male and female Wistar rats were maternally deprived for 24 hours starting on the morning of postnatal day (PND) 9. Upon weaning on PND22 half of each group received a control diet (CD) and the other half HFD. MD rats of both sexes had significantly reduced accumulated food intake and weight gain compared to controls when raised on the CD. In contrast, when maintained on a HFD energy intake and weight gain did not differ between control and MD rats of either sex. However, high fat intake induced hyperleptinemia in MD rats as early as PND35, but not until PND85 in control males and control females did not become hyperleptinemic on the HFD even at PND102. High fat intake stimulated hypothalamic inflammatory markers in both male and female rats that had been exposed to MD, but not in controls. Reduced insulin sensitivity was observed only in MD males on the HFD. These results indicate that MD modifies the metabolic response to HFD intake, with this response being different between males and females. Thus, the development of obesity and secondary complications in response to high fat intake depends on numerous factors.

Topics: Animals; Animals, Newborn; Blood Glucose; Body Weight; Diet, High-Fat; Eating; Environment; Female; Insulin; Leptin; Male; Maternal Deprivation; Neuropeptide Y; Obesity; Rats; Rats, Wistar; Sex Characteristics; Triglycerides; Weaning; Weight Gain

Metformin demonstrates anorectic effects in vivo and inhibits neuropeptide Y expression in cultured hypothalamic neurons. Here we investigated the mechanisms implicated in the modulation of feeding by metformin in animals rendered obese by long-term high-fat diet (diet-induced obesity [DIO]) and in animals resistant to obesity (diet resistant [DR]). Male Long-Evans rats were kept on normal chow feeding (controls) or on high-fat diet (DIO, DR) for 6 months. Afterward, rats were treated 14 days with metformin (75 mg/kg) or isotonic sodium chloride solution and killed. Energy efficiency, metabolic parameters, and gene expression were analyzed at the end of the high-fat diet period and after 14 days of metformin treatment. At the end of the high-fat diet period, despite higher leptin levels, DIO rats had higher levels of hypothalamic neuropeptide Y expression than DR or control rats, suggesting a central leptin resistance. In DIO but also in DR rats, metformin treatment induced significant reductions of food intake accompanied by decreases in body weight. Interestingly, the weight loss achieved by metformin was correlated with pretreatment plasma leptin levels. This effect was paralleled by a stimulation of the expression of the leptin receptor gene (ObRb) in the arcuate nucleus. These data identify the hypothalamic ObRb as a gene modulated after metformin treatment and suggest that the anorectic effects of the drug are potentially mediated via an increase in the central sensitivity to leptin. Thus, they provide a rationale for novel therapeutic approaches associating leptin and metformin in the treatment of obesity.

Topics: Agouti-Related Protein; Animals; Blood Glucose; Body Weight; Eating; Humans; Hypoglycemic Agents; Hypothalamus; Insulin; Leptin; Male; Metformin; Neuropeptide Y; Obesity; Pro-Opiomelanocortin; Random Allocation; Rats; Rats, Long-Evans; Receptors, Leptin; Reverse Transcriptase Polymerase Chain Reaction; RNA; Statistics, Nonparametric

The underlying mechanisms controlling food intake and satiety are thoroughly controlled, but seem to be insufficient under conditions of almost unlimited food supply. Hence, overweight and obesity are serious problems especially in industrialized countries. To assess the possible influence of CD26, exerting a dipeptidyl peptidase activity (DPP4) cleaving several energy homeostasis-relevant peptides, we investigated wild type and DPP4-deficient dark agouti rats in a model of diet-induced obesity and found a reduced weight gain in DPP4-deficient rats. When investigating the specific increase of whole body fat volume by MRI to assess the distribution pattern (subcutaneous vs. intraabdominal), there was an altered ratio under dietary conditions only in DPP4-deficient rats, which was due to lower intraabdominal fat amounts. Furthermore, we investigated the number of cells immunopositive for the leptin receptor (OB-R), the orexigenic leptin antagonist neuropeptide Y (NPY), as well as of the NPY receptors Y1, Y2, and Y5 within hypothalamic nuclei. Independent from the body weight, higher levels of NPY and all receptors were expressed in DPP4-deficent rats. Under obese conditions, hypothalamic Y2-levels were reduced in both strains. Concerning NPY and Y1, there were partly oppositional effects, with reduced hypothalamic Y1 levels only in wild types, and increased NPY levels only in DPP4-deficient rats. These effects might be responsible for unaltered food intake in DPP4-deficent rats compared to wild types, despite reduced weight gain. However, since the food intake remained unaffected, these effects suggest that DPP4 exerts its effects on intraabdominal fat also via peripheral actions.

Topics: Animals; Appetite Regulation; Dietary Fats; Dipeptidyl Peptidase 4; Disease Models, Animal; Energy Intake; Gene Knockout Techniques; Intra-Abdominal Fat; Male; Neuropeptide Y; Obesity; Rats; Rats, Inbred Strains; Receptors, Neuropeptide Y; Weight Gain

Maternal obesity can influence susceptibility to obesity and type 2 diabetes in progeny. We examined the relationship of maternal insulin resistance (IR), a metabolically important consequence of increased adiposity, to adverse consequences of obesity for fetal development. We used mice heterozygous for a null allele of the insulin receptor (Insr) to study the contributions of maternal IR to offspring phenotype without the potential confound of obesity per se, and how maternal consumption of high-fat diet (HFD) may, independently and interactively, affect progeny. In progeny fed a 60% HFD, body weight and adiposity were transiently (5-7 weeks) increased in wild-type (+/+) offspring of Insr(+/-) HFD-fed dams compared to offspring of wild-type HFD-fed dams. Offspring of HFD-fed wild-type dams had increased body weight, blood glucose, and plasma insulin concentrations compared to offspring of chow-fed wild-type dams. Quantification of proopiomelanocortin (POMC) and neuropeptide-Y (NPY) populations in the arcuate nucleus of the hypothalamus (ARH) of offspring of wild-type vs. Insr(+/-) dams was performed to determine whether maternal IR affects the formation of central feeding circuits. We found a 20% increase in the number of Pomc-expressing cells at postnatal day 9 in offspring of Insr(+/-) dams. In conclusion, maternal HFD consumption-distinct from overt obesity per se-was a major contributor to increased body weight, adiposity, IR, and liver triglyceride (TG) phenotypes in progeny. Maternal IR played a minor role in predisposing progeny to obesity and IR, though it acted synergistically with maternal HFD to exacerbate early obesity in progeny.

Topics: Adiposity; Animals; Blood Glucose; Dietary Fats; Female; Hypothalamus; Insulin; Insulin Resistance; Liver; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Neuropeptide Y; Obesity; Phenotype; Pregnancy; Pregnancy Complications; Prenatal Nutritional Physiological Phenomena; Pro-Opiomelanocortin; Receptor, Insulin; Triglycerides; Weight Gain

Regulation of energy homeostasis is mainly mediated by factors in the hypothalamus and the brainstem. Understanding these regulatory mechanisms is of great clinical relevance in the treatment of obesity and related diseases. The homeobox gene Sax2 is expressed predominantly in the brainstem, in the vicinity of serotonergic neurons, and in the ventral neural tube starting during early development. Previously, we have shown that the loss of function of the Sax2 gene in mouse causes growth retardation starting at birth and a high rate of postnatal lethality, as well as a dramatic metabolic phenotype. To further define the role of Sax2 in energy homeostasis, age-matched adult wild-type, Sax2 heterozygous and null mutant animals were exposed to a high-fat diet. Although food uptake among the different groups was comparable, Sax2 null mutants fed a high-fat diet exhibited a significantly lower weight gain compared to control animals. Unlike their counterparts, Sax2 null mutants did not develop insulin resistance and exhibited significantly lower leptin levels under both standard chow and high-fat diet conditions. Furthermore, neuropeptide Y, an important regulator of energy homeostasis, was significantly decreased in the forebrain of Sax2 null mutants on a high-fat diet. These data strongly suggest a critical role for Sax2 gene expression in diet-induced obesity. Sax2 gene expression may be required to allow the coordinated crosstalk of factors involved in the maintenance of energy homeostasis, possibly regulating the transcription of specific factors involved in energy balance.

Topics: Adipose Tissue, Brown; Adipose Tissue, White; Animals; Blood Glucose; Body Temperature; Body Weight; Brain; Dietary Fats; Eating; Energy Metabolism; Female; Gene Expression; Glycogen; Heterozygote; Homeodomain Proteins; Insulin; Leptin; Lipid Metabolism; Liver; Male; Mice; Mice, 129 Strain; Mice, Inbred C57BL; Mice, Knockout; Mice, Mutant Strains; Neuropeptide Y; Nuclear Proteins; Obesity; Pro-Opiomelanocortin; Serotonin; Sex Characteristics; Transcription Factors

The aim of this study was to demonstrate differential effects of growth hormone (GH) on food intake in lean and obese rats and to investigate whether an anticipated anorectic response in obese rats might be associated with increased lipid oxidation and altered hypothalamic neuropeptide levels. GH (4 mg/kg/day) was administered during 5-21 days to non-obese and obese rats. Whereas GH stimulated food intake in the non-obese rats, the obese animals responded with a significantly (p<0.05) suppressed food intake for 4-5 days. On day 4, the obese rats injected with GH and those injected with vehicle consumed 9.2 ± 0.66 g and 12.7 ± 1.05 g, respectively. The suppression of food intake was associated with significantly (p<0.05) increased lipid oxidation. A similar, but statistically not verified, trend was seen in pair-fed rats not exposed to GH. However, while these animals appeared to economize their energy expenditure, the GH-exposed animals did not, thus creating a significant (p<0.05) difference between these two groups. The increased lipid oxidation and energy expenditure observed in the rats exposed to GH were associated with significantly (p<0.05) decreased levels of hypothalamic galanin (111 ± 33.2 pmol/g vs. those of the pair-fed controls: 228.5 ± 49.4 pmol/g). This difference was, however, not sustained. Thus, on day 21 both hypothalamic galanin and the food intake in the GH group were back to normal. Hypothalamic NPY remained unchanged by GH at all times. In conclusion, the present study suggests that increased lipid oxidation and decreased hypothalamic galanin are components in the mechanism by which GH inhibits food intake in an obese phenotype.

Topics: Animals; Diet, Fat-Restricted; Dietary Fats; Eating; Energy Metabolism; Female; Galanin; Growth Hormone; Hypothalamus; Insulin; Insulin-Like Growth Factor I; Leptin; Lipid Metabolism; Lipids; Neuropeptide Y; Obesity; Oxidation-Reduction; Rats; Rats, Wistar; Thyroid Hormones

Eating rate has recently been shown to influence energy intake and appetite during an ad libitum meal, and alter postprandial secretion of glucagon-like peptide-1 (GLP-1) and peptide-YY (PYY) following a fixed-portion meal. Whether these effects influence satiety, as measured by energy intake at the subsequent meal, is unclear. We manipulated eating rate during a fixed-portion meal in order to examine how eating behavior and associated periprandial and postprandial responses of putative endocrine mediators of appetite would affect energy intake at the following meal in fifteen non-obese (BMI<25 kg/m²) and ten obese (BMI ≥ 30 kg/m²) healthy adult men and women. In random order, each participant consumed a standardized, fixed-portion meal in 7 (FM), 14 (MM) or 28 (SM) minutes. Fullness, measured by the Satiety Labeled Intensity Magnitude (SLIM) scale, serum insulin, glucose, leptin, pancreatic polypeptide (PP), PYY, GLP-1, neuropeptide-Y, and plasma cholecystokinin (CCK) were measured for 3h following the fixed-portion meal. Ad libitum energy intake at the next meal was then measured. Eating slowly delayed time to peak fullness (P ≤ 0.05), but did not alter peak fullness. Peak PP concentrations were attenuated during FM compared to MM and SM (P ≤ 0.05) and were reached earlier during MM compared to SM (P ≤ 0.05). A meal-by-time interaction (P ≤ 0.05), but no differences in AUC, peak, or time to peak were observed for CCK. No additional between meal differences in AUC, peak or time to peak for any endocrine mediator of appetite was observed. Ad libitum energy intake was not different between trials. In conclusion, the rate at which a fixed-portion meal is consumed does not appear to alter satiety despite a small effect on PP and CCK responses.

Topics: Adolescent; Adult; Appetite; Blood Glucose; Cholecystokinin; Eating; Energy Intake; Feeding Behavior; Female; Glucagon-Like Peptide 1; Humans; Insulin; Leptin; Male; Middle Aged; Neuropeptide Y; Obesity; Pancreatic Polypeptide; Peptide YY; Postprandial Period; Satiation; Time Factors

Obesity is a growing epidemic characterized by excess fat storage in adipocytes. Although lipoprotein receptors play important roles in lipid uptake, their role in controlling food intake and obesity is not known. Here we show that the lipoprotein receptor LRP1 regulates leptin signaling and energy homeostasis. Conditional deletion of the Lrp1 gene in the brain resulted in an obese phenotype characterized by increased food intake, decreased energy consumption, and decreased leptin signaling. LRP1 directly binds to leptin and the leptin receptor complex and is required for leptin receptor phosphorylation and Stat3 activation. We further showed that deletion of the Lrp1 gene specifically in the hypothalamus by Cre lentivirus injection is sufficient to trigger accelerated weight gain. Together, our results demonstrate that the lipoprotein receptor LRP1, which is critical in lipid metabolism, also regulates food intake and energy homeostasis in the adult central nervous system.

Topics: Agouti-Related Protein; Animals; Appetite Regulation; Brain; Cell Line; Energy Metabolism; Female; Glucose Intolerance; Homeostasis; Hyperlipidemias; Hypothalamus; Insulin Resistance; Leptin; Lipid Metabolism; Low Density Lipoprotein Receptor-Related Protein-1; Male; Mice; Mice, Knockout; Neuropeptide Y; Obesity; Receptors, LDL; Tumor Suppressor Proteins; Up-Regulation

Storage of excess calories as triglycerides is central to obesity and its associated disorders. Glycerol-3-phosphate acyltransferases (GPATs) catalyze the initial step in acylglyceride syntheses, including triglyceride synthesis. We utilized a novel small-molecule GPAT inhibitor, FSG67, to investigate metabolic consequences of systemic pharmacological GPAT inhibition in lean and diet-induced obese (DIO) mice. FSG67 administered intraperitoneally decreased body weight and energy intake, without producing conditioned taste aversion. Daily FSG67 (5 mg/kg, 15.3 μmol/kg) produced gradual 12% weight loss in DIO mice beyond that due to transient 9- to 10-day hypophagia (6% weight loss in pair-fed controls). Continued FSG67 maintained the weight loss despite return to baseline energy intake. Weight was lost specifically from fat mass. Indirect calorimetry showed partial protection by FSG67 against decreased rates of oxygen consumption seen with hypophagia. Despite low respiratory exchange ratio due to a high-fat diet, FSG67-treated mice showed further decreased respiratory exchange ratio, beyond pair-fed controls, indicating enhanced fat oxidation. Chronic FSG67 increased glucose tolerance and insulin sensitivity in DIO mice. Chronic FSG67 decreased gene expression for lipogenic enzymes in white adipose tissue and liver and decreased lipid accumulation in white adipose, brown adipose, and liver tissues without signs of damage. RT-PCR showed decreased gene expression for orexigenic hypothalamic neuropeptides AgRP or NPY after acute and chronic systemic FSG67. FSG67 given intracerebroventricularly (100 and 320 nmol icv) produced 24-h weight loss and feeding suppression, indicating contributions from direct central nervous system sites of action. Together, these data point to GPAT as a new potential therapeutic target for the management of obesity and its comorbidities.

Topics: Adiposity; Agouti-Related Protein; Animals; Dietary Fats; Disease Models, Animal; Dose-Response Relationship, Drug; Eating; Enzyme Inhibitors; Fatty Liver; Glycerol-3-Phosphate O-Acyltransferase; Insulin Resistance; Mice; Mice, Inbred Strains; Mitochondria, Liver; Neuropeptide Y; Obesity; Oxygen Consumption; Thinness; Triglycerides

Obstructive sleep apnea (OSA) is prevalent in 7.5% in urban Asian Indians. Peroxisome proliferator activated receptor gamma2 (PPARγ2) has been implicated in adipocyte differentiation. Neuropeptide Y (NPY) is also considered as a candidate gene for excess body fat accumulation. The association of PPARγ2 (Pro12Ala)} and NPY (Leu7Pro) gene polymorphisms with OSA has not been studied in Asian Indians.. To study the distribution of PPARγ2 (Pro12Ala) and NPY (Leu7Pro) polymorphism in Asian Indians with and without OSA.. This study was carried out in 252 obese subjects [(body mass index (BMI > 25 kg/m2]; 142 with OSA and 110 without OSA. Measurements included anthropometric and biochemical parameters (fasting blood glucose, lipid profile, various circumferences and skin-fold thicknesses). PPARγ2 (Pro12Ala) and NPY (Leu7Pro) gene} polymorphisms were studied in all subjects. The frequency of the variant allele (Ala12) of PPARγ2 gene was significantly higher in subjects with OSA (14.4%) when compared with subjects without OSA (5.5%; χ2= 9.7; p = 0.001). The distribution of the variant allele (Pro7) of NPY gene was comparable in subjects with OSA (3.5%) and without OSA (3.6%; χ2= 0.001, p = 0.94).. This study reveals a significantly higher frequency of PPARγ2 (Ala12) allele in obese Asian Indians with OSA when compared to obese Asian Indians without OSA.

Topics: Adult; Blood Glucose; Female; Genetic Association Studies; Genotype; Humans; India; Lipids; Male; Middle Aged; Mutation, Missense; Neuropeptide Y; Obesity; Polymorphism, Genetic; PPAR gamma; Sleep Apnea, Obstructive; Sleep Stages

Obesity impairs arcuate (ARC) neuropeptide Y (NPY)/agouti-releated peptide (AgRP) neuronal function and renders these homeostatic neurones unresponsive to the orexigenic hormone ghrelin. In the present study, we investigated the effect of diet-induced obesity (DIO) on feeding behaviour, ARC neuronal activation and mRNA expression following another orexigenic stimulus, an overnight fast. We show that 9 weeks of high-fat feeding attenuates fasting-induced hyperphagia by suppressing ARC neuronal activation and hypothalamic NPY/AgRP mRNA expression. Thus, the lack of appropriate feeding responses in DIO mice to a fast is caused by failure ARC neurones to recognise and/or respond to orexigenic cues. We propose that fasting-induced hyperphagia is regulated not by homeostatic control of appetite in DIO mice, but rather by changes in the reward circuitry.

Topics: Agouti-Related Protein; Animals; Arcuate Nucleus of Hypothalamus; Diet; Diet, Atherogenic; Down-Regulation; Fasting; Feeding Behavior; Hyperphagia; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Neuropeptide Y; Obesity

Hypothalamic neuropeptide Y (NPY) has been implicated in control of energy balance, but the physiological importance of NPY in the dorsomedial hypothalamus (DMH) remains unclear. Here we report that knockdown of NPY expression in the DMH by adeno-associated virus-mediated RNAi reduced fat depots in rats fed regular chow and ameliorated high-fat diet-induced hyperphagia and obesity. DMH NPY knockdown resulted in development of brown adipocytes in inguinal white adipose tissue through the sympathetic nervous system. This knockdown increased uncoupling protein 1 expression in both inguinal fat and interscapular brown adipose tissue (BAT). Consistent with the activation of BAT, DMH NPY knockdown increased energy expenditure and enhanced the thermogenic response to a cold environment. This knockdown also increased locomotor activity, improved glucose homeostasis, and enhanced insulin sensitivity. Together, these results demonstrate critical roles of DMH NPY in body weight regulation through affecting food intake, body adiposity, thermogenesis, energy expenditure, and physical activity.

Topics: Adipocytes, Brown; Adipose Tissue, White; Animals; Body Weight; Cells, Cultured; Dependovirus; Diet, Atherogenic; Down-Regulation; Eating; Energy Metabolism; Glucose; Glucose Tolerance Test; Homeostasis; Hypothalamus; Immunoblotting; Insulin; Ion Channels; Male; Mitochondrial Proteins; Neuropeptide Y; Obesity; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Signal Transduction; Uncoupling Protein 1

To investigate the immunolocalization of the pancreatic polypeptide (PP)-fold peptide family, important regulatory factors for food intake, in the gastrointestinal tract of Suncus murinus, and to discuss the relation with the obesity-resistance, visceral fat accumulation-resistance phenomenon in Suncus murinus.. The gastrointestinal tract of adult Suncus murinus, except for the stomach and pylorus, was divided into five sections (S1, corresponding to the duodenum, S2, S3 and S4, corresponding to the jejunum and ileum, and S5, corresponding to the colon and rectum in other mammals), to investigate the PP family and their receptor-producing cells by means of immunohistochemistry.. NPY, PYY, Y1 and Y4-immunoreactive cells were distributed widely throughout the gastrointestinal tract, moreover, the PP family and their receptor-immunoreactive cells were predominantly distributed at the end of the gastrointestinal tract, the rectum.. In this study, we investigated the distribution of the PP family and their receptor-producing cells in the gastrointestinal tract of Suncus murinus in detail for the first time. It was presumed that the wide distribution of Y4 in the gastrointestinal tract may be related to (associated with) the phenomenon of natural obesity-resistance, visceral fat accumulation-resistance in aging Suncus murinus.

Topics: Animals; Gastric Mucosa; Gastrointestinal Tract; Male; Models, Animal; Neuropeptide Y; Obesity; Pancreatic Polypeptide; Receptors, Cell Surface; Receptors, Neuropeptide Y; Shrews

It has been suggested that nutritional manipulations during the first weeks of life can alter the development of the hypothalamic circuits involved in energy homeostasis. We studied the expression of a large number of the hypothalamic neuropeptide mRNAs that control body weight in mice that were overfed during breastfeeding (mice grown in a small litter, SL) and/or during adolescence (adolescent mice fed a high-fat diet, AHF). We also investigated possible alterations in mRNA levels after 50 days of a high-fat diet (high-fat challenge, CHF) at 19 weeks of age. Both SL and AHF conditions caused overweight during the period of developmental overfeeding. During adulthood, all of the mouse groups fed a CHF significantly gained weight in comparison with mice fed a low-fat diet, but the mice that had undergone both breast and adolescent overfeeding (SL-AHF-CHF mice) gained significantly more weight than the control CHF mice. Of the ten neuropeptide mRNAs studied, only neuropeptide Y (NPY) expression was decreased in all of the groups of developmentally overfed adult mice, but CHF during adulthood by itself induced a decrease in NPY, agouti-related protein (AgRP) and orexin (Orx) mRNA levels. Moreover, in the developmentally overfed CHF mice NPY, AgRP, galanin (GAL) and galanin-like peptide (GalP) mRNA levels significantly decreased in comparison with the control CHF mice. These results show that, during adulthood, hypothalamic neuropeptide systems are altered (NPY) and/or abnormally respond to a high-fat diet (NPY, AgRP, GAL and GalP) in mice overfed during critical developmental periods.

Topics: Agouti-Related Protein; Animals; Animals, Newborn; Body Weight; Diet, Fat-Restricted; Diet, Ketogenic; Dietary Fats; Female; Galanin; Galanin-Like Peptide; Gene Expression; Gene Expression Regulation, Developmental; Hypothalamus; Intracellular Signaling Peptides and Proteins; Male; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Neuropeptide Y; Neuropeptides; Obesity; Orexins; Overnutrition; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

This study tested the effects of (1→3),(1→4) β-D-glucan from oats, on activation of the gut-hypothalamic (PYY₃₋₃₆-NPY) axis, satiety, and weight loss in diet-induced obesity (DIO) mice. DIO mice were fed standard lab chow diets or varied doses of β-glucan for 6 weeks. Energy intake, satiety, body weight changes and peptide Y-Y₃₋₃₆ (PYY₃₋₃₆) were measured together with a satiety test and measurement of neuropeptide Y (NPY) mRNA expression in the hypothalamic arcuate nucleus (Arc). The average energy intake (-13%, p<0.05) and body weight gain was lower with increasing β-glucan over 6 wk with acute suppression of energy intake over 4 h. The highest β-glucan diet significantly increased plasma PYY₃₋₃₆, with suppression of Arc NPY mRNA.

Topics: Animals; Arcuate Nucleus of Hypothalamus; Avena; beta-Glucans; Body Weight; Diet; Dose-Response Relationship, Drug; Energy Intake; Gastrointestinal Tract; Male; Mice; Mice, Inbred C57BL; Neuropeptide Y; Obesity; Peptide Fragments; Peptide YY; RNA, Messenger; Satiety Response

Neuropeptide Y (NPY) produced by arcuate nucleus (ARC) neurons has a strong orexigenic effect on target neurons. Hypothalamic NPY levels undergo wide-ranging oscillations during the circadian cycle and in response to fasting and peripheral hormones (from 0.25 to 10-fold change). The aim of the present study was to evaluate the impact of a moderate long-term modulation of NPY within the ARC neurons on food consumption, body weight gain and hypothalamic neuropeptides. We achieved a physiological overexpression (3.6-fold increase) and down-regulation (0.5-fold decrease) of NPY in the rat ARC by injection of AAV vectors expressing NPY and synthetic microRNA that target the NPY, respectively. Our work shows that a moderate overexpression of NPY was sufficient to induce diurnal over-feeding, sustained body weight gain and severe obesity in adult rats. Additionally, the circulating levels of leptin were elevated but the immunoreactivity (ir) of ARC neuropeptides was not in accordance (POMC-ir was unchanged and AGRP-ir increased), suggesting a disruption in the ability of ARC neurons to response to peripheral metabolic alterations. Furthermore, a dysfunction in adipocytes phenotype was observed in these obese rats. In addition, moderate down-regulation of NPY did not affect basal feeding or normal body weight gain but the response to food deprivation was compromised since fasting-induced hyperphagia was inhibited and fasting-induced decrease in locomotor activity was absent.These results highlight the importance of the physiological ARC NPY levels oscillations on feeding regulation, fasting response and body weight preservation, and are important for the design of therapeutic interventions for obesity that include the NPY.

Topics: Adipocytes; Adipogenesis; Animals; Arcuate Nucleus of Hypothalamus; Cell Size; Dependovirus; Down-Regulation; Eating; Energy Metabolism; Fasting; Feedback, Physiological; Genetic Vectors; HEK293 Cells; Humans; Hyperphagia; Male; MicroRNAs; Neurons; Neuropeptide Y; Obesity; PPAR gamma; Rats; Rats, Wistar; Time Factors; Weight Gain

Sleep and feeding rhythms are highly coordinated across the circadian cycle, but the brain sites responsible for this coordination are unknown. We examined the role of neuropeptide Y (NPY) receptor-expressing neurons in the mediobasal hypothalamus (MBH) in this process by injecting the targeted toxin, NPY-saporin (NPY-SAP), into the arcuate nucleus (Arc). NPY-SAP-lesioned rats were initially hyperphagic, became obese, exhibited sustained disruption of circadian feeding patterns, and had abnormal circadian distribution of sleep-wake patterns. Total amounts of rapid eye movement sleep (REMS) and non-REMS (NREMS) were not altered by NPY-SAP lesions, but a peak amount of REMS was permanently displaced to the dark period, and circadian variation in NREMS was eliminated. The phase reversal of REMS to the dark period by the lesion suggests that REMS timing is independently linked to the function of MBH NPY receptor-expressing neurons and is not dependent on NREMS pattern, which was altered but not phase reversed by the lesion. Sleep-wake patterns were altered in controls by restricting feeding to the light period, but were not altered in NPY-SAP rats by restricting feeding to either the light or dark period, indicating that disturbed sleep-wake patterns in lesioned rats were not secondary to changes in food intake. Sleep abnormalities persisted even after hyperphagia abated during the static phase of the lesion. Results suggest that the MBH is required for the essential task of integrating sleep-wake and feeding rhythms, a function that allows animals to accommodate changeable patterns of food availability. NPY receptor-expressing neurons are key components of this integrative function.

Topics: Animals; Arcuate Nucleus of Hypothalamus; Caloric Restriction; Circadian Rhythm; Corticosterone; Eating; Feeding Behavior; Hyperphagia; In Situ Hybridization; Male; Neurons; Neuropeptide Y; Obesity; Photoperiod; Rats; Rats, Sprague-Dawley; Receptors, Neuropeptide Y; Saponins; Sleep; Sleep Wake Disorders; Sleep, REM; Time Factors; Wakefulness

Progranulin (PGRN) is a secreted glycoprotein with multiple biological functions, including modulation of wound healing and inflammation. Hypothalamic PGRN has been implicated in the development of sexual dimorphism. In the present study, a potential role for PGRN in the hypothalamic regulation of appetite and body weight was investigated. In adult rodents, PGRN was highly expressed in periventricular tanycytes and in hypothalamic neurons, which are known to contain glucose-sensing machinery. Hypothalamic PGRN expression levels were decreased under low-energy conditions (starvation and 2-deoxy-D-glucose administration) but increased under high-energy condition (postprandially). Intracerebrovetricular administration of PGRN significantly suppressed nocturnal feeding as well as hyperphagia induced by 2-deoxyglucose, neuropeptide Y, and Agouti-related peptide. Moreover, the inhibition of hypothalamic PGRN expression or action increased food intake and promoted weight gain, suggesting that endogenous PGRN functions as an appetite suppressor in the hypothalamus. Investigation of the mechanism of action revealed that PGRN diminished orexigenic neuropeptide Y and Agouti-related peptide production but stimulated anorexigenic proopiomelanocortin production, at least in part through the regulation of hypothalamic AMP-activated protein kinase. Notably, PGRN was also expressed in hypothalamic microglia. In diet-induced obese mice, microglial PGRN expression was increased, and the anorectic response to PGRN was blunted. These findings highlight a physiological role for PGRN in hypothalamic glucose-sensing and appetite regulation. Alterations in hypothalamic PGRN production or action may be linked to appetite dysregulation in obesity.

Topics: Agouti-Related Protein; Animals; Appetite Regulation; Body Weight; Eating; Glucose; Granulins; Hypothalamus; Intercellular Signaling Peptides and Proteins; Mice; Microglia; Neuropeptide Y; Obesity; Progranulins

Neuropeptide Y (NPY) increases appetite and food intake in animals. Conflicting evidence has been found for the association between polymorphisms of the NPY gene and obesity in humans.. The objective of the investigation was to study four single-nucleotide polymorphisms (SNPs) in the NPY gene [rs17149106 (G>T), rs16147 (C>T), rs16139 (T>C), rs5574 (C>T)] with body adiposity.. The study design included a candidate gene association study from two cohorts.. Two thousand seventy-one women from the Nurses' Health Study and 1268 men from the Health Professionals Follow-Up study participated in the study.. Weight and height were self-reported at baseline and updated every 2 yr to calculate body mass index (BMI).. Two SNPs (rs17149106 (G>T) and rs16139 (T>C)), with minor allele frequencies of 4%, were associated with elevated risks of obesity (BMI ≥ 30 kg/m(2)) in both cohorts. The pooled adjusted odds ratios [95% confidence interval (CI)] were 1.72 (95% CI 1.20-2.47) and 1.79 (95% CI 1.24-2.60), respectively. Haplotype analyses reflected the associations with the individual SNP. TTCC carriers, with the minor allele of both SNPs, had an increased risk of obesity (odds ratio 1.89; 95% CI 1.29-2.75) compared with those carrying the common haplotype GCTT. Carriers of the rs16139 C allele had greater BMI than noncarriers with a pooled mean difference of +0.58 kg/m(2) (95% CI 0.01-1.15) among women and men. Both rs17149106 and rs16139 were associated with weight gain since adolescence/early adulthood but were not associated with abdominal adiposity as measured by waist circumference and waist to hip ratio.. NPY gene variants were significantly associated with weight changes from young adulthood to middle age and with risk of obesity.

Topics: Adult; Aged; Body Mass Index; Body Weight; Female; Genetic Association Studies; Genetic Predisposition to Disease; Humans; Male; Middle Aged; Neuropeptide Y; Obesity; Polymorphism, Single Nucleotide; Prospective Studies; Waist Circumference; Waist-Hip Ratio

Obesity poses a serious problem to human population as it increases the risk of diabetes, hypertension, metabolic syndrome. In pregnancy obesity increases the frequency of its complications.. The main aim of the study was to estimate the increase of body mass and insulin and neuropeptide Y concentrations in pregnant women.. The changes of body mass and BMI in women before pregnancy and before delivery and the concentrations of insulin and neuropeptide Y in blood were estimated.. The increase of body mass and BMI during the pregnancy period was higher in the group with high body mass and I stage obesity and increase of insulin concentration depended on increase of the body mass. Higher concentration of NPY was found in the group of women with normal body mass and obese if compared to stages II and III of obesity No correlation between insulin increase and concentration of NPY was found.. In most pregnant women body mass gain is excessive and leads to obesity of different stages. Insulin concentration increases as BMI increases. Neuropeptide Y concentration in the obese women group was lower than in the normal weight group.

Topics: Adult; Body Constitution; Body Mass Index; Female; Humans; Insulin; Neuropeptide Y; Obesity; Pregnancy; Pregnancy Complications; Pregnancy Trimesters; Pregnancy, High-Risk; Prenatal Care; Reference Values; Risk Factors; Women's Health; Young Adult

Neuropeptide Y and its Y receptors are important players in the regulation of energy homeostasis. However, while their functions in feeding regulation are well recognized, functions in other critical aspects of energy homeostasis are largely unknown. To investigate the function of Y1 receptors in the regulation of energy homeostasis, we examined energy expenditure, physical activity, body composition, oxidative fuel selection and mitochondrial oxidative capacity in germline Y1(-/-) mice as well as in a conditional Y1-receptor-knockdown model in which Y1 receptors were knocked down in peripheral tissues of adult mice.. Germline Y1(-/-) mice of both genders not only exhibit a decreased respiratory exchange ratio, indicative of increased lipid oxidation, but interestingly also develop late-onset obesity. However, the increased lipid oxidation is a primary effect of Y1 deletion rather than secondary to increased adiposity, as young Y1(-/-) mice are lean and show the same effect. The mechanism behind this is likely because of increased liver and muscle protein levels of carnitine palmitoyltransferase-1 (CPT-1) and maximal activity of key enzymes involved in beta-oxidation; beta-hydroxyacyl CoA dehydrogenase (betaHAD) and medium-chain acyl-CoA dehydrogenase (MCAD), leading to increased mitochondrial capacity for fatty acid transport and oxidation. These effects are controlled by peripheral Y1-receptor signalling, as adult-onset conditional Y1 knockdown in peripheral tissues also leads to increased lipid oxidation, liver CPT-1 levels and betaHAD activity. Importantly, these mice are resistant to diet-induced obesity.. This work shows the primary function of peripheral Y1 receptors in the regulation of oxidative fuel selection and adiposity, opening up new avenues for anti-obesity treatments by targeting energy utilization in peripheral tissues rather than suppressing appetite by central effects.

Topics: 3-Hydroxyacyl CoA Dehydrogenases; Acyl-CoA Dehydrogenase; Animals; Body Composition; Carnitine O-Palmitoyltransferase; Energy Metabolism; Fatty Acids; Female; Homeostasis; Male; Mice; Mitochondria; Motor Activity; Neuropeptide Y; Obesity; Oxidation-Reduction; Receptors, Neuropeptide Y

The complexity pathogenesis in the nonalcoholic fatty liver disease (NAFLD) involves an interplay between adipokines and neuroendocrine regulation of energy balance, including the role of neuropeptide Y (NPY)/agouti-related protein (AgRP) system. The first aim of this study was to assess the effect of long-term interdisciplinary intervention on NAFLD in obese adolescents, and the second objective was to establish the relationship between NPY/AgRP ratio and adiponectinemia. Fifty-five postpuberty obese adolescents were submitted to interdisciplinary intervention. The group was divided between subjects with and without NAFLD (n = 19 and 36, respectively). Blood samples were collected to measure glycemia, hepatic transaminases, lipid profile, insulin resistance, and sensitivity. Adiponectin, NPY, and AgRP concentrations were measured by enzyme-linked immunosorbent assay. Food intake was measured using 3-day diet records. It was observed at baseline that important clinical parameters including body weight, body mass index, visceral fat, homeostasis model assessment of insulin resistance, quantitative insulin sensitivity check index, triglycerides, very low-density lipoprotein cholesterol, and hepatic transaminases were more altered in NAFLD patients. After the intervention, these parameters, total energy, and macronutrient intake were reduced significantly in both groups. The most important finding was the positive correlation between AgRP and visceral fat in all patients and the negative correlation between NPY/AgRP and adiponectinemia only in NAFLD obese adolescents. The NAFLD patients presented more altered clinical parameters than the non-NAFLD subjects, including the negative correlation between adiponectinemia and NPY/AgRP. These results suggested that NAFLD obese adolescents presented an inflammatory profile that can influence the neuroendocrine regulation of energy balance, suggesting an additional impairment in the weight loss therapy.

Topics: Adiponectin; Adolescent; Agouti-Related Protein; Alanine Transaminase; Aspartate Aminotransferases; Cholesterol; Fatty Liver; Female; gamma-Glutamyltransferase; Humans; Insulin; Intra-Abdominal Fat; Male; Neuropeptide Y; Obesity; Statistics, Nonparametric; Triglycerides; Ultrasonography; Weight Loss; Young Adult

The mechanisms for how saturated fat and sugar-based beverages contribute to human obesity are poorly understood. This paper describes a series of experiments developed to examine the response of hypothalamic neuropeptides to diets rich in sugar and fat, using three different diets: a high-fat high-sugar (HFHS) choice diet with access to chow, saturated fat and a 30% sugar solution; a high-fat (HF) choice diet with access to chow and saturated fat; or to a high-sugar (HS) choice diet with access to chow and a sugar solution.. We first studied caloric intake, body weight gain, hormonal alterations and hypothalamic neuropeptide expression when male Wistar rats were subjected to an HFHS choice, an HF choice or an HS choice diet for 1 week. Next, we studied caloric intake and body weight gain when rats were subjected to the choice diets for 5 weeks. Finally, we measured neuropeptide expression in hepatic vagotomized rats subjected to an HFHS choice, an HF choice or an HS choice diet for 1 week.. In rats on an HF choice diet, plasma leptin concentrations and proopiomelanocortin (POMC) mRNA increased and neuropeptide Y (NPY) mRNA decreased. Rats on an HFHS choice diet showed identical plasma leptin concentrations as rats on an HF choice diet. However, NPY mRNA increased and POMC mRNA decreased. An HS choice diet for 1 week did not alter hypothalamic neuropeptide expression or plasma leptin concentrations. As hormonal changes did not explain the differences in hypothalamic neuropeptide expression between rats on the choice diets, we addressed whether neuronal feedback signals mediated the hypothalamic neuropeptide response. The POMC mRNA response to different diets depended on an intact innervation of liver and upper intestinal tract.. Our data suggest that the specific combination of saturated fat and a 30% sugar solution results in hyperphagia-induced obesity and alters hypothalamic neuropeptide expression, and that the response of the melanocortin system is mediated by the hepatic vagus.

Topics: Animals; Body Weight; Dietary Fats; Dietary Sucrose; Energy Intake; Gene Expression; Hyperphagia; Leptin; Liver; Male; Neuropeptide Y; Obesity; Pro-Opiomelanocortin; Rats; Rats, Wistar

Ghrelin acts as an endocrine link connecting physiological processes regulating food intake, body composition, growth, and energy balance. Ghrelin is the only peptide known to undergo octanoylation. The enzyme mediating this process, ghrelin O-acyltransferase (GOAT), is expressed in the gastrointestinal tract (GI; primary source of circulating ghrelin) as well as other tissues. The present study demonstrates that stomach GOAT mRNA levels correlate with circulating acylated-ghrelin levels in fasted and diet-induced obese mice. In addition, GOAT was found to be expressed in both the pituitary and hypothalamus (two target tissues of ghrelin's actions), and regulated in response to metabolic status. Using primary pituitary cell cultures as a model system to study the regulation of GOAT expression, we found that acylated-ghrelin, but not desacyl-ghrelin, increased GOAT expression. In addition, growth-hormone-releasing hormone (GHRH) and leptin increased, while somatostatin (SST) decreased GOAT expression. The physiologic relevance of these later results is supported by the observation that pituitary GOAT expression in mice lacking GHRH, SST and leptin showed opposite changes to those observed after in vitro treatment with the corresponding peptides. Therefore, it seems plausible that these hormones directly contribute to the regulation of pituitary GOAT. Interestingly, in all the models studied, pituitary GOAT expression paralleled changes in the expression of a dominant spliced-variant of ghrelin (In2-ghrelin) and therefore this transcript may be a primary substrate for pituitary GOAT. Collectively, these observations support the notion that the GI tract is not the only source of acylated-ghrelin, but in fact locally produced des-acylated-ghrelin could be converted to acylated-ghrelin within target tissues by locally active GOAT, to mediate its tissue-specific effects.

Topics: Acyltransferases; Animals; Cells, Cultured; Fasting; Gene Dosage; Gene Expression Regulation, Enzymologic; Ghrelin; Growth Hormone-Releasing Hormone; Hypothalamus; Insulin; Insulin-Like Growth Factor I; Leptin; Membrane Proteins; Mice; Neuropeptide Y; Obesity; Pituitary Gland; RNA, Messenger; Somatostatin; Stomach

Because adipose tissue is highly vascularized, modifying adipose tissue vasculature may provide a novel method for reducing body fat. A peptide sequence that elicits apoptosis of endothelium in white fat potently reduced body weight. We sought to determine how inhibiting adipose tissue vasculature changes key aspects of energy balance regulation and the neuroendocrine system that maintains energy balance.. Lean and obese mice or rats were treated with proapoptotic peptide for 4 or 27 days. Daily energy intake and expenditure were measured in mice on a low- (LFD) or high-fat diet (HFD) and in rats on a HFD. A conditioned taste aversion test was performed to assess whether proapoptotic peptide produces visceral illness. Hypothalamic neuropeptide Y, agouti-related peptide, and proopiomelanocoritin (POMC) mRNA expression and plasma leptin levels were evaluated.. Proapoptotic peptide completely reversed HFD-induced obesity in mice and reduced body weight in mice and rats on a HFD but not in those on a LFD. Fat loss occurred with no change of energy expenditure but reduced food intake that occurred without signs of illness and despite reduced circulating leptin and reduced hypothalamic POMC gene expression, indicating that the decrease in food intake is independent of the action of leptin.. These experiments provide compelling evidence for a previously unknown relationship between the status of adipose tissue vasculature and the regulation of food intake.

Topics: Adipose Tissue; Agouti-Related Protein; Animals; Apoptosis; Body Composition; Body Weight; Diet, Fat-Restricted; Dietary Fats; Eating; Endothelial Cells; Energy Intake; Hypothalamus; Leptin; Mice; Mice, Inbred C57BL; Mice, Obese; Neovascularization, Physiologic; Neuropeptide Y; Obesity; Peptide Fragments; Peptides; Pro-Opiomelanocortin; Rats; RNA, Messenger

The mechanisms linking intrauterine growth retardation (IUGR) with adulthood obesity and diabetes are unclear. These studies investigated energy homeostasis in 8- and 20-wk-old male and female mice subjected to protein deficiency in utero. Pregnant C57BL/6J female mice were fed a protein-deficient diet (6% protein). Undernourished offspring (UO) and controls (CO) were cross-fostered to lactating dams fed a 20% control diet. The 24-h profiles of energy expenditure, feeding behavior, physical activity, and whole-body substrate preference was assessed using 8-wk UO and CO weaned onto control diet. Blood chemistries, glucose tolerance, and expression of genes involved in hepatic lipid and glucose metabolism were analyzed in 8- and 20-wk-old CO and UO fed control or a high-fat diet. UO exhibited IUGR with catch-up growth at 8 wk of age and increased severity of diet-induced obesity and insulin resistance by 20 wk of age. Therefore, fetal malnutrition in the C57BL/6J mouse increases sensitivity to diet-induced obesity. Abnormal daily rhythms in food intake and metabolism, increased lipogenesis, and inflammation preceded obesity in the UO group. Arrhythmic expression of circadian oscillator genes was evident in brain, liver, and muscle of UO at 8 and 20 wk of age. Expression of the clock-associated nuclear receptor and transcription repressor Rev-erbalpha was reduced in liver and muscle of UO. Altered circadian physiology may be symptomatic of the metabolic dysregulation associated with IUGR, and altered feeding behavior and substrate metabolism may contribute to the obese phenotype.

Topics: Adipose Tissue, White; Analysis of Variance; Animals; ARNTL Transcription Factors; Blood Glucose; Brain; Circadian Rhythm; CLOCK Proteins; Eating; Energy Metabolism; Feeding Behavior; Female; Gene Expression; Glucose Tolerance Test; Insulin Resistance; Lipid Metabolism; Liver; Male; Mice; Motor Activity; Muscle, Skeletal; Neuropeptide Y; Obesity; Period Circadian Proteins; Pregnancy; Prenatal Exposure Delayed Effects; Prenatal Nutritional Physiological Phenomena; Pro-Opiomelanocortin; Protein Deficiency; Severity of Illness Index

Little progress has been made to identify the central neuroendocrine pathway involved in the energy intake control in nonalcoholic fatty liver disease (NAFLD) patients.. To assess the influence of orexigenic neuropeptides in the nutritional aspects of NAFLD obese adolescents submitted to a long-term interdisciplinary approach.. Fifty adolescents aged 15-19 years, with body mass index at least 95th percentile, consisting of 25 patients without NAFLD and 25 with NAFLD. The NAFLD diagnosis was determined by ultrasonography. Blood samples were collected to analyze glycemia, hepatic transaminases, and lipid profile. Insulin resistance was estimated by Homeostasis Model Assessment Insulin Resistance Index. Neuropeptide Y (NPY) and agouti related protein concentrations were measured by enzyme-linked immunosorbent assay. Analyses of food intake were made by 3 days recordatory inquiry.. At baseline conditions, the patients with NAFLD had significantly higher values of body mass, body mass index, visceral fat, triglycerides, VLDL-C, and hepatic transaminases. After the long-term intervention, they presented a significant reduction in these parameters. In both the groups, it was observed a significant decrease in energy intake, macronutrients and dietetic cholesterol. Only the patients with NAFLD presented a positive correlation between the saturated fatty acids intake and the orexigenic neuropeptides NPY and agouti related protein, and carbohydrate with NPY. Indeed, it was observed a positive correlation between energy intake, lipid (%) and saturated fatty acids with visceral fat accumulation.. Our findings showed an important influence of diet composition in the orexigenic system, being essential consider that the excessive saturated fatty acids intake could be a determinant factor to increase nonalcoholic fatty liver disease.

Topics: Adolescent; Agouti-Related Protein; Eating; Energy Metabolism; Exercise; Fatty Acids; Fatty Liver; Female; Humans; Intra-Abdominal Fat; Male; Neuropeptide Y; Nutrition Assessment; Obesity; Subcutaneous Fat; Ultrasonography; Young Adult

Surgical intervention produces sustainable weight loss and metabolic improvement in obese individuals. Vertical sleeve gastrectomy (VSG) produces dramatic, sustained weight loss; we investigated whether these changes result from improved sensitivity to leptin.. VSG was performed in Long-Evans rats with diet-induced obesity. Naïve or sham-operated rats, fed either ad libitum or pair-fed with the VSG group, were used as controls. Following surgery, body weights and food intake were monitored. We investigated energy expenditure, meal patterns, leptin sensitivity, and expression of pro-opiomelanocortin/agouti-related peptide/neuropeptide Y in the hypothalamus of the rats.. We observed sustained losses in weight and body fat in male and female rats after VSG. Weight loss persisted after the disappearance of a transient, postsurgical food intake reduction. Resting energy expenditure was similar between control and VSG rats. VSG rats maintained their reduced body weights. However, they responded to a chronic food restriction challenge by overeating, which resulted in prerestriction, rather than pre-VSG, body weights. Consistent with lower adiposity, VSG decreased plasma leptin levels. Although VSG slightly improved leptin's anorectic action, the response was comparable to that observed in controls matched for adiposity by caloric restriction. Changes in hypothalamic neuropeptide expression were consistent with the lower body weight and lower leptin levels but cannot account for the sustained weight loss.. VSG causes sustained reduction in body weight, which results from loss of fat mass. The maintenance of weight loss observed did not result from changes in sensitivity to leptin.

Topics: Agouti-Related Protein; Animals; Eating; Energy Metabolism; Female; Gastrectomy; Leptin; Malabsorption Syndromes; Male; Neuropeptide Y; Obesity; Rats; Rats, Long-Evans; Weight Loss

Carboxypeptidase E (CPE) is a prohormone/proneuropeptide processing enzyme, and mice bearing CPE mutations exhibit an obese and diabetic phenotype. Studies on CPE knockout (KO) mice revealed poor prohormone processing, resulting in deficiencies in peptide hormones/neuropeptides such as insulin, gonadotropin-releasing hormone, and cocaine- and amphetamine-regulated transcript (CART). Here, we show that CPE KO mice, an obese animal model, have low bone mineral density (BMD) accompanied by elevated plasma CTX-1 (carboxy-terminal collagen crosslinks), and osteocalcin, indicators of increased bone turnover. Receptor activator for NF-kappaB ligand (RANKL) expression was elevated approximately 2-fold relative to osteoprotegerin in the femur of KO animals, suggesting increased osteoclastic activity in the KO mice. In the hypothalamus, mature CART, a peptide involved in eating behavior and implicated in bone metabolism, was undetectable. The melanocortin and neuropeptide Y (NPY) systems in the hypothalamus have also been implicated in bone remodeling, since MC4R KO and NPY KO mice have increased BMD. However, reduction of alpha-MSH, the primary ligand of MC4R by up to 94% and the lack of detectable NPY in the hypothalamus of CPE KO do not recapitulate the single-gene KO phenotypes. This study highlights the complex physiological interplay between peptides involved in energy metabolism and bone formation and furthermore suggests the possibility that patients, bearing CPE and CART mutations leading to inactive forms of these molecules, may be at a higher risk of developing osteoporosis.

Topics: Absorptiometry, Photon; alpha-MSH; Animals; Biomarkers; Bone Density; Bone Remodeling; Bone Resorption; Calcium; Carboxypeptidase H; Enzyme-Linked Immunosorbent Assay; Female; Hypothalamus; Male; Mice; Mice, Knockout; Nerve Tissue Proteins; Neuropeptide Y; Obesity; Osteoclasts; Osteoprotegerin; Peptide Hormones; Pituitary Gland, Intermediate; Protein Array Analysis; RANK Ligand

Several studies indicate that maternal undernutrition sensitizes the offspring to the development of metabolic disorders, such as obesity. Using a model of perinatal maternal 50% food-restricted diet (FR50), we recently reported that rat neonates from undernourished mothers exhibit decreased leptin plasma levels associated with alterations of hypothalamic proopiomelanocortin system. The present study aimed at examining the consequences of FR50 on the brain-adipose axis in male rat neonates. Using quantitative RT-PCR array containing 84 obesity-related genes, we demonstrated that most of the genes involved in energy metabolism regulation are expressed in rat gonadal white adipose tissue (WAT) and are sensitive to maternal perinatal undernutrition (MPU). In contrast, hypothalamic gene expression was not substantially affected by MPU. Gene expression of uncoupling protein 1 (UCP1), a marker of brown adipocytes, showed an almost 400-fold stimulation in postnatal day 21 (PND21) FR50 animals, suggesting that their gonadal WAT possesses a brown-like phenotype. This was confirmed by histological and immunoshistochemical procedures, which demonstrated that PND21 FR50 gonadal adipocytes are multilocular, resembling those present in interscapular brown adipose tissue, and exhibit an overexpression of UCP1 and neuropeptide Y (NPY) at the protein level. Control animals contained almost exclusively "classical" unilocular white adipocytes that did not show high UCP1 and NPY labeling. After weaning, FR50 animals exhibited a transient hyperphagia that was associated with the disappearance of brown-like fat pads in PND30 WAT. Our results demonstrate that MPU delays the maturation of gonadal WAT during critical developmental time windows, suggesting that it could have long-term consequences on body weight regulation in the offspring.

Topics: Adipocytes; Adipose Tissue; Adipose Tissue, Brown; Adipose Tissue, White; Animals; Animals, Newborn; Body Weight; Energy Metabolism; Gene Expression; Hypothalamus; Leptin; Male; Malnutrition; Neuropeptide Y; Obesity; Phenotype; Pro-Opiomelanocortin; Proteins; Rats; Rats, Wistar; Reverse Transcriptase Polymerase Chain Reaction; Weaning

To observe the difference in fatty degree, glucose-lipid disorder and adipose-hormones between diet induced obesity (DIO) rats and diet induced obesity resistance (DIO-R) rats, and to explore the effect and acting mechanism of Chinese drugs for strengthening Pi (CD-SP) and those for both strengthening Pi and dissolving phlegm (CD-SPDP) in inhibiting obesity.. Excepting eight rats allocated in the blank control group, the other 54 rats were fed with high-lipid forage for 12 weeks to establish models of obesity. Finally, 30 DIO rats and 8 DIO-R rats (shown by their body weight) were obtained. The DIO rats were divided into three groups, which were given gastric perfusion, respectively, with normal saline (Group A), CD-SP (Group B), and CD-SPDP (Group C). Fourteen weeks later, the animals' body weight (BW), length (BL), blood levels of fasting insulin (FIn), fasting glucose (FBG), triglyceride (TG), cholesterol (TC), leptin (LP), neuropeptide Y (NPY), C-reactive protein (CRP), tumor necrosis factor-alpha(TNF-alpha), adiponectin (AN), and resistin (RS) were measured; insulin resistance index (IRI) was calculated, and the degree of obesity and lipid content in abdominal cavity of rats were estimated. Moreover, the levels of LP, CRP, TNF-alpha, AN and RS in homogenate of rats' adipose tissues (ATH) were determined.. After 12 weeks of high-lipid diet, the BW of DIO rats was higher than that of normal or DIO-R rats. After a 14-week continuous high-lipid diet feeding, in DIO rats, BW, lipid coefficient (LC), and IRI were significantly increased (P<0.01); serum levels of TNF-alpha, LP and AN were lower, NPY was higher, while the ATH levels of LP and AN were lower and TNF-alpha was higher in DIO rats than in DIO-R rats (P<0.05 or P<0.01); blood levels of FBG and lipids in DIO rats showed an increasing trend but was statistically insignificant (P>0.05); no significant difference was found in serum levels of CRP and RS due to the overly high data dispersion. Comparisons of the 3 DIO groups showed that BW, body weight index (BWI), LC and IRI were significantly lowered after treatment (P<0.01) in Group C, while these indexes were not significantly different between Group A and B; the serum levels of TNF-alpha, LP, and AN increased, NPY decreased in Group B and C, ATH levels of LP and AN increased, and TNF-alpha decreased in the two groups; but NPY, LP, and AN in blood and ATH were higher in Group C than those in Group B (P<0.05 or P<0.01).. CD-SPDP could inhibit DIO and IR, showing that the effect is better than that of CD-SP, and its mechanism is related to promotion of LP and AN secretion and elevation of serum NPY.

Topics: Adipokines; Animals; Blood Glucose; C-Reactive Protein; Diet, Atherogenic; Dietary Fats; Drug Evaluation, Preclinical; Drugs, Chinese Herbal; Leptin; Male; Neuropeptide Y; Obesity; Random Allocation; Rats; Rats, Wistar; Syndrome; Tumor Necrosis Factor-alpha

The aim of this study was to evaluate the role of orexigenic and anorexigenic factors in an interdisciplinary weight loss therapy for obese adolescents with symptoms of eating disorders.. Thirty-seven post-pubertal, obese adolescents (14 to 19 years old) with symptoms of eating disorders were submitted to long-term interdisciplinary therapy (1 year). Bulimic and binge eating symptoms were measured using the Bulimic Investigatory Test, Edinburgh, and the Binge Eating Scale respectively. Neuropeptide Y, melanin-concentrating hormone, total ghrelin, alpha-melanocyte stimulating hormone and leptin were measured using radioimmunoassay.. After long-term interdisciplinary therapy, the adolescents showed significantly improved body composition, visceral and subcutaneous fat and reduced symptoms of bulimia and binge eating. Intriguingly, orexigenic peptides were up-regulated after short-term therapy and down-regulated at the end of therapy, whereas the anorexigenic pathway was improved with therapy. Furthermore, after long-term therapy, a negative correlation was observed between leptin concentration and melanin-concentrating hormone.. We suggest that long-term therapy promotes an intrinsic association between weight loss, improvement of eating disorder symptoms and a decrease in orexigenic factors. Together, these results represent a more effective course by which patients can normalise behaviours related to eating disorders as well the actions of hormones involved in energy balance, and thus advance obesity control.. Long-term interdisciplinary therapy was effective to improve anorexigenic and orexigenic factors that influence energy balance and avoid the development of eating disorders in obese adolescents. However, the associations between eating disorders and neuroendocrine factors need to be confirmed in future studies.

Topics: Adolescent; Binge-Eating Disorder; Body Mass Index; Bulimia Nervosa; Energy Intake; Female; Ghrelin; Humans; Hypothalamic Hormones; Male; Melanins; Neuropeptide Y; Obesity; Patient Care Team; Physical Therapy Modalities; Pituitary Hormones; Weight Loss

Neuropeptide Y (NPY) gene has been shown to have a critical role in the regulation of satiety, reproduction, central endocrine and cardiovascular systems. Among the primary functions associated with NPY are its acute effects on feeding behavior and energy expenditure. The aim of this study is to evaluate the relationship between obesity and NPY gene polymorphisms in a South Indian Population.. Three polymorphisms in NPY gene (Leu7Pro, Ser50Ser and A7735G) were analyzed in 263 individuals of an endogamous Kota population. On the basis of body mass index (BMI), they were divided into two groups. Associations were tested using logistic regression and haplotype analyses and linkage disequilibrium (LD).. There was no evidence of deviation from Hardy-Weinberg equilibrium. Logistic regression analysis did not reveal significant association with obesity and NPY single-nucleotide polymorphisms (SNPs) in the present study. All three SNPs were in weak LD with low r (2) values. Haplotype analysis also did not yield significant association between NPY gene and obesity (global P=0.756).. Our study did not validate the association between previously implicated SNPs in NPY gene and obesity in an Indian population. Population-specific validation of putative associations has far reaching implications for the future personal genomics medicine applications.

Topics: Adult; Aged; Aged, 80 and over; Body Mass Index; Genetics, Population; Haplotypes; Humans; India; Linkage Disequilibrium; Logistic Models; Middle Aged; Neuropeptide Y; Obesity; Polymorphism, Single Nucleotide; Young Adult

Energy homeostasis is regulated by a complex interaction of molecules and pathways, and new antiobesity treatments are likely to require multiple pharmacological targeting of anorexigenic or orexigenic pathways to achieve effective loss of excess body weight and adiposity. Cannabinoids, acting via the cannabinoid-1 (CB1) receptor, and neuropeptide Y (NPY) are important modulators of feeding behaviour, energy metabolism and body composition. We investigated the interaction of CB1 and NPY in the regulation of energy homeostasis, hypothesizing that dual blockade of CB1 and NPY signalling will induce greater weight and/or fat loss than that induced by single blockade of either system alone.. We studied the effects of the CB1 antagonist Rimonabant on food intake, body weight, body composition, energy metabolism and bone physiology in wild-type (WT) and NPY knockout (NPY(-/-)) mice. Rimonabant was administered orally at 10 mg/kg body weight twice per day for 3 weeks. Oral Rimonabant was delivered voluntarily to mice via a novel method enabling studies to be carried out in the absence of gavage-induced stress.. Mice with dual blockade of CB1 and NPY signalling (Rimonabant-treated NPY(-/-) mice) exhibited greater reductions in body weight and adiposity than mice with single blockade of either system alone (Rimonabant-treated WT or vehicle-treated NPY(-/-) mice). These changes occurred without loss of lean tissue mass or bone mass. Furthermore, Rimonabant-treated NPY(-/-) mice showed a lower respiratory exchange ratio than that seen in Rimonabant-treated WT or vehicle-treated NPY(-/-) mice, suggesting that this additive effect of dual blockade of CB1 and NPY involves promotion of lipid oxidation. On the other hand, energy expenditure and physical activity were comparable amongst all treatment groups. Interestingly, Rimonabant similarly and transiently reduced spontaneous and fasting-induced food intake in WT and NPY(-/-) mice in the first hour after administration only, suggesting independent regulation of feeding by CB1 and NPY signalling. In contrast, Rimonabant increased serum corticosterone levels in WT mice, but this effect was not seen in NPY(-/-) mice, indicating that NPY signalling may be required for effects of CB1 on the hypothalamo-pituitary-adrenal axis.. Dual blockade of CB1 and NPY signalling leads to additive reductions in body weight and adiposity without concomitant loss of lean body mass or bone mass. An additive increase in lipid oxidation in dual CB1 and NPY blockade may contribute to the effect on adiposity. These findings open new avenues for more effective treatment of obesity via dual pharmacological manipulations of the CB1 and NPY systems.

Topics: Animals; Body Composition; Eating; Energy Metabolism; Homeostasis; Mice; Neuropeptide Y; Obesity; Oxidation-Reduction; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Receptors, Neuropeptide Y; Rimonabant

The neuronal circuits involved in the regulation of feeding behavior and energy expenditure are soft-wired, reflecting the relative activity of the postsynaptic neuronal system, including the anorexigenic proopiomelanocortin (POMC)-expressing cells of the arcuate nucleus. We analyzed the synaptic input organization of the melanocortin system in lean rats that were vulnerable (DIO) or resistant (DR) to diet-induced obesity. We found a distinct difference in the quantitative and qualitative synaptology of POMC cells between DIO and DR animals, with a significantly greater number of inhibitory inputs in the POMC neurons in DIO rats compared with DR rats. When exposed to a high-fat diet (HFD), the POMC cells of DIO animals lost synapses, whereas those of DR rats recruited connections. In both DIO rats and mice, the HFD-triggered loss of synapses on POMC neurons was associated with increased glial ensheathment of the POMC perikarya. The altered synaptic organization of HFD-fed animals promoted increased POMC tone and a decrease in the stimulatory connections onto the neighboring neuropeptide Y (NPY) cells. Exposure to HFD was associated with reactive gliosis, and this affected the structure of the blood-brain barrier such that the POMC and NPY cell bodies and dendrites became less accessible to blood vessels. Taken together, these data suggest that consumption of an HFD has a major impact on the cytoarchitecture of the arcuate nucleus in vulnerable subjects, with changes that might be irreversible due to reactive gliosis.

Topics: Animals; Arcuate Nucleus of Hypothalamus; Diet; Dietary Fats; Female; Gliosis; Hypothalamus; Immunohistochemistry; Male; Melanocortins; Mice; Mice, Inbred C57BL; Mice, Transgenic; Microscopy, Electron; Neurons; Neuropeptide Y; Obesity; Pro-Opiomelanocortin; Rats; Rats, Sprague-Dawley; Synapses; Synaptic Transmission

An increase in brain suppressor of cytokine signaling 3 (SOCS3) has been implicated in the development of both leptin and insulin resistance. Socs3 mRNA is localized throughout the brain, and it remains unclear which brain areas are involved in the effect of SOCS3 levels on energy balance. We investigated the role of SOCS3 expressed in the mediobasal hypothalamus (MBH) in the development of diet-induced obesity in adult rats. Socs3 mRNA was down-regulated by local injection of adeno-associated viral vectors expressing a short hairpin directed against Socs3, after which we determined the response to high-fat high-sucrose choice diet. In contrast to neuronal Socs3 knockout mice, rats with SOCS3 knockdown limited to the MBH showed increased body weight gain, larger amounts of white adipose tissue, and higher leptin concentrations at the end of the experiment. These effects were partly due to the decrease in locomotor activity, as 24 h food intake was comparable with controls. In addition, rats with Socs3 knockdown in the MBH showed alterations in their meal patterns: average meal size in the light period was increased and was accompanied by a compensatory decrease in meal frequency in the dark phase. In addition, neuropeptide Y (Npy) mRNA levels were significantly increased in the arcuate nucleus of Socs3 knockdown rats. Since leptin is known to stimulate Npy transcription in the absence of Socs3, these data suggest that knockdown of Socs3 mRNA limited to the MBH increases Npy mRNA levels, which subsequently decreases locomotor activity and alters feeding patterns.

Topics: Animals; Body Composition; Body Weight; Brain; Down-Regulation; Energy Metabolism; Feeding Behavior; Gene Knockdown Techniques; HEK293 Cells; Humans; Hypothalamus; Insulin; Leptin; Male; Neuropeptide Y; Obesity; Rats; Rats, Wistar; RNA, Messenger; RNA, Small Interfering; Signal Transduction; Suppressor of Cytokine Signaling Proteins; Weight Gain

Topics: Adolescent; Anti-Obesity Agents; Child; Health Promotion; Humans; Lactones; Neuropeptide Y; Obesity; Orlistat; Young Adult

We aimed at exploring the expression of neuropeptide Y (NPY), omentin and visfatin in adipose tissues of adults along with clinical parameters and hormones.. We included 168 adult patients (31 surgical obese patients and 31 surgical controls, 76 non-surgical obese patients, 30 non-surgical controls). We measured plasma NPY (by radioimmunoassay), cortisol (with an electrochemiluminescence immunoassay) and urinary cortisol metabolites (by gas chromatography/mass spectrometry). Expression of NPY, omentin and visfatin in subcutaneous and visceral adipose tissue specimens of the surgical patients was quantified using real-time PCR.. NPY was detectable in adipose tissue specimens and, like plasma NPY concentrations, comparable between groups. Omentin gene expression was higher in visceral than in subcutaneous adipose tissues (p < 0.0001). Visfatin expression was lower in the subcutaneous tissue of obese patients compared with controls (p < 0.05). Cortisol was lower in obese adults compared with controls (136.5 +/- 74.1 vs. 162.2 +/- 56.1 ng/ml; p < 0.05), cortisol metabolites were comparable between groups.. In our obese adults, plasma NPY levels and the glucocorticoid measures were not elevated. Even though the expression of NPY, omentin and visfatin was comparable between obese individuals and controls, we have to consider differences in the total production rate of adipose tissue-derived factors.

Topics: Adult; Cytokines; Endocrine System; Female; Gene Expression; GPI-Linked Proteins; Humans; Hydrocortisone; Intra-Abdominal Fat; Lectins; Male; Middle Aged; Neuropeptide Y; Nicotinamide Phosphoribosyltransferase; Obesity; Subcutaneous Fat

Circulating ghrelin is decreased in obesity, and peripheral ghrelin does not induce food intake in obese mice. We investigated whether ghrelin resistance was a centrally mediated phenomenon involving dysregulated neuropeptide Y (NPY) and agouti-related peptide (AgRP) circuits. We show that diet-induced obesity (DIO) (12 wk) suppresses the neuroendocrine ghrelin system by decreasing acylated and total plasma ghrelin, decreasing ghrelin and Goat mRNA in the stomach, and decreasing expression of hypothalamic GHSR. Peripheral (ip) or central (intracerebroventricular) ghrelin injection was able to induce food intake and arcuate nucleus Fos immunoreactivity in chow-fed but not high-fat diet-fed mice. DIO decreased expression of Npy and Agrp mRNA, and central ghrelin was unable to promote expression of these genes. Ghrelin did not induce AgRP or NPY secretion in hypothalamic explants from DIO mice. Injection of NPY intracerebroventricularly increased food intake in both chow-fed and high-fat diet-fed mice, indicating that downstream NPY/AgRP neural targets are intact and that defective NPY/AgRP function is a primary cause of ghrelin resistance. Ghrelin resistance in DIO is not confined to the NPY/AgRP neurons, because ghrelin did not stimulate growth hormone secretion in DIO mice. Collectively, our data suggests that DIO causes ghrelin resistance by reducing NPY/AgRP responsiveness to plasma ghrelin and suppressing the neuroendocrine ghrelin axis to limit further food intake. Ghrelin has a number of functions in the brain aside from appetite control, including cognitive function, mood regulation, and protecting against neurodegenerative diseases. Thus, central ghrelin resistance may potentiate obesity-related cognitive decline, and restoring ghrelin sensitivity may provide therapeutic outcomes for maintaining healthy aging.

Topics: Agouti-Related Protein; Animals; Arcuate Nucleus of Hypothalamus; Cognition; Diet, Atherogenic; Drug Resistance; Eating; Ghrelin; Goats; Growth Hormone; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Neurons; Neuropeptide Y; Obesity

To explore the potential role of neuropeptide Y (NPY) in the pathophysiological process of hypertension caused by obstructive sleep apnea syndrome (OSAS).. The concentration of serum NPY were measured with radioimmunoassay (RIA) in 417 subjects (97 normotensive controls without OSAS, 113 cases of normotensive with OSAS, 73 cases of hypertensive without OSAS and 134 cases of hypertensive with OSAS. Further, the mean NPY level were compared in four groups and the possible effective factors on NPY were discussed.. (1) The concentration of NPY in four groups were (50.5 +/- 37.2) pmol/L in normal controls, (76.0 +/- 39.9) pmol/L in normotensive with OSAS group, (66.9 +/- 36.2) pmol/L in hypertensive without OSAS group and (86.8 +/- 36.8) pmol/L in hypertensive with OSAS group. Whether the patients with OSAS combined with hypertension or not, the concentration of NPY in the serum raised remarkably compared with those without OSAS and hypertension, the highest level of serum NPY was detected in OSAS combined with hypertension group. (2) Pearson correlation analysis indicated that both SBP and DBP related to the serum NPY significantly in non-OSAS group (AHI <10), while the BMI, abdominal circumference, AHI as well as the lowest level of SaO2 correlated to NPY besides SBP in OSAS group with (AHI > or =10). (3) Multiple linear regression model showed that the abdominal circumference and AHI were contributing factors to SBP, while neck circumference and BMI were contributing factors to DBP. The level of NPY in the serum were significantly affected by AHI and BMI, in which the former one had greater influence.. The increased level of serum NPY may play weakly potential roles in the pathophysiological process of hypertension caused by OSAS.

Topics: Adult; Blood Pressure; Case-Control Studies; Female; Humans; Hypertension; Male; Middle Aged; Neuropeptide Y; Obesity; Sleep Apnea, Obstructive

The leptin receptor (LEPR) is a key gene in the control of food intake and energy homeostasis. The sequence variant LEPR{NM_001024587.1}:c.1987C>T has been associated with growth, fatness, and body composition in several pig populations. The purpose of this work was to confirm the phenotypic effects of this SNP in two new experimental backcrosses involving Iberian, Landrace, and Duroc breeds, and to evaluate the quantitative effects of the SNP on the hypothalamic expression of LEPR and two other downstream genes. Results indicate significant additive effects of the SNP on body weight, back fat thickness, and hypothalamic LEPR gene expression in both populations. Allele T fixed in the Iberian breed is systematically associated with a higher growth and fat deposition and leads to an intense reduction of LEPR hypothalamic expression, providing new functional evidence that supports the causality of the analyzed SNP with respect to previously reported and newly observed phenotypic effects. Also, some effects of the LEPR genotype on neuropeptide Y (NPY) and cocaine- and amphetamine-regulated transcript (CART) genes are detected, although they are conditioned by the breed. Finally, a change in mRNA structure and an increase in free energy is predicted for allele T, agreeing with a cis-acting functional effect on mRNA stability, which also supports the causality hypothesis. The lower expression of the LEPR gene in Iberian pigs fits with obesity by leptin resistance observed in this breed. A reduction in leptin signaling could thus be considered one of the determinants of the obese phenotype characteristic of Iberian breed.

Topics: Animals; Body Composition; Energy Metabolism; Female; Gene Expression Regulation; Genotype; Hypothalamus; Leptin; Linear Models; Male; Nerve Tissue Proteins; Neuropeptide Y; Nucleic Acid Conformation; Obesity; Polymorphism, Single Nucleotide; Receptors, Leptin; RNA, Messenger; Sus scrofa

A previous study demonstrated that ginseng crude saponins prevent obesity induced by a high-fat diet in rats. Ginseng crude saponins are known to contain a variety of bioactive saponins. The present study investigated and compared the antiobesity activity of protopanaxadiol (PD) and protopanaxatriol (PT) type saponins, major active compounds isolated from crude saponins. Male 4-week-old Sprague-Dawley rats were fed with normal diet (N) or high-fat diet (HF). After 5 weeks, the HF diet group was subdivided into the control HF diet, HF diet-PD and HF diet-PT group (50 mg/kg/day, 3 weeks, i.p.). Treatment with PD and PT in the HF diet group reduced the body weight, total food intake, fat contents, serum total cholesterol and leptin to levels equal to or below the N diet group. The hypothalamic expression of orexigenic neuropeptide Y was significantly decreased with PD or PT treatment, whereas that of anorexigenic cholecystokinin was increased, compared with the control HF diet group. In addition, PD type saponins had more potent antiobesity properties than PT saponins, indicating that PD-type saponins are the major components contributing to the antiobesity activities of ginseng crude saponins. The results suggest that the antiobesity activity of PD and PT type saponins may result from inhibiting energy gain, normalizing hypothalamic neuropeptides and serum biochemicals related to the control of obesity.

Topics: Animals; Anti-Obesity Agents; Body Weight; Cholecystokinin; Cholesterol; Eating; Hypothalamus; Leptin; Male; Neuropeptide Y; Obesity; Panax; Rats; Rats, Sprague-Dawley; Sapogenins; Triglycerides

Important and novel roles for neuropeptide Y (NPY) signaling in the control of bone homeostasis have recently been identified, with deletion of either the Y1 or Y2 receptors resulting in a generalized increase in bone formation. Whereas the Y2 receptor-mediated anabolic response is mediated by a hypothalamic relay, the Y1-mediated response is likely mediated by osteoblastic Y1 receptors. The presence of Y1 receptors on osteoblasts and various other peripheral tissues suggests that, in addition to neuronal input, circulating factors may also interact with the Y1-mediated pathways. The skeletal and adipose tissue (peripheral and marrow) responses to Y1 receptor deficiency were examined after (1) leptin deficiency, (2) gonadectomy, and (3) hypothalamic NPY overexpression. Bone formation was consistently increased in intact Y1(-/-) mice. However, the hypogonadism of gonadectomy or leptin deficiency blocked this anabolism in male Y1(-/-) mice, whereas females remained unchanged. The Y1-mediated bone anabolic pathway thus seems to be dependent on the presence of intact androgen signaling. Y1 deficiency also led to increased body weight and/or adiposity in all experimental models, with the exception of male ob/ob, showing a general adipogenic effect of Y1 deficiency that is not dependent on androgens. Interestingly, marrow adipocytes were regulated differently than general adipose depots in these models. Taken together, this interaction represents a novel mechanism for the integration of endocrine and neural signals initiated in the hypothalamus and provides further insight into the coordination of bone and energy homeostasis.

Topics: Adipose Tissue; Adiposity; Animals; Blood Glucose; Body Weight; Bone and Bones; Bone Resorption; Female; Gene Deletion; Gonadal Steroid Hormones; Homeostasis; Leptin; Male; Mice; Neuropeptide Y; Obesity; Osteogenesis; Receptors, Neuropeptide Y; Signal Transduction; Thinness; Weight Gain

In order to identify novel genes involved in appetite and body weight regulation we have developed a microarray based method suitable for detecting small changes in gene expression in discrete groups of hypothalamic neurons. The method is based on a combination of stereological sampling, laser capture microdissection (LCM), PCR based amplification (SuperAmp), and one-color cDNA microarray analysis. To validate the method we assessed and compared fasting induced changes in mRNA levels of Neuropeptide Y (NPY) and proopiomelanocortin (POMC) in the hypothalamic arcuate nucleus (ARC) of diet-induced obese rats using cDNA microarrays, quantitative PCR and in situ hybridization. All methods revealed statistically significant fasting-induced changes in NPY and POMC expression. An additional 3480 differentially expressed probes (fold change >1.22, t-test p=0.05) were identified in the microarray analysis. Our findings demonstrate a consistent gene expression pattern across three different gene expression detection methods and strongly suggest that LCM coupled microarray analysis combined with SuperAmp can be used as a semi-quantitative mRNA profiling tool. Importantly, the sensitivity of the method greatly improves the usefulness of the microarray technology for gene expression profiling in non-homogeneous tissues such as the brain.

Topics: Analysis of Variance; Animals; Arcuate Nucleus of Hypothalamus; Dietary Fats; Fasting; Gene Expression Profiling; Gene Expression Regulation; Male; Microarray Analysis; Microdissection; Neuropeptide Y; Obesity; Pro-Opiomelanocortin; Rats; RNA, Messenger; Transcription, Genetic

Key appetite regulators and their receptors are already present in the fetal hypothalamus, and may respond to hormones such as leptin. Intrauterine food restriction or hyperglycemia can reprogram these circuits, possibly predisposing individuals to adverse health outcomes in adulthood. Given the global obesity epidemic, maternal overweight and obesity is becoming more prevalent. Earlier, we observed rapid growth of pups from obese dams during the suckling period. However, it is unclear whether this is because of alterations in leptin and hypothalamic appetite regulators at birth.. Female Sprague-Dawley rats were fed palatable high-fat diet (HFD) or chow for 5 weeks to induce obesity before mating. The same diet continued during gestation. At day 1, after birth, plasma and hypothalamus were collected from male and female pups.. Body weight and organ mass were recorded. Leptin and insulin levels were measured in the plasma by radioimmunoassay. Hypothalamic mRNA expression of neuropeptide-Y (NPY), pro-opiomelanocortin, leptin receptor and its downstream signal, STAT3 (signal transducer and activator of transcription 3), were measured using real-time PCR.. Body and organ weights of pups from obese dams were similar to those from lean dams, across both genders. However, plasma leptin levels were significantly lower in offspring from obese dams (male: 0.53+/-0.13 vs 1.05+/-0.21 ng ml(-1); female: 0.33+/-0.09 vs 2.12+/-0.57 ng ml(-1), respectively; both P<0.05). Hypothalamic mRNA expression of NPY, pro-opiomelanocortin, leptin receptor and STAT3 were also significantly lower in pups from obese dams.. Long-term maternal obesity, together with lower leptin levels in pups from obese dams may contribute to the lower expression of key appetite regulators on day 1 of life, suggesting altered intrauterine neuron development in response to intrauterine overnutrition, which may contribute to eating disorders later in life.

Topics: Agouti-Related Protein; Animals; Animals, Newborn; Appetite Regulation; Biomarkers; Female; Hypothalamus; Insulin; Leptin; Male; Maternal Nutritional Physiological Phenomena; Neuropeptide Y; Obesity; Pregnancy; Pro-Opiomelanocortin; Rats; Rats, Sprague-Dawley; Receptors, Leptin; RNA, Messenger; Signal Transduction; STAT3 Transcription Factor

Monosodium glutamate (MSG) treatment of neonatal mice results in a selective damage to the arcuate nucleus (ARC) and development of obesity with increased adiposity at sustained body weight in the adulthood. Feeding pattern of the MSG obese mice is unusual. Our previous results showed that after 24-h fasting, MSG mice consumed negligible amount of food in several hours and therefore, it was impossible to register the effect of peptides attenuating food intake such as cholecystokinin (CCK) or cocaine- and amphetamine-regulated transcript (CART) peptide. To overcome this problem, two findings were used: firstly, orexigenic effect of neuropeptide Y (NPY) was attenuated both by CCK or CART peptide in lean fed mice and secondly, orexigenic effect of NPY was preserved in fed rats with MSG obesity. In this study, short-term food intake in fed lean and MSG obese C57BL/6 male mice was measured after simultaneous central administration of orexigenic NPY with either CART peptide or peripherally administered CCK. Anorexigenic action of exogenous CART peptide was preserved in MSG obese mice. On the other hand, satiety effect of exogenous CCK was completely lost in MSG obese mice. In conclusion, effective leptin signaling in ARC is necessary for satiety effect of CCK.

Topics: Animals; Appetite Regulation; Arcuate Nucleus of Hypothalamus; Cholecystokinin; Disease Models, Animal; Male; Mice; Mice, Inbred C57BL; Nerve Tissue Proteins; Neuropeptide Y; Obesity; Sodium Glutamate

Dipeptidyl peptidase IV (DPP-IV) inactivates the incretin hormone glucagon-like peptide. It can also affect the orexigenic hormone neuropeptide Y (NPY(1-36)) which is truncated by DPP-IV to NPY(3-36), as a consequence NPY's affinity changes from receptor Y1, which mediates the antilipolytic function of NPY, to other NPY receptors. Little is known whether DPP-IV inhibitors for the treatment of type 2 diabetic (T2DM) patients could influence these pathways.. To investigate the in vitro effects of NPY with DPP-IV inhibition in isolated abdominal subcutaneous (AbdSc) adipocytes on fat metabolism, and assessment of NPY receptor and DPP-IV expression in adipose tissue (AT).. Ex vivo human AT was taken from women undergoing elective surgery (body mass index: 27.5 (mean +/- s.d.) +/- 5 kg/m2, age: 43.7 +/- 10 years, n = 36). Isolated AbdSc adipocytes were treated with human recombinant (rh)NPY (1-100 nM) with and without DPP-IV inhibitor (1 M); glycerol release and tissue distribution of DPP-IV, Y1 and Y5 messenger RNA (mRNA) were measured and compared between lean and obese subjects.. rhNPY reduced glycerol release, an effect that was further enhanced by co-incubation with a DPP-IV inhibitor [control: 224 (mean +/- s.e.) +/- 37 micromol/l; NPY, 100 nM: 161 +/- 27 micromol/l**; NPY 100 nM/DPP-IV inhibitor, 1 M: 127 +/- 14 micromol/l**; **p < 0.01, n = 14]. DPP-IV was expressed in AbdSc AT and omental AT with relative DPP-IV mRNA expression lower in AbdSc AT taken from obese [77 +/- 6 signal units (SU)] vs. lean subjects (186 +/- 29 SU*, n = 10). Y1 was predominantly expressed in fat and present in all fat depots but higher in obese subjects, particularly the AbdSc AT-depot (obese: 1944 +/- 111 SU vs. lean: 711 +/- 112 SU**, n = 10). NPY appears to be regulated by AT-derived DPP-IV. DPP-IV inhibitors augment the antilipolytic effect of NPY in AT. Further studies are required to show whether this explains the lack of weight loss in T2DM patients treated with DPP-IV inhibitors.

Topics: Adipocytes; Adult; Cells, Cultured; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Female; Glycerol; Humans; Lipolysis; Middle Aged; Neuropeptide Y; Obesity; Recombinant Proteins; Reverse Transcriptase Polymerase Chain Reaction; Subcutaneous Fat, Abdominal

Adipose tissue has been the object of intense research in the field of obesity and diabetes diseases in the last decade. Examination of adipocyte-secreted peptides led to the identification of a unique polypeptide, resistin (RSTN), which has been suggested as a link between obesity and diabetes. RSTN plays a clearly documented role in blocking insulin (INS)-induced hypoglycaemia. As brain injection of INS affects feeding behaviour, we studied the possible interaction between INS and RSTN in food-deprived rats, measuring effects on food intake. In addition, we examined how RSTN might affect neuropeptide Y (NPY)-induced feeding, as studies have shown that rat RSTN can interfere with the NPY system.. Overnight food-deprived rats were injected into the third brain ventricle (3V) with either INS (10 or 20 mUI), RSTN (0.1-0.4 nmol/rat), or saline before access to food. Another group of rats was injected into the 3V with RSTN alone, NPY alone or RSTN plus NPY. Their food intake and body weight were measured.. Our results confirm the hypophagic effect of RSTN on food deprivation-induced food intake, and more importantly, show that RSTN neither potentiates nor blocks the effects of INS on food intake, but does reduce the hyperphagic effect of NPY.. The observation that RSTN does not modify feeding INS-induced hypophagia, but does influence NPY-induced feeding, points to the possibility that RSTN may be involved in control of food intake through an NPY-ergic mechanism as INS.

Topics: Adipose Tissue; Animals; Appetite Regulation; Body Weight; Brain; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Humans; Hyperphagia; Injections, Intraventricular; Insulin; Male; Metabolic Networks and Pathways; Neuropeptide Y; Obesity; Rats; Rats, Wistar; Resistin

Intraventricular administration of glial cell line-derived neurotrophic factor (GDNF) in primate and humans to study Parkinson's disease (PD) has revealed the potential for GDNF to induce weight loss. Our previous data indicate that bilateral continuous hypothalamic GDNF overexpression via recombinant adeno-associated virus (rAAV) results in significant failure to gain weight in young rats and weight loss in aged rats. Based on these previous results, we hypothesized that because the nigrostriatal tract passes through the lateral hypothalamus, motor hyperactivity mediated by nigrostriatal dopamine (DA) may have been responsible for the previously observed effect on body weight. In this study, we compared bilateral injections of rAAV2/5-GDNF in hypothalamus versus substantia nigra (SN) in aged Brown-Norway X Fisher 344 rats. Nigrostriatal GDNF overexpression resulted in significantly greater weight loss than rats treated in hypothalamus. The nigral or hypothalamic GDNF-induced weight loss was unrelated to motor activity levels of the rats, though some of the weight loss could be attributed to a transient reduction in food intake. Forebrain DA levels did not account for the observed effects on body weight, although GDNF-induced increases in nucleus accumbens DA may have partially contributed to this effect in the hypothalamic GDNF-treated group. However, only nigrostriatal GDNF overexpression induced activation of phosphorylated extracellular signal-regulated kinase (p-ERK) in a small population of corticotrophin-releasing factor [corticotrophin-releasing hormone (CRH)] neurons located specifically in the medial parvocellullar division (MPD) of the paraventricular nucleus of the hypothalamus. Activation of these hypothalamic CRH neurons likely accounted for the observed metabolic effects leading to weight loss in obese rats.

Topics: Adiposity; Aging; Animals; Blotting, Western; Body Weight; Catecholamines; Chromatography, High Pressure Liquid; Dependovirus; Dopamine; Eating; Enzyme-Linked Immunosorbent Assay; Glial Cell Line-Derived Neurotrophic Factor; Hypothalamus; Immunohistochemistry; Male; Neuropeptide Y; Obesity; Rats; Rats, Inbred F344; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; Substantia Nigra; Weight Loss

Maternal obesity due to long-term high-fat diet (HFD) consumption leads to faster growth in offspring during suckling, and increased adiposity at 20 days of age. Decreased expression of the orexigenic neuropeptide Y (NPY) and increased anorexigenic proopiomelanocortin (POMC) mRNA expression were observed in the fed state. However, hunger is the major drive to eat and hypothalamic appetite regulators change in response to meals. Therefore, it is important to compare both satiated and fasting states. Female Sprague-Dawley rats (8 weeks old) were fed a cafeteria-style HFD (15.33 kJ/g) or chow for 5 weeks before mating, with the same diet continuing throughout gestation and lactation. At postnatal day 20, male pups were killed either after overnight fasting or in the fed state. Pups from obese dams were hyperphagic during both pre- and postweaning periods. Pups from obese dams had higher hypothalamic mRNA expression of POMC and NPY Y1 receptor, but lower hypothalamic melanocortin-4 receptor (MC4R) and its downstream target single-minded gene 1 (Sim1), in the fed state. Overnight fasting reduced circulating glucose, insulin, and leptin and increased hypothalamic NPY Y1 receptor mRNA in pups from both lean and obese dams. Hypothalamic NPY and agouti-related protein (AgRP) were only increased by fasting in pups from obese dams; reductions in MC4R and Sim1 were only seen in pups from lean dams. At weaning, the suppressed orexigenic signals in offspring from obese dams were normalized after overnight fasting, although anorexigenic signaling appeared impaired in these animals. This may contribute to their hyperphagia and faster growth.

Topics: Agouti-Related Protein; Animals; Animals, Newborn; Appetite Regulation; Basic Helix-Loop-Helix Transcription Factors; Blood Glucose; Disease Models, Animal; Fasting; Female; Hyperphagia; Hypothalamus; Insulin; Leptin; Male; Maternal Nutritional Physiological Phenomena; Neuropeptide Y; Obesity; Pregnancy; Prenatal Exposure Delayed Effects; Pro-Opiomelanocortin; Rats; Rats, Sprague-Dawley; Receptor, Melanocortin, Type 4; Repressor Proteins; RNA, Messenger

The Study of the Effects of Diet on Metabolism and Nutrition (STEDMAN) Project uses comprehensive metabolic profiling to probe biochemical mechanisms of weight loss in humans. Measurements at baseline, 2 and 4 weeks, 6 and 12 months included diet, body composition, metabolic rate, hormones, and 80 intermediary metabolites measured by mass spectrometry. In 27 obese adults in a behavioral weight loss intervention, median weight decreased 13.9 lb over the first 6 months, then reverted towards baseline by 12 months. Insulin resistance (HOMA) was partially ameliorated in the first 6 months and showed sustained improvement at 12 months despite weight regain. Ghrelin increased with weight loss and reverted to baseline, whereas leptin and PYY fell at 6 months and remained persistently low. NPY levels did not change. Factors possibly contributing to sustained improvement in insulin sensitivity despite weight regain include adiponectin (increased by 12 months), IGF-1 (increased during weight loss and continued to increase during weight regain), and visceral fat (fell at 6 months but did not change thereafter). We observed a persistent reduction in free fatty acids, branched chain amino acids, and related metabolites that may contribute to improved insulin action. These findings provide evidence for sustained benefits of weight loss in obese humans and insights into mechanisms.

Topics: Adiponectin; Adult; Behavior Therapy; Biomarkers; Body Weight; Diet; Energy Metabolism; Female; Ghrelin; Humans; Insulin Resistance; Insulin-Like Growth Factor I; Leptin; Middle Aged; Neuropeptide Y; Obesity; Peptide YY; Weight Gain; Weight Loss

Topics: Amyloid; Anti-Obesity Agents; Appetite; Bariatric Surgery; Diabetes Complications; Diabetes Mellitus; Diet, Carbohydrate-Restricted; Fatty Liver; Female; Gastric Emptying; Humans; Insulin; Islet Amyloid Polypeptide; Lipolysis; Male; Neuropeptide Y; Obesity

Calorie restriction (CR), which is thought to be largely dependent on the neuroendocrine system modulated by insulin/insulin-like growth factor-I (IGF-I) and leptin signaling, decreases morbidity and increases lifespan in many organisms. To elucidate whether insulin and leptin sensitivities are indispensable in the metabolic adaptation to CR, we investigated the effects of CR on obese Zucker (fa/fa) rats and lean control (+/+) rats. CR did not fully improve insulin resistance in (fa/fa) rats. Nonetheless, CR induced neuropeptide Y (NPY) expression in the hypothalamic arcuate nucleus and metabolism related gene expression changes in the liver in (fa/fa) rats and (+/+) rats. Up-regulation of NPY augmented plasma corticosterone levels and suppressed pituitary growth hormone (GH) expression, thereby modulating adipocytokine production to induce tissue-specific insulin sensitivity. Thus, central NPY activation via peripheral signaling might play a crucial role in the effects of CR, even in insulin resistant and leptin receptor deficient conditions.

Topics: Animals; Arcuate Nucleus of Hypothalamus; Body Weight; Caloric Restriction; Gene Expression Regulation; Ghrelin; Gluconeogenesis; Growth Hormone; Hepatocyte Nuclear Factor 4; Insulin; Leptin; Liver; Mitochondria; Nerve Degeneration; Neuropeptide Y; Obesity; Oxidation-Reduction; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Pituitary Gland; Protein Binding; Rats; Rats, Zucker; Receptors, Leptin; RNA-Binding Proteins; Thinness; Transcription Factors

Increasing evidence suggests that the renin-angiotensin-system contributes to the etiology of obesity. To evaluate the role of the renin-angiotensin-system in energy and glucose homeostasis, we examined body weight and composition, food intake, and glucose tolerance in rats given the angiotensin-converting enzyme inhibitor, captopril ( approximately 40 mg/kg . d). Rats given captopril weighed less than controls when fed a high-fat diet (369.3 +/- 8.0 vs. 441.7 +/- 8.5 g after 35 d; P < 0.001) or low-fat chow (320.1 +/- 4.9 vs. 339.8 +/- 5.1 g after 21 d; P < 0.0001). This difference was attributable to reductions in adipose mass gained on high-fat (23.8 +/- 2.0 vs. 65.12 +/- 8.4 g after 35 d; P < 0.0001) and low-fat diets (12.2 +/- 0.7 vs. 17.3 +/- 1.3 g after 21 d; P < 0.001). Rats given captopril ate significantly less [3110.3 +/- 57.8 vs. 3592.4 +/- 88.8 kcal (cumulative 35 d high fat diet intake); P < 0.001] despite increased in neuropeptide-Y mRNA expression in the arcuate nucleus of the hypothalamus and had improved glucose tolerance compared with free-fed controls. Comparisons with pair-fed controls indicated that decreases in diet-induced weight gain and adiposity and improved glucose tolerance were due, primarily, to decreased food intake. To determine whether captopril caused animals to defend a lower body weight, animals in both groups were fasted for 24 h and subsequently restricted to 20% of their intake for 2 d. When free food was returned, captopril and control rats returned to their respective body weights and elicited comparable hyperphagic responses. These results suggest that angiotensin-converting enzyme inhibition protects against the development of diet-induced obesity and glucose intolerance.

Topics: Adipose Tissue; Administration, Oral; Angiotensin I; Angiotensin-Converting Enzyme Inhibitors; Animals; Body Weight; Captopril; Dietary Fats; Eating; Energy Metabolism; Glucose; Injections, Intraventricular; Injections, Subcutaneous; Male; Neuropeptide Y; Obesity; Peptidyl-Dipeptidase A; Rats; Rats, Long-Evans; Renin; RNA, Messenger

Increasing neuropeptide Y (NPY) signaling in the paraventricular nucleus (PVN) by recombinant adeno-associated virus (rAAV)-mediated overexpression of NPY in rats, results in hyperphagia and obesity in rats. To determine the importance of hyperphagia in the observed obesity phenotype, we pair-fed a group of AAV-NPY-injected rats to AAV-control-injected rats and compared parameters of energy balance to ad libitum fed AAV-NPY-injected rats. For 3 weeks, AAV-NPY-injected rats, received the same amount of food as ad libitum-fed rats injected with control rAAV They did not gain more body weight than these controls. When allowed access to food ad libitum, these AAV-NPY-injected rats increased food intake, which subsequently decreased when rats reached the same body weight as AAV-NPY-injected rats that were fed ad libitum for the entire study. These data indicate that overexpression of NPY in the PVN results in obesity by increasing food intake until a certain body weight is achieved.

Topics: Adenoviridae; Animals; Body Temperature; Body Weight; Disease Models, Animal; Eating; Hyperphagia; Injections; Male; Neuropeptide Y; Obesity; Paraventricular Hypothalamic Nucleus; Rats; Rats, Wistar

Weight regain after weight loss is a major hurdle for combating obesity. The aim of this study is to examine orexigenic and anorectic neuropeptides of the hypothalamic arcuate nucleus (Arc) in response to weight loss after chronic energy intake restriction. Thirty mice were fed with a high-fat diet for 8 weeks and then classified as diet-induced obese (DIO; n=10) or diet-resistant (DR; n=10) mice according to the highest and lowest body weight gainers. Five mice from DIO and DR groups were placed on an energy restricted diet or continued on their high-fat diet ad libitum for 6 weeks. An additional five mice were on a LF diet throughout the course of this study as controls. Results showed that a six-week energy restricted diet completely reversed the increased body weight, fat mass and leptin in the DIO mice to the levels of the LF and DR mice. Arc neuropeptide Y (NPY) and agouti-related protein (AgRP) mRNA expression in DIO mice after obesity reversal were significantly higher than DIO mice without obesity reversal (17%, 47%, both p<0.05), while the Arc pro-opiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART) mRNA showed no difference. Both NPY and AgRP expression in DIO mice were negatively correlated with plasma leptin (R=-0.78, p<0.05; R=-0.72, p<0.05). In conclusion, while chronic energy restriction will lead to weight loss, it can up-regulate hypothalamic orexigenic peptides, which may be an important contributing factor to weight regain after a weight loss program from an energy restricted diet.

Topics: Agouti-Related Protein; Animals; Arcuate Nucleus of Hypothalamus; Body Composition; Body Weight; Diet; Diet, Reducing; Dietary Fats; Leptin; Male; Mice; Mice, Inbred C57BL; Nerve Tissue Proteins; Neuropeptide Y; Obesity; Pro-Opiomelanocortin; RNA, Messenger

Pre- and neonatal overfeeding programmes a permanent obesity disposition and accompanying diabetic and cardiovascular disorders, by unknown mechanisms. We proposed that early overfeeding may alter DNA methylation patterns of hypothalamic promoter regions of genes critically involved in the lifelong regulation of food intake and body weight. We induced neonatal overfeeding by rearing Wistar rats in small litters (SL) and thereafter mapped the DNA methylation status of CpG dinucleotides of gene promoters from hypothalamic tissue, using bisulfite sequencing. Neonatal overfeeding led to rapid early weight gain, resulting in a metabolic syndrome phenotype, i.e. obesity, hyperleptinaemia, hyperglycaemia, hyperinsulinaemia, and an increased insulin/glucose ratio. Accompanying, without group difference to controls, the promoter of the main orexigenic neurohormone, neuropeptide Y, was methylated at low levels (i.e. < 5%). In contrast, in SL rats the hypothalamic gene promoter of the main anorexigenic neurohormone, proopiomelanocortin (POMC), showed hypermethylation (P < 0.05) of CpG dinucleotides within the two Sp1-related binding sequences (Sp1, NF-kappaB) which are essential for the mediation of leptin and insulin effects on POMC expression. Consequently, POMC expression lacked upregulation, despite hyperleptinaemia and hyperinsulinaemia. Accordingly, the extent of DNA methylation within Sp1-related binding sequences was inversely correlated to the quotients of POMC expression/leptin (P = 0.02) and POMC expression/insulin (P < 0.001), indicating functionality of acquired epigenomic alterations. These data for the first time demonstrate a nutritionally acquired alteration of the methylation pattern and, consequently, the regulatory 'set point' of a gene promoter that is critical for body weight regulation. Our findings reveal overfeeding as an epigenetic risk factor of obesity programming and consecutive diabetic and cardiovascular disorders and diseases, in terms of the metabolic syndrome.

Topics: Animals; DNA; DNA Methylation; Epigenesis, Genetic; Gene Expression Regulation; Humans; Hyperphagia; Hypothalamus; Metabolic Diseases; Neuropeptide Y; Obesity; Pro-Opiomelanocortin; Promoter Regions, Genetic; Rats; Rats, Wistar

Orexigenic neuropeptides NPY and AgRP play major roles in feeding and are closely related to obesity and diabetic metabolic syndrome. This study explored the inhibitory effect of rutecarpine on feeding and obesity in high-fat-diet-induced (C57BL/6) and leptin-deficient (ob/ob) obese mice. Both mice strains developed obesity, but the obesity was inhibited by the reduced food intake resulting from rutecarpine treatment (0.01%, p<0.01). Blood cholesterol, non-fasting glucose, insulin, and leptin levels were reduced, compared with the control group. Rutecarpine inhibited the expression of NPY and AgRP in the arcuate nucleus (ARC) of the hypothalamus and suppressed the expression of both neuropeptides in N29-4 neuronal cells. These results indicate that rutecarpine ameliorates obesity by inhibiting food intake, which involves inhibited expression of the orexigenic neuropeptides NPY and AgRP.

Topics: Agouti-Related Protein; Animals; Cell Line; Down-Regulation; Eating; Hypothalamus; Indole Alkaloids; Mice; Mice, Inbred C57BL; Neurons; Neuropeptide Y; Obesity; Promoter Regions, Genetic; Quinazolines; Weight Gain

Leptin-stimulated Stat3 activation in proopiomelanocortin (POMC)-expressing neurons of the hypothalamus plays an important role in maintenance of energy homeostasis. While Stat3 activation in POMC neurons is required for POMC expression, the role of elevated basal Stat3 activation as present in the development of obesity has not been directly addressed. Here, we have generated and characterized mice expressing a constitutively active version of Stat3 (Stat3-C) in POMC neurons (Stat3-C(POMC) mice). On normal chow diet, these animals develop obesity as a result of hyperphagia and decreased POMC expression accompanied by central leptin and insulin resistance. This unexpected finding coincides with POMC-cell-specific, Stat3-mediated upregulation of SOCS3 expression inhibiting both leptin and insulin signaling as insulin-stimulated PIP(3) (phosphatidylinositol-3,4,5 triphosphate) formation and protein kinase B (AKT) activation in POMC neurons as well as with the fact that insulin's ability to hyperpolarize POMC neurons is largely reduced in POMC cells of Stat3-C(POMC) mice. These data indicate that constitutive Stat3 activation is not sufficient to promote POMC expression but requires simultaneous PI3K (phosphoinositide 3-kinase)-dependent release of FOXO1 repression. In contrast, upon exposure to a high-fat diet, food intake and body weight were unaltered in Stat3-C(POMC) mice compared with control mice. Taken together, these experiments directly demonstrate that enhanced basal Stat3 activation in POMC neurons as present in control mice upon high-fat feeding contributes to the development of hypothalamic leptin and insulin resistance.

Topics: Agouti-Related Protein; Animals; Body Composition; Body Weight; Disease Models, Animal; Eating; Electrophoretic Mobility Shift Assay; Enzyme-Linked Immunosorbent Assay; Feedback; Gene Expression Regulation; Glucose Tolerance Test; Green Fluorescent Proteins; Hypothalamus; In Vitro Techniques; Insulin; Insulin Resistance; Leptin; Leukemia Inhibitory Factor; Membrane Proteins; Mice; Mice, Transgenic; Neural Inhibition; Neurons; Neuropeptide Y; Obesity; Patch-Clamp Techniques; Phosphatidylinositol 3-Kinases; Pro-Opiomelanocortin; Signal Transduction; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins; Transfection

Using microarray analysis, in situ hybridization and immunocytochemistry, we found that the transcription factor TBX3 is produced in three discrete neuronal populations of the adult mouse brain, the arcuate nucleus (including in NPY but not dopaminergic neurons), the histaminergic tuberomammillary nucleus and in cholinergic neurons of the solitary tract nucleus. The immunoreactive protein had a nuclear location in these neurons, consistent with its function as a transcription factor. Although the function of tbx3 in these neurons is unknown, a review of the literature strongly suggests that these neuronal populations may be abnormal in Ulnar-Mammary syndrome patients with tbx3 mutations, explaining previously overlooked phenotypes in this syndrome, such as obesity, sexual dysfunction and possibly sleep abnormalities.

Topics: Acetylcholine; Animals; Arcuate Nucleus of Hypothalamus; Brain Mapping; Cell Nucleus; Gene Expression Regulation; Hypothalamic Area, Lateral; Immunohistochemistry; Male; Mice; Mice, Inbred C57BL; Neurons; Neuropeptide Y; Obesity; Solitary Nucleus; Syndrome; T-Box Domain Proteins; Transcription Factors

Obesity represents a low-grade inflammatory disease and appears a risk factor for insulin resistance, but little is known on whether this may contribute to the development of autoimmune inflammatory diseases. The aim of this work was to study the early-life diet-induced obesity in Lewis rats which are known to be highly susceptible to autoimmunity.. Obesity was induced by reduced litter size (4 pups per litter) followed by high-fat diet (SHF rats). Control rats (8 pups per litter) were fed with standard diet (CN rats). Oral glucose tolerance test (3 g glucose per kg b.w.) was performed by intra-gastric tube in conscious rats after 12 h fast. Adipocyte size was assessed by light microscope after collagenase digestion. Hypothalamic arcuate (ARC) and paraventricular nuclei (PVN) were isolated by the punching technique. Target mRNAs were quantified by real-time PCR with the use of TaqMan probes and primers. Serum hormones (leptin, ghrelin, adiponectin, visfatin and insulin) were assayed by specific RIAs .. During the experimental period SHF rats had the same body weight gain and caloric intake as CN rats. At the age of 8 weeks SHF rats showed increased epididymal fat mass and adipocyte volume, impaired glucose tolerance, normal basal fasting insulin, visfatin, and ghrelin level, but decreased adiponectin and high leptin level. In the ARC, the SHF rats showed increased expression of mRNA for orexigenic neuropeptide Y (NPY), agouti-related protein (AgRP) and anorexigenic pro-inflammatory cytokine IL-6. In the PVN, the SHF rats showed increased expression of mRNA for anorexigenic melanocortin 4 receptor (MC4R) and IL-6.. Overexpression of orexigenic NPY and AgRP in the ARC indicates leptin resistance in SHF rats. The increased expression of MC4R in PVN points to the activation of melanocortin anorexigenic system which, along with increased hypothalamic IL-6, might prevent the animals from overfeeding. Higher adiposity in these rats results from the high fat-diet composition and not from increased caloric intake. Furthermore, enhanced leptin production appears the main factor indicating the predisposition to autoimmunity in these overfed rats.

Topics: Adipocytes, White; Adiponectin; Adipose Tissue, White; Adiposity; Aging; Agouti-Related Protein; Analysis of Variance; Animals; Appetite Regulation; Arcuate Nucleus of Hypothalamus; Area Under Curve; Body Weight; Cell Size; Dietary Fats; Energy Intake; Feeding Behavior; Gene Expression; Ghrelin; Glucose Intolerance; Insulin; Interleukin-6; Leptin; Litter Size; Male; Neuropeptide Y; Nicotinamide Phosphoribosyltransferase; Obesity; Paraventricular Hypothalamic Nucleus; Rats; Rats, Inbred Lew; Receptor, Melanocortin, Type 4; RNA, Messenger

Hormonal and metabolic factors signal the status of energy balance to hypothalamic nuclei. Obesity is characterized by neuronal, metabolic and hormonal alterations. We therefore hypothesized that hypothalamic responses to challenges of energy balance may differ between lean and obese animals. To test this, we compared c-Fos expression in the hypothalamic arcuate (ARC) and paraventricular nuclei (PVN) and the lateral hypothalamic area (LHA) of mice (1-year-old) with late-onset obesity (LOO) and of lean controls under different feeding conditions. Fourteen hours of fasting induced high c-Fos expression in neuropeptide-Y-positive ARC neurons, in the PVN and in the rostral LHA in lean but not in LOO mice. c-Fos expression in melanin-concentrating hormone (MCH) and orexin-containing neurons in the caudal LHA was not affected by fasting. LOO mice showed fasting hyperinsulinemia, hyperleptinemia, elevated fasting blood glucose and an attenuated hyperphagic response during refeeding. Moreover, the anorectic response to leptin and hypoglycemic response to insulin were reduced in LOO mice. We conclude that adiposity blunts the neuronal responses to metabolic challenges in hypothalamic centers which control feeding behavior and energy balance. Elevated blood glucose may be one factor that suppresses hypothalamic responsiveness in obese mice. A similar impact of hyperinsulinemia and hyperleptinemia in LOO mice is also likely although under the current experimental conditions responsiveness to some effects of these hormones appeared to be reduced.

Topics: Age of Onset; Animals; Arcuate Nucleus of Hypothalamus; Blood Glucose; Fasting; Green Fluorescent Proteins; Hyperinsulinism; Hyperphagia; Hypothalamic Area, Lateral; Intracellular Signaling Peptides and Proteins; Leptin; Male; Melanins; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neurons; Neuropeptide Y; Neuropeptides; Obesity; Orexins; Paraventricular Hypothalamic Nucleus; Proto-Oncogene Proteins c-fos

Currently used antiobesity remedies offer only a modest weight reduction, and have untoward effects that can complicate treatment efforts. Motivated by the needs of the pharmacotherapy of obesity, the study explored the role of neuropeptide Y, leptin, and corticotrophin-releasing hormone.. The study used Ingenuity Pathway Analysis which is a tool for automated discovery and visualization of molecular interactions.. In ingestion-controlling networks, neuropeptide Y, leptin, and corticotrophin-releasing hormone molecules are commonly combined into the units designated as 'maximal motifs'. The analysis of this triad allowed suggesting that maximal motifs are not more than a compendium of admission rules and transmission alternatives of their nodes catalogued in the dataset. Nonetheless, these options seem to endow them with the flexibility needed to respond dynamically as a functional unit to changing internal (metabolic) conditions or environmental challenges.. Thus far, each peptide represents a separate target for pharmaceutical interventions (as judged by US patents scanned). The study concludes with predictions regarding designs of 'multitargeted' antiobesity agents since only by hitting a combination of targets can an appropriate therapeutic effect be achieved.

Topics: Anti-Obesity Agents; Corticotropin-Releasing Hormone; Databases, Factual; Drug Discovery; Humans; Leptin; Models, Theoretical; Neuropeptide Y; Obesity; Polypharmacy

The leucine7 to proline7 (Leu7Pro) polymorphism in preproneuropeptide Y (preproNPY) has been associated with accelerated atherosclerosis and type II diabetes, both of which are obesity-related diseases. The current study evaluated the impact of obesity on the disease risk linked to the Leu7Pro polymorphism of preproNPY in 393 elderly subjects. In 6 years follow-up, the polymorphism alone did not change the risk for abnormal glucose regulation, while obesity was associated with a significant 3-fold risk (odds ratio (OR) 2.95; 95% confidence interval (CI) 1.81-4.81, P<0.001) and the Leu7Pro polymorphism-obesity interaction, with a remarkable 12-fold risk (OR 12.33; 95% CI 1.18-128.35, P<0.05). The Leu7Pro polymorphism modified significantly the 10-year incidence of cardiovascular events, causing a 7.6-fold increase in the hazard ratio (HR 7.58; 95% CI 2.87-20.03, P<0.001) in the obese but not in the nonobese subjects. The results indicate that obesity may be a pivotal factor in multiplying the disease risk associated with the Leu7Pro polymorphism in preproNPY.

Topics: Aged; Blood Glucose; Blood Pressure; Body Mass Index; Body Weight; Cardiovascular Diseases; Diabetes Mellitus; Female; Follow-Up Studies; Glucose Tolerance Test; Humans; Male; Neuropeptide Y; Obesity; Polymorphism, Single Nucleotide; Risk Factors

Neuropeptide Y (NPY) conjugated with a ribosomal inactivating toxin, saporin (SAP), is a toxin that targets NPY receptor-expressing cells. Injection of NPY-SAP into the rat arcuate nucleus (Arc) and basomedial hypothalamus (BMH) destroys two populations of NPY-receptor-expressing neurons important for the control of food intake and body weight, NPY and pro-opiomelanocortin (POMC) and cocaine and amphetamine related transcript (CART) neurons, and produces profound hyperphagia and obesity. Here, we investigated the contribution of lateral hypothalamus (LHA) orexigenic peptides, orexins and melanocortin concentrating hormone (MCH), to these lesion effects. We microinjected NPY-SAP into two sites on each side of the Arc, causing a loss of NPY and POMC/CART neurons that was limited to the Arc. Lesioned rats rapidly became hyperphagic and obese. However, MCH and prepro-orexin mRNA expression were not increased in the LHA in the lesioned rats, but were decreased at some levels of the LHA or were unchanged. NPY-SAP-induced obesity therefore differs from dietary obesity and from obesity associated with leptin or leptin receptor deficiency in which MCH gene expression is increased. The Arc NPY-SAP lesion produces obesity and hyperphagia that does not require overexpression of hypothalamic neuropeptides currently considered to provide major stimulatory drive for food intake: NPY, agouti gene-related protein, MCH or orexins. The source of the seemingly unregulated stimulatory drive for feeding in these animals has not been identified, but may be associated with hindbrain or endocrine mechanisms.

Topics: Animals; Arcuate Nucleus of Hypothalamus; Body Weight; Eating; Female; Hyperphagia; Hypothalamic Area, Lateral; Hypothalamic Hormones; Intracellular Signaling Peptides and Proteins; Male; Melanins; Microinjections; Nerve Tissue Proteins; Neurons; Neuropeptide Y; Neuropeptides; Obesity; Orexins; Pituitary Hormones; Protein Precursors; Rats; Rats, Sprague-Dawley; Up-Regulation

Previous studies suggest that both overfeeding and undernutrition during development increase the risk of obesity and hypertension in adulthood. In this study, we examined both short- (24 d) and long- (16 wk) term effects of early postnatal over- and underfeeding in rats on body weight, body composition, plasma hormones, adiposity markers, and hypothalamic neuropeptide Y content. Cardiovascular changes were also examined by measuring blood pressure and cardiac fibrosis. Rats raised in litters of 3, 12, or 18 pups per mother were used to model early onset overfeeding, control, and underfeeding, respectively. At 24 d of age, pups raised in small litters (SL) were 10% heavier than pups from normal litters, accompanied by increased organ mass and fat mass, elevated plasma leptin, corticosterone, and uncoupling protein-1 mRNA in brown adipose tissue. On the other hand, pups raised in large litters were 17% lighter with no significant changes in plasma leptin. Overfeeding during the first 3 wk of life led to increased plasma leptin concentration in adulthood, whereas underfed rats remained significantly lighter throughout the study, with no evidence of catch-up growth. Rats raised in SL were more susceptible to developing cardiac fibrosis with a 22% increase in collagen deposition compared with control rats at 16 wk of age (P < 0.05). This was independent of any changes in blood pressure. This study demonstrates that nutritional changes early in postnatal development can have long-lasting effects on body weight, adiposity, and some mediators involved in energy homeostasis and can also lead to structural changes in the heart in adulthood. This highlights the importance of identifying potential early life risk factors involved in the modulation of childhood nutrition.

Topics: Adiposity; Aging; Animals; Animals, Newborn; Blood Pressure; Body Weight; Corticosterone; Energy Intake; Female; Fibrosis; Food Deprivation; Heart Diseases; Hyperphagia; Hypothalamus; Insulin; Leptin; Litter Size; Longitudinal Studies; Male; Neuropeptide Y; Obesity; Random Allocation; Rats; Rats, Sprague-Dawley

Under the hypothesis of obesity as a polygenetic disease numerous genes have been associated with an obese phenotype and metabolic co-morbidities. The cannabinoid receptor 1 (CB 1) is part of an underinvestigated system that participates in appetite control. Previous publications suggest that the endocannabinoid systems interact with the better understood leptin-melanocortin axis. Neuropeptide Y (NPY) is a player in the latter. Finally resistin has been shown to influence NPY expression in the brain. In a cohort of 1721 caucasion men and women with a BMI of 25kg/m(2) or more we therefore investigated three candidate polymorphisms at baseline and following 3 months low fat caloric restriction diet by polymerase chain reaction and restriction digestion: the 1359 G/A variant of the cannabinoid receptor 1 (CB1), the L7P variation in neuropeptide Y (NPY) and the -420C>G polymorphism in resistin. Comparing groups according to genotype for each gene separately revealed significant results at baseline only for the CB1 gene. However, upon dieting significant data was found for all 3 genes. Carriers of at least one A allele in CB1 lost more weight and reduced LDL cholesterol more than wildtype patients. LL homocygotes in NPY had a greater reduction in glucose, triglycerides, and LDL cholesterol whereas in resistin carriers of the G allele had a greater reduction in weight and triglycerides. Creating two groups defined by NPY and resistin genotype, respectively, with similar BMI values resulted in significant differences concerning weight loss and metabolic improvement. In conclusion, genetic polymorphisms associated with obesity may become relevant only under the condition of a low calory diet. The presence of a certain genotype may then be beneficial for obesity treatment.

Topics: Adult; Body Mass Index; Cholesterol, LDL; Cohort Studies; Diet, Fat-Restricted; Female; Genetic Variation; Genotype; Humans; Male; Middle Aged; Neuropeptide Y; Obesity; Polymorphism, Genetic; Receptor, Cannabinoid, CB1; Resistin; Weight Loss

In response to stress, some people lose while others gain weight. This is believed to be due to either increased beta-adrenergic activation, the body's main fat-burning mechanism, or increased intake of sugar- and fat-rich "comfort foods." A high-fat, high-sugar (HFS) diet alone, however, cannot account for the epidemic of obesity, and chronic stress alone tends to lower adiposity in mice. Here we discuss how chronic stress, when combined with an HFS diet, leads to abdominal obesity by releasing a sympathetic neurotransmitter, neuropeptide Y (NPY), directly into the adipose tissue. In vitro, when "stressed" with dexamethasone, sympathetic neurons shift toward expressing more NPY, which stimulates endothelial cell (angiogenesis) and preadipocyte proliferation, differentiation, and lipid-filling (adipogenesis) by activating the same NPY-Y2 receptors (Y2Rs). In vivo, chronic stress, consisting of cold water or aggression in HFS-fed mice, stimulates the release of NPY and the expression of Y2Rs in visceral fat, increasing its growth by 50% in 2 weeks. After 3 months, this results in metabolic syndrome-like symptoms with abdominal obesity, inflammation, hyperlipidemia, hyperinsulinemia, glucose intolerance, hepatic steatosis, and hypertension. Remarkably, local intra-fat Y2R inhibition pharmacologically or via adenoviral Y2R knock-down reverses or prevents fat accumulation and metabolic complications. These studies demonstrated for the first time that chronic stress, via the NPY-Y2R pathway, amplifies and accelerates diet-induced obesity and the metabolic syndrome. Our findings also suggest the use of local administration of Y2R antagonists for treatment of obesity and NPY-Y2 agonists for fat augmentation in other clinical applications.

Topics: Adipose Tissue; Animals; Diet; Dietary Carbohydrates; Dietary Fats; Glucocorticoids; Humans; Metabolic Syndrome; Mice; Mice, Inbred C57BL; Neuropeptide Y; Obesity; Receptors, Neuropeptide Y; Stress, Psychological; Weight Gain

Palatable food disrupts normal appetite regulation, which may contribute to the etiology of obesity. Neuropeptide Y (NPY) and cholecystokinin play critical roles in the regulation of food intake and energy homeostasis, while adiponectin and carnitine palmitoyltransferase (CPT) are important for insulin sensitivity and fatty acid oxidation. This study examined the impact of short- and long-term consumption of palatable high-fat diet (HFD) on these critical metabolic regulators.. Male C57BL/6 mice were exposed to laboratory chow (12% fat), or cafeteria-style palatable HFD (32% fat) for 2 or 10 weeks. Body weight and food intake were monitored throughout. Plasma leptin, hypothalamic NPY and cholecystokinin, and mRNA expression of leptin, adiponectin, their receptors and CPT-1, in fat and muscles were measured.. Caloric intake of the palatable HFD group was 2-3 times greater than control, resulting in a 37% higher body weight. Fat mass was already increased at 2 weeks; plasma leptin concentrations were 2.4 and 9 times higher than control at 2 and 10 weeks, respectively. Plasma adiponectin was increased at 10 weeks. Muscle adiponectin receptor 1 was increased at 2 weeks, while CPT-1 mRNA was markedly upregulated by HFD at both time points. Hypothalamic NPY and cholecystokinin content were significantly decreased at 10 weeks.. Palatable HFD induced hyperphagia, fat accumulation, increased adiponectin, leptin and muscle fatty acid oxidation, and reduced hypothalamic NPY and cholecystokinin. Our data suggest that the adaptive changes in hypothalamic NPY and muscle fatty acid oxidation are insufficient to reverse the progress of obesity and metabolic consequences induced by a palatable HFD.

Topics: Adiponectin; Animals; Body Weight; Cholecystokinin; Dietary Fats; Eating; Energy Metabolism; Hyperphagia; Leptin; Male; Mice; Mice, Inbred C57BL; Neuropeptide Y; Obesity; Receptors, Adiponectin; RNA, Messenger

We assessed the effect of early-onset exercise as a means of preventing childhood obesity using juvenile male rats selectively bred to develop diet-induced obesity (DIO) or to be diet resistant (DR) when fed a 31% fat high-energy diet. Voluntary wheel running begun at 36 days of age selectively reduced adiposity in DIO vs. DR rats. Other 4-wk-old DIO rats fed a high-energy diet and exercised (Ex) for 13 wk increased their core temperature, gained 22% less body weight, and had 39% lighter fat pads compared with sedentary (Sed) rats. When wheels were removed after 6 wk (6 wk Ex/7 wk Sed), rats gained less body weight over the next 7 wk than Sed rats and still had comparable adipose pad weights to 13-wk-exercised rats. In fact, only 3 wk of exercise sufficed to prevent obesity for 10 wk after wheel removal. Terminally, the 6-wk-Ex/7-wk-Sed rats had a 55% increase in arcuate nucleus proopiomelanocortin mRNA expression vs. Sed rats, suggesting that this contributed to their sustained obesity resistance. Finally, when Sed rats were calorically restricted for 6 wk to weight match them to Ex rats (6 wk Rstr/7 wk Al), they increased their intake and body weight when fed ad libitum and, after 7 wk more, had higher leptin levels and adiposity than Sed rats. Thus, early-onset exercise may favorably alter, while early caloric restriction may unfavorably influence, the development of the hypothalamic pathways controlling energy homeostasis during brain development.

Topics: Adipose Tissue; Animal Feed; Animals; Body Weight; Brain-Derived Neurotrophic Factor; Caloric Restriction; Eating; Hypothalamus; Insulin; Leptin; Male; Neuropeptide Y; Obesity; Physical Conditioning, Animal; Pro-Opiomelanocortin; Rats; Rats, Inbred Strains; Receptors, Leptin; RNA, Messenger; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins

1. Inhibitors of intestinal glucosidases have been shown to improve glycaemic control in diabetic and obese humans and animals. In the present study, we have investigated the effect of 3 months treatment with acarbose on adiposity, food intake and the modulation of hypothalamic neuropeptide Y (NPY) in obese diabetic Wistar (WDF) rats and the possible correlation between changes in overall insulin sensitivity and the level of circulating adipokines, leptin and adiponectin. In addition, we investigated the effect of acarbose on adipocyte insulin signalling. 2. Mature male WDF rats were randomly distributed to one of three treatment groups (no acarbose or 20 or 40 mg of acarbose/100 g diet). After 3 months, blood glucose, cholesterol, triglyceride, insulin, leptin and adiponectin were analysed. Insulin signalling was determined in isolated adipocytes as the stimulation of mitogen-activated protein kinase (MAPK) and Akt phosphorylation; the level of hypothalamic NPY was assessed by immunohistochemistry. 3. Acarbose-treated rats had lower levels of blood glucose, cholesterol, triglyceride, insulin and leptin and an increase in adiponectin compared with untreated animals. There were no changes in bodyweight and adiposity. Stimulation of adipocyte MAPK activity by insulin was higher in rats treated with both doses of acarbose, whereas higher stimulation of Akt phosphorylation was observed with the highest dose of acarbose. Although food intake was not significantly reduced in rats treated with acarbose, the acarbose-treated rats had lower NPY expression in the arcuate nucleus. 4. We conclude that the improvement in overall insulin sensitivity in WDF rats after prolonged acarbose treatment is paralleled by increases in circulating adiponectin and adipocyte insulin responsiveness. Acarbose neither decreases food intake nor reverts obesity, but decreases leptin levels and the expression of the orexigenic NPY in the hypothalamus.

Topics: Acarbose; Adipocytes; Adiponectin; Animals; Diabetes Mellitus; Dose-Response Relationship, Drug; Drug Administration Schedule; Gene Expression Regulation; Hypoglycemic Agents; Hypothalamus; Insulin; Leptin; Male; Neuropeptide Y; Obesity; Rats; Rats, Wistar

This study examined changes in neuropeptide Y (NPY) Y2 receptor binding in the brains of C57BL/6 mice in response to different levels of high-fat diets via three dietary intervention methods: high-fat diet, switching from high- to low-fat diet and finally, energy restricted high-fat diet. Forty-five C57Bl/6 male mice were fed a high-fat diet for 8 weeks and then classified as diet-induced obese (DIO) or diet-resistant (DR) mice according to the highest and lowest body weight gainers, respectively. The DIO and DR mice were then randomly divided into three groups each and either continued on their high-fat diet ad libitum (DIO-H and DR-H), changed to a low-fat diet (DIO-L and DR-L) or pair-fed via energy restricted high-fat diet (DIO-P and DR-P) for a further 6 weeks. During the course of this study, body weight, energy intake and plasma peptide YY (PYY) were measured. The study revealed that the replacement of a high-fat diet with a low-fat diet was associated with a significant lowering of ventromedial hypothalamic (VMH) Y2 receptor binding in both the DIO-L and DR-L mice (-37%, -36%), and also a lowered plasma PYY level in the DIO-L mice (-25%). Despite a continued consumption of the high-fat diet, energy restricted pair feeding caused a lower VMH Y2 receptor binding in the obese mice (DIO-P) following weight loss compared to the DR-P mice (-14%). In conclusion, this study showed that changing diets from high- to low-fat can significantly lower the VMH Y2 receptor binding irrespective to the obesity phenotype. Energy restriction, even while on high-fat feeding, can cause a lower VMH Y2 receptor binding compared to DR mice even after body weight loss to similar levels. This suggests either a possible intrinsic nature of the DIO mice or a body weight set-point re-establishment to drive body weight regain.

Topics: Animals; Body Weight; Diet; Dietary Fats; Energy Intake; Humans; Male; Mice; Mice, Inbred C57BL; Neuropeptide Y; Obesity; Receptors, Neuropeptide Y; Ventromedial Hypothalamic Nucleus

This study aims to clarify the effects of exercise on levels of appetite regulatory hormones in plasma and hypothalamus of obese rats. Diet-induced obese rats undergo short- (40 min) and long-term (40 min, 5 days/week for 8 weeks) exercises. The rats ran at a speed of 20 m/min on a 5 degrees slope treadmill. Rats undergoing short-term exercise were divided into C, E0, E1, E3, E12, and E24. Rats undergoing long-term exercise (LE) were compared to long-term control (LC). Concentrations of ghrelin, obestatin, and neuropeptide Y (NPY) were measured using radio immuno-assay. Expression of ghrelin receptor (GHSR-1a), putative obestatin receptor (GPR-39), and NPY in the hypothalamus was measured by quantitative RT-PCR. After short-term exercise, the plasma concentrations of ghrelin and obestatin were not changed, but NPY decreased. Ghrelin and obestatin in the hypothalamus decreased, and recovered 12 until 24 h. NPY increased and recovered after 24 h. Expression of GHSR-1a and NPY was not changed and GPR-39 was not observed. In LE, these changes are different in plasma and hypothalamus. It would be concluded appetite and body weight of obese rats are decreased by exercise through reduced level of ghrelin in the hypothalamus. Obestatin seems to have no effect in exercise-induced change in appetite.

Topics: Animals; Appetite; Body Weight; Brain Chemistry; Eating; Exercise Test; Exercise Therapy; Ghrelin; Hypothalamus; Lipids; Male; Neuropeptide Y; Obesity; Peptide Hormones; Physical Conditioning, Animal; Rats; Rats, Sprague-Dawley; Receptors, Ghrelin; Time Factors; Tissue Extracts; Weight Loss

Newborn rat pups artificially raised on a high-carbohydrate (HC) milk formula are chronically hyperinsulinemic and develop adult-onset obesity. As HC rats display aberrations in body weight regulation, hypothalamic adaptations predisposing to obesity have been investigated in this study. The artificial rearing of neonatal rat pups on the HC milk formula resulted in significant increases in the mRNA levels of neuropeptide Y, agouti-related polypeptide, and galanin in the hypothalamus of 12-day-old HC rats. Simultaneously, decreases in the mRNA levels of POMC, melanocortin receptor-4, cocaine- and amphetamine-regulated transcript, and corticotrophin-releasing factor were observed in the hypothalamus of these rats. These changes persisted in 100-day-old HC rats despite weaning onto a rodent diet on postnatal day 24. Marked hyperphagia and increased body weight gain were observed in the post-weaning period. The mRNA levels and protein content of insulin receptor beta (IR-beta) and leptin receptor (long form) showed significant decreases in the hypothalamus of both 12- and 100-day-old HC rats. Further investigation of insulin signaling in the hypothalamus of HC rats indicated significant decreases in the proximal signaling components (insulin receptor substrate proteins 1 and 2 and phosphotidylinositol 3-kinase) in 100-day-old HC rats. These results suggest that hypothalamic neuropeptides respond to the increased carbohydrate availability with associated hormonal alterations during the period of dietary modulation and that these adaptations by persisting in the post-weaning period predispose the HC rats for adult-onset obesity.

Topics: Agouti-Related Protein; Animals; Animals, Newborn; Dietary Carbohydrates; Female; Hypothalamus; Leptin; Male; Neuropeptide Y; Obesity; Pro-Opiomelanocortin; Rats; Rats, Sprague-Dawley; Receptor, Insulin; RNA, Messenger

Menopause and premature gonadal steroid deficiency are associated with increases in fat mass and body weight. Ovariectomized (OVX) mice also show reduced locomotor activity. Glucose-dependent-insulinotropic-polypeptide (GIP) is known to play an important role both in fat metabolism and locomotor activity. Therefore, we hypothesized that the effects of estrogen on the regulation of body weight, fat mass, and spontaneous physical activity could be mediated in part by GIP signaling. To test this hypothesis, C57BL/6 mice and GIP-receptor knockout mice (Gipr(-/-)) were exposed to OVX or sham operation (n = 10 per group). The effects on body composition, markers of insulin resistance, energy expenditure, locomotor activity, and expression of hypothalamic anorexigenic and orexigenic factors were investigated over 26 wk in all four groups of mice. OVX wild-type mice developed obesity, increased fat mass, and elevated markers of insulin resistance as expected. This was completely prevented in OVX Gipr(-/-) animals, even though their energy expenditure and spontaneous locomotor activity levels did not significantly differ from those of OVX wild-type mice. Cumulative food intake in OVX Gipr(-/-) animals was significantly reduced and associated with significantly lower hypothalamic mRNA expression of the orexigenic neuropeptide Y (NPY) but not of cocaine-amphetamine-related transcript (CART), melanocortin receptors (MCR-3 and MCR-4), or thyrotropin-releasing hormone (TRH). GIP receptors thus interact with estrogens in the hypothalamic regulation of food intake in mice, and their blockade may carry promising potential for the prevention of obesity in gonadal steroid deficiency.

Topics: Animals; Body Composition; Eating; Energy Metabolism; Female; Gastric Inhibitory Polypeptide; Mice; Mice, Inbred C57BL; Mice, Knockout; Motor Activity; Nerve Tissue Proteins; Neuropeptide Y; Obesity; Ovariectomy; Receptors, Gastrointestinal Hormone; Receptors, Melanocortin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Thyrotropin-Releasing Hormone

Obesity is strongly associated with female infertility, but the mechanisms underlying this relationship are largely unknown.. We investigated the effect of increasing dietary fat percentage upon body mass, hypothalamic neuropeptide gene expression, adipose hormone secretion and fertility in females of the inbred mouse strains C57BL/6J and DBA/2J. To assess the effect of obesity independent of dietary influence, we also compared these parameters in wild-type female C57BL/6J mice to those congenic for the obesogenic mutations ob/ob and A(y)/a.. After 24 weeks, rather than exhibiting an obese, leptin-resistant phenotype like their female DBA/2J counterparts, wild-type female C57BL/6J mice remained lean, fertile and manifested increased hypothalamic LEPR-B expression. Although both mutant genotypes were associated with obesity and subfertility, ob/ob mice demonstrated significantly increased hypothalamic LEPR-B expression, whereas A(y)/a mice had a significant reduction. Interestingly, wild-type female C57BL/6J mice were noted to manifest significantly higher and lower levels of adiponectin and tissue plasminogen activator inhibitor-1 (tPAI-1), respectively, than weight-matched wild-type female DBA/2J mice.. We conclude that (1) resistance to the obese-infertile phenotype in female C57BL/6J mice is associated with increased hypothalamic leptin receptor expression and alterations in adipokine levels consistent with decreased adipose tissue inflammation and (2) that long-standing hyperleptinemic obesity in mice is associated with a downregulation of the hypothalamic leptin receptor.

Topics: Adiponectin; Agouti-Related Protein; Animals; Body Weight; Dietary Fats; Female; Gonadotropin-Releasing Hormone; Hypothalamus; Infertility, Female; Insulin; Intercellular Signaling Peptides and Proteins; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Neuropeptide Y; Obesity; Pregnancy; Pro-Opiomelanocortin; Receptors, Cell Surface; Receptors, Leptin; Resistin; Tissue Plasminogen Activator

Despite high leptin levels, most obese humans and rodents lack responsiveness to its appetite-suppressing effects. We demonstrate that leptin modulates NPY/AgRP and alpha-MSH secretion from the ARH of lean mice. High-fat diet-induced obese (DIO) mice have normal ObRb levels and increased SOCS-3 levels, but leptin fails to modulate peptide secretion and any element of the leptin signaling cascade. Despite this leptin resistance, the melanocortin system downstream of the ARH in DIO mice is over-responsive to melanocortin agonists, probably due to upregulation of MC4R. Lastly, we show that by decreasing the fat content of the mouse's diet, leptin responsiveness of NPY/AgRP and POMC neurons recovered simultaneously, with mice regaining normal leptin sensitivity and glycemic control. These results highlight the physiological importance of leptin sensing in the melanocortin circuits and show that their loss of leptin sensing likely contributes to the pathology of leptin resistance.

Topics: Agouti-Related Protein; alpha-MSH; Animals; Arcuate Nucleus of Hypothalamus; Body Composition; Diet; Dietary Fats; Dose-Response Relationship, Drug; Gene Expression Regulation; Hypothalamus; In Vitro Techniques; Intercellular Signaling Peptides and Proteins; Leptin; Male; Melanocortins; Mice; Mice, Inbred C57BL; Neurons; Neuropeptide Y; Obesity; Pro-Opiomelanocortin; RNA, Messenger; Signal Transduction; Weight Loss

There is epidemiological evidence that perinatal nutritional factors may have long-term effects on obesity. Which nutrients or food components are involved in this programming mechanism are unknown. Breast milk contains leptin, a hormone that regulates food intake and energy expenditure, and previous studies in rats have shown that leptin orally administered during lactation exerts anorexigenic effects.. To evaluate whether supplementation with physiological doses of oral leptin during lactation has long-term effects on body weight regulation.. A daily oral dose of leptin (equivalent to five times the amount of leptin ingested normally from maternal milk during the suckling period) or the vehicle was given to suckling male rats during lactation. Animals were fed after weaning with a normal fat (NF) or a high-fat (HF) diet. We followed body weight and food intake of animals until the age of 6 months, and measured the size of adipose tissue depots, the thermogenic capacity, the expression of leptin in the stomach and adipose tissues and the expression of two appetite-related peptides (neuropeptide Y (NPY) and proopiomelanocortin (POMC)), leptin receptor (OB-Rb) and suppressor of cytokine signalling 3 (SOCS-3) in the hypothalamus at the age of 6 months.. Leptin-treated animals had, in adulthood, lower body weight and fat content and ate fewer calories than their untreated controls. Unlike adipocitary leptin production, adult animals that were leptin-treated during lactation displayed higher gastric leptin production without changes in OB-Rb mRNA levels. In addition, in response to HF diet, leptin-treated animals (contrary to controls) showed lower hypothalamic NPY/POMC mRNA ratio. Hypothalamic OB-Rb mRNA levels decreased in control animals as an effect of HF diet feeding, but remained unchanged in leptin-treated animals; SOCS-3 mRNA levels were lower in leptin-treated animals than in their controls, both under normal or HF diet.. The animals that received leptin during lactation become more protected against fat accumulation in adult life and seem to be more sensitive to the short- and long-term regulation of food intake by leptin. Thus, leptin plays an important role in the earlier stages of neonatal life, as a component of breast milk, in the prevention of later obesity.

Topics: Adipose Tissue; Administration, Oral; Aging; Animals; Animals, Newborn; Body Weight; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Gastric Mucosa; Lactation; Leptin; Male; Neuropeptide Y; Obesity; Pro-Opiomelanocortin; Rats; Rats, Wistar; RNA, Messenger; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins

The escalating rates of obesity and type 2 diabetes have reached pandemic proportions. It has been proposed that the risk of developing metabolic disorders in adult life is influenced by environmental factors, which operate during the early periods of development. We have previously shown that an interaction between the prenatal and the postnatal dietary environment amplifies the propensity towards diet-induced obesity, although the mechanisms are unclear. In the present study, we investigated the interaction between prenatal undernutrition and postnatal high-fat nutrition on key genes of the hypothalamic appetite regulatory network. Pregnant Wistar rats were fed a standard chow diet either ad libitum (AD) or at 30% of AD intake throughout gestation (UN). From weaning, female AD and UN offspring were fed either a standard chow (ADC n = 8, UNC n = 8) or a high-fat diet (45% kcal as fat; ADHF n = 8, UNHF n = 8) ad libitum for the remainder of the study. At 24 weeks of age, body composition was assessed by dual energy X-ray absorptiometry analysis and total RNA was extracted from whole rat hypothalami. Real-time PCR was performed to characterise pro-opiomelanocortin (POMC), neuropeptide Y (NPY), agouti-related protein (AgRP) and OBRb gene expression at the mRNA level. Our results demonstrate that the amplification of postnatal obesity develops as a consequence of an interaction between prenatal under-nutrition and postnatal high-fat nutrition. This phenotype also shows significant alterations in POMC, NPY, AgRP and OBRb gene expression together with elevations in circulating levels of both plasma leptin and insulin. These findings are consistent with the predictive adaptive response hypothesis that neuroendocrine development during fetal life may be based on predictions about postnatal environmental conditions. Increased susceptibility to diet-induced obesity develops if a mismatch between the anticipated and the actual conditions are encountered.

Topics: Agouti Signaling Protein; Agouti-Related Protein; Animals; Appetite Regulation; Body Composition; Dietary Fats; Disease Susceptibility; Female; Gene Expression; Hyperphagia; Hypothalamus; Insulin; Intercellular Signaling Peptides and Proteins; Leptin; Malnutrition; Maternal Nutritional Physiological Phenomena; Neuropeptide Y; Obesity; Pregnancy; Prenatal Exposure Delayed Effects; Pro-Opiomelanocortin; Rats; Rats, Wistar; RNA, Messenger

Obese individuals often suffer from depression. The olfactory bulbectomy (OBX) model is an animal model of depression that produces behavioral, physiological, and neurochemical alterations resembling clinical depression. The OBX model was employed to assess depression-related changes in food intake in obesity-prone, Osborne-Mendel (OM) rats and obesity-resistant, S5B/Pl rats. OBX increased food intake in OM rats beginning 7 days following surgery, however, OBX did not alter food intake in S5B/Pl rats at any time point. Fourteen days following surgery, OBX significantly increased locomotor activity (total lines crossed and rears) in the openfield test in OM and S5B/Pl rats. Fifteen days following surgery, prepro-neuropeptide Y (NPY) mRNA levels were significantly increased in the hypothalamus of bulbectomized OM rats and in the medial nucleus of the amygdala of bulbectomized OM and S5B/Pl rats. OBX decreased NPY Y2 receptor mRNA levels in the hypothalamus and medial nucleus of the amygdala in OM rats, while increasing NPY Y2 receptor mRNA levels in the medial nucleus of the amygdala of S5B/Pl rats. These data indicate that though both obesity-prone and obesity-resistant strains were susceptible to the locomotor effects of OBX, food intake and hypothalamic prepro-NPY mRNA were only increased in OM rats. Therefore, strain specific alterations in hypothalamic NPY may account for increased food intake in the obesity-prone rats following OBX, and suggests a potential mechanism to explain the comorbidity of obesity and depression.

Topics: Animals; Body Weight; Disease Models, Animal; Eating; Exploratory Behavior; Hypothalamus; Male; Neuropeptide Y; Obesity; Olfactory Bulb; Rats; Rats, Inbred Strains; Receptors, Neuropeptide Y; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Time Factors

To find out whether the immunohistochemical expression of neuropeptid Y (NPY) and leptin receptor (LR) in the rat hypothalamus is influenced by adlay seed water extract (adlay), obesity in rats was induced by high fat diet (HFD) for 8 weeks; these rats were injected with 50 mg/100 g body weight adlay daily for 4 weeks. The results showed that the optical density of NPY immunoreactivity in paraventricular nucleus of rats increased approximately by 3.4 fold in HFD group compared to the normal diet group. Conversely, that of HFD + adlay group was about 2.6 fold lower than HFD group. The pattern of LR expression was similar to that of NPY. Both of NPY and LR mRNA levels, determined by real time PCR, in HFD + adlay group were decreased compared to those of HFD group, but there were no significant changes in the level of LR. These results suggest that adlay may regulate neuroendocrine activity in the brain. Accordingly, administration of adlay may be considered for therapies targeting obesity.

Topics: Animals; Cholesterol; Coix; DNA, Complementary; Feeding Behavior; Hypothalamus; Immunohistochemistry; Leptin; Male; Models, Animal; Neuropeptide Y; Obesity; Plant Extracts; Rats; Rats, Sprague-Dawley; Receptors, Cell Surface; Receptors, Leptin; RNA, Messenger; Triglycerides

To investigate the effect of high-fat diet on expressions of hypothalamic neuropeptide Y (NPY) and Y1, Y2, Y5 receptors and the mechanism relative to the susceptibility of obesity.. Thirty-six female SD rats were randomly divided into high-fat diet group (HF, n=27) and chow food group (CF, n=9), and given either HF or CF diet for 13 weeks. Then the HF diet group was subdivided into dietary induced obesi-ty (DIO) and dietary induced obesity resistant (DIO-R) rat according to the final body weight. Body weight, caloric intake, energy efficiency, visceral fat pads were measured and compared. The levels of plasma and hypothalamic NPY were determined by Radioimmunoassay. Real-time Polymerase Chain Reaction (PCR) was used to measure the gene expression of NPY and its receptors in hypothalamus.. Body weight, caloric intake, energy efficiency and visceral fat pads in DIO rats were higher significantly than those in CF or DIO-R rats (p<0.01). No difference in plasma NPY level was detected among the three groups (p>0.05); the hypothalamic NPY level was significantly higher in DIO group than in CF or DIO-R group (p<0.01). Gene expression levels of NPY and Y1, Y2, Y5 receptors were higher significantly in DIO group than in CF or DIO-R group (p<0.01), while no significant difference was found between DIO-R and CF rats (p>0.05), except that Y2 receptor was lower in DIO-R rats (p<0.01).. SD rat fed with a HF diet showed different susceptibility to obesity, and up-regulated hypothalamic NPY and Y1, Y2, Y5 receptor gene expressions were closely associated with being predisposed to obesity and overeating of DIO rats.

Topics: Adipose Tissue; Animals; Body Weight; Diet; Dietary Fats; Energy Intake; Energy Metabolism; Female; Hypothalamus; Neuropeptide Y; Obesity; Radioimmunoassay; Rats; Receptors, Neuropeptide Y; Reverse Transcriptase Polymerase Chain Reaction; Weight Gain

Male Sprague-Dawley rats maintained from birth on a high-fat diet were examined to determine whether a specific measure before puberty can identify and allow one to characterize prepubertal rats at normal weight with high vs low risk for adult obesity.. Measures from weaning (day 21) to around puberty (day 45) were taken of weight gain, absolute body weight and daily energy intake on a high-fat diet and related to the amount of body fat accumulated at maturity (80-100 days of age). Rats identified by a specific prepubertal measure as obesity-prone (OP) vs obesity-resistant (OR) were then characterized before and after puberty.. Prepubertal weight gain from days 30 to 35 of age was the strongest and earliest positive correlate of ultimate body fat accrual in adult rats. The highest (8-10 g/day) compared to lowest (5-7 g/day) weight-gain scores identified accurately and reproducibly distinct OP and OR subgroups at day 35 that became obese or remained lean, respectively, as adults. The OP rats with rapid prepubertal weight gain and 50% greater adiposity at maturity (day 100) exhibited the expected phenotype of already-obese rats. These included elevated levels of leptin, insulin, triglycerides and glucose, increased galanin (GAL) peptide levels in the paraventricular nucleus (PVN) and reduced neuropeptide Y (NPY) levels in the arcuate nucleus (ARC). Before puberty (day 35), the OP rats with normal fat pad weights, energy intake and endocrine profile similar to OR rats exhibited these disturbances characteristic of obese rats. They had decreased capacity for fat oxidation in muscle, increased GAL expression in PVN and reduced expression of NPY and agouti-related protein in ARC.. Prepubertal weight gain can identify OP rats on day 35 when they have minimal body fat but exhibit specific metabolic and neurochemical disturbances expected to promote obesity and characteristics of already-obese adult rats.

Topics: Aging; Animals; Animals, Newborn; Arcuate Nucleus of Hypothalamus; Body Weight; Dietary Fats; Disease Models, Animal; Energy Metabolism; Galanin; Genetic Predisposition to Disease; Male; Neuropeptide Y; Obesity; Paraventricular Hypothalamic Nucleus; Phenotype; Predictive Value of Tests; Rats; Risk Factors; Weight Gain

It is well established that reproductive function is metabolically gated. However, the mechanisms whereby energy stores and metabolic cues influence fertility are yet to be completely deciphered. Recently, the hypothalamic KiSS-1/GPR54 system has emerged as a fundamental regulator of the gonadotropic axis, which conveys the modulatory actions of sex steroids to GnRH neurons. Evidence is also mounting that KiSS-1 neurons may also represent the link between systemic metabolic signals and central control of reproduction. To further explore this possibility, we examined the impact of changes in energy status and key metabolic regulators on the hypothalamic expression of KiSS-1 and GPR54 genes, using different mouse models and the hypothalamic cell line N6. Time-course analysis of the effects of short-term fasting revealed a rapid (12- and 24-h) decline in KiSS-1 and GPR54 mRNA levels, which preceded that of GnRH (48 h). In contrast, diet-induced obesity or obesity associated with leptin deficiency (ob/ob vs. wild-type mice) failed to induce overt changes in hypothalamic expression of KiSS-1 and GPR54 genes. However, leptin infusion of ob/ob mice evoked a significant increase in KiSS-1 and GPR54 mRNA levels compared with pair-fed controls. Moreover, leptin, but not insulin or IGF-I, stimulated KiSS-1 mRNA expression in the mouse hypothalamic cell line N6. In addition, neuropeptide Y (NPY) null mice showed decreased KiSS-1 mRNA levels at the hypothalamus, whereas exposure to NPY increased expression of KiSS-1 in hypothalamic N6 cells. In sum, our present data further characterize the functional relevance and putative key mediators (such as leptin and NPY) of the metabolic regulation of the hypothalamic KiSS-1 system in the mouse.

Topics: Animals; Cell Line; Diet; Fasting; Gene Expression Regulation; Gonadotropin-Releasing Hormone; Hypothalamus; Kisspeptins; Leptin; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Obese; Neuropeptide Y; Obesity; Proteins; Receptors, G-Protein-Coupled; Receptors, Kisspeptin-1; RNA, Messenger

The relationship between stress and obesity remains elusive. In response to stress, some people lose weight, whereas others gain. Here we report that stress exaggerates diet-induced obesity through a peripheral mechanism in the abdominal white adipose tissue that is mediated by neuropeptide Y (NPY). Stressors such as exposure to cold or aggression lead to the release of NPY from sympathetic nerves, which in turn upregulates NPY and its Y2 receptors (NPY2R) in a glucocorticoid-dependent manner in the abdominal fat. This positive feedback response by NPY leads to the growth of abdominal fat. Release of NPY and activation of NPY2R stimulates fat angiogenesis, macrophage infiltration, and the proliferation and differentiation of new adipocytes, resulting in abdominal obesity and a metabolic syndrome-like condition. NPY, like stress, stimulates mouse and human fat growth, whereas pharmacological inhibition or fat-targeted knockdown of NPY2R is anti-angiogenic and anti-adipogenic, while reducing abdominal obesity and metabolic abnormalities. Thus, manipulations of NPY2R activity within fat tissue offer new ways to remodel fat and treat obesity and metabolic syndrome.

Topics: 3T3-L1 Cells; Adipose Tissue, White; Animals; Cold Temperature; Diet; Dietary Fats; Gene Deletion; Gene Expression Regulation; Male; Metabolic Syndrome; Mice; Mice, Inbred C57BL; Mice, Nude; Neuropeptide Y; Obesity; Receptors, Neuropeptide Y; Stress, Physiological; Up-Regulation

Topics: Abdomen; Animals; Diet; Dietary Fats; Mice; Neuropeptide Y; Obesity; Stress, Physiological

To studied the relationship that exists between leptin, ghrelin, insulin, neuropeptide Y (NPY), anthropometric, and metabolic variables in Saudi females.. The study was conducted at the Department of Genetics, King Faisal Specialist Hospital & Research Center, Riyadh, Kingdom of Saudi Arabia from November 2004 to August 2005. One hundred and twenty-two Saudi females were divided into 3 body mass index (BMI) groups: lean (N=60), overweight (N=17), and obese (N=45). Fasting leptin, ghrelin, insulin, NPY and glucose concentrations were determined.. Leptin levels in overweight and obese groups were significantly higher than those in lean group. Leptin levels showed a positive correlation with BMI in obese (0.81), overweight (0.78), and lean (0.48). In contrast, ghrelin concentration decreased in obese and overweight subjects compared to lean subjects. Ghrelin levels were negatively correlated with BMI in obese (-0.81), overweight (-0.58), and lean subjects (-0.62). Negative correlations were found between serum insulin and ghrelin concentrations in lean and obese subjects. Glucose and insulin levels were significantly higher in the obese group compared to controls. No differences were found in serum NPY between the 3 groups.. Leptin levels increased remarkably with increasing BMI. A leptin resistance state seems to exist in many obese and overweight individuals. Ghrelin concentration was decreased in overweight and obese subjects. These data demonstrate a significant inverse relationship between ghrelin and leptin levels in overweight and obese subjects.

Topics: Adult; Body Mass Index; Case-Control Studies; Female; Ghrelin; Humans; Insulin; Leptin; Neuropeptide Y; Obesity; Overweight; Peptide Hormones; Saudi Arabia

The hypothalamus plays a central role in the regulation of metabolism by sensing metabolic demands and releasing regulatory neurotransmitters. This study investigated the response of the hypothalamus to glucose ingestion in rats by blood oxygen level-dependent functional magnetic resonance imaging (BOLD-fMRI) and immunohistochemical techniques to determine the role of the hypothalamus in glyco-regulation during disturbances in carbohydrate metabolism.. The signal intensity of the hypothalamus was monitored by fMRI for 60 minutes after oral glucose intake in 48 healthy rats (age 14 months), which included 24 normal weight rats (weighing (365 +/- 76.5) g) and 24 overweight rats (weighing (714 +/- 83.5) g). Then, 12 rats (6 normal, 6 overweight) underwent a repeat fMRI scan after consuming an equivalent amount of water without glucose on a separate day. The procedure for fMRI with water intake was the same as for glucose ingestion. fMRI data was processed using time cluster analysis and intensity averaging method. After fMRI, the expression of neuropeptide Y (NPY) and 5-hydroxytryptamine (5-HT) in the hypothalamus of all rats was determined by immunohistochemistry. Positive cells for NPY or 5-HT were counted.. There was a transient, but significant, decrease in fMRI signal intensity in all rats (mean (3.12 +/- 0.78)%) in the hypothalamus within 19.5 - 25.5 minutes of oral glucose ingestion. In overweight rats, the decrease in signal intensity in response to the glucose ingestion was more markedly attenuated than that observed in normal weight rats ((2.2 +/- 1.5)% vs (4.2 +/- 0.7)% inhibition, t = 2.12, P < 0.05). There was no significant response in the hypothalamus after oral water ingestion. The percentage of NPY positive cells in obese rats were slightly lower than those in control group (21% vs 23%, t = 0.71, P > 0.05); but there was no significant difference between the two groups; the percentage of 5-HT positive cells in obese rats were significantly lower than those in the control group (22% vs 31%, t = 3.25, P < 0.01).. There is a transient, but significant, decrease in BOLD signal intensity in the hypothalamus following glucose ingestion, which is similar to that observed in humans. The response of the hypothalamus to glucose ingestion was different in overweight and normal weight rats. The percentage of NPY positive cells in obese rats were lower than those in the control group, although this difference was not statistically significant. The percentage of 5-HT positive cells in obese rats was significantly lower than those in the control group.

Topics: Animals; Glucose; Hypothalamus; Immunohistochemistry; Magnetic Resonance Imaging; Neuropeptide Y; Obesity; Oxygen; Rats; Serotonin

Neuropeptide Y (NPY), whose role in appetite regulation is well known, is also expressed in pancreatic islets. Although previous studies indicated that application of NPY to pancreatic islets inhibits insulin secretion, its physiological role in the regulation of insulin secretion is not fully understood. We hypothesized that NPY in islets tonically suppresses insulin secretion and the reduction of islet NPY increases insulin secretion. To address the hypothesis, islet function of NPY-deficient mice was analyzed. Although there was little change in glucose homeostasis in vivo, pancreatic islets from NPY-deficient mice had higher basal insulin secretion (1.5 times), glucose-stimulated insulin secretion (1.5 times), and islet mass (1.7 times), compared with wild-type mouse. Next we sought to determine whether the expression of NPY and Y(1) receptor in islets was altered in hyperinsulinemia associated with obesity. Islets from C57BL/6J mice on a high-fat diet had 1.9 times higher basal insulin secretion and 2.4 times higher glucose-stimulated insulin secretion than control mice, indicating islet adaptation to obesity. Expression of NPY and Y(1) receptor mRNA levels was decreased by 70 and 64%, respectively, in high-fat diet islets, compared with controls. NPY and Y(1) receptor in islets were also reduced by 91 and 80%, respectively, in leptin-deficient ob/ob mice that showed marked hyperinsulinemia. Together these results suggest that endogenous NPY tonically inhibits insulin secretion from islets and a reduction of islet NPY may serve as one of the mechanisms to increase insulin secretion when islets compensate for insulin resistance associated with obesity.

Topics: Animals; Blood Glucose; Body Weight; Dietary Fats; Female; Gene Deletion; Insulin; Insulin Resistance; Insulin Secretion; Insulin, Long-Acting; Islets of Langerhans; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Neuropeptide Y; Obesity; Receptors, Neuropeptide Y

Adipose tissue is not only the main organ for energy storage, but it also has endocrine properties, producing "adipokines" responsible for energy homeostasis, insulin sensitivity, and inflammation. Leptin, produced by adipocytes, is the key hormone in appetite regulation and suppression of orexigenic, hypothalamic neuropeptide Y (NPY). We wanted to establish and compare levels of leptin and NPY in different obesity types in childhood, and to investigate their correlations with auxological parameters. Twenty-one obese children (seven girls and 14 boys), divided into two groups, were compared with 14 controls. The mean age of the study group was 10.81 +/- 3.69 years and the mean puberty stage was 2.21. The mean body mass index (BMI) was 32.80 kg/m2 (range 23.30-47.02) and the mean overweight 30.73 kg (range 8.00-74.00). The mean leptin level was higher in boys and in the group with central obesity, but was not significant. Leptin/NPY ratio and leptin/BMI ratio was also higher in the central obesity group and there was a more significant difference compared with controls. We found significant correlation of the leptin level with body mass (BM), body mass excess (BME), and BMI (p < 0.05). The mean leptin level in obese children was very high (36.39 ng/ml). Leptin and NPY levels showed inverse values in two different obesity types. Results are suggestive for leptin resistance rather than leptin deficiency in our group of obese children. Orexitropic signaling proteins correlated significantly with auxological parameters. Determination of the leptin and NPY concentrations provided evidence that obesity represents disease with neuroendocrine dysfunction and high leptin/NPY ratio, which could be a useful marker for central obesity.

Topics: Body Mass Index; Child; Female; Humans; Intracellular Signaling Peptides and Proteins; Leptin; Male; Neuropeptide Y; Obesity

Peripheral administration of baclofen significantly reduced food intake and body weight increase in both diabetic (db/db) and diet-induced obese mice for 5 weeks, whereas it had no significant effects on energy balance in their lean control mice. Despite the decreased body weight, neuropeptide Y expression in the arcuate nucleus was significantly decreased, whereas pro-opiomelanocortin expression was significantly increased by baclofen treatment. These data demonstrate that the inhibitory effects of baclofen on body weight in the obese mice were mediated via the arcuate nucleus at least partially, and suggest that GABA(B) agonists could be a new therapeutic reagent for obesity.

Topics: Adipokines; Adipose Tissue, White; Administration, Oral; Animals; Anti-Obesity Agents; Arcuate Nucleus of Hypothalamus; Baclofen; Blood Glucose; Diet; Eating; GABA Agonists; GABA-B Receptor Agonists; Male; Mice; Mice, Obese; Neuropeptide Y; Obesity; Pro-Opiomelanocortin; RNA, Messenger; Weight Loss

Topics: Adipose Tissue; Adipose Tissue, Brown; Humans; Hyperphagia; Neuropeptide Y; Obesity; Receptors, Neuropeptide Y; Sympathetic Nervous System

Chronic central administration of neuropeptide Y (NPY) has dramatic effects on energy balance; however, the exact role of the hypothalamic paraventricular nucleus (PVN) in this is unknown. The aim of this study was to further unravel the contribution of NPY signaling in the PVN to energy balance.. Recombinant adeno-associated viral particles containing NPY (rAAV-NPY) were injected in the rat brain with coordinates targeted at the PVN. For three weeks, body weight, food intake, endocrine parameters, body temperature, and locomotor activity were measured. Furthermore, effects on insulin sensitivity and expression of NPY, agouti-related protein (AgRP), and pro-opiomelanocortin in the arcuate nucleus were studied.. Food intake was increased specifically in the light period, and dark phase body temperature and locomotor activity were reduced. This resulted in obesity characterized by increased fat mass; elevated plasma insulin, leptin, and adiponectin; decreased AgRP expression in the arcuate nucleus; and decreased insulin sensitivity; whereas plasma corticosterone was unaffected.. These data suggest that increased NPY expression targeted at the PVN is sufficient to induce obesity. Interestingly, plasma concentrations of leptin and insulin were elevated before a rise in food intake, which suggests that NPY in the PVN influences leptin and insulin secretion independently from food intake. This strengthens the role of the PVN in regulation of energy balance by NPY.

Topics: Adenoviridae; Adiponectin; Agouti-Related Protein; Animals; Arcuate Nucleus of Hypothalamus; Body Composition; Body Temperature; Body Weight; Glucose Tolerance Test; Insulin; Leptin; Male; Motor Activity; Neuropeptide Y; Obesity; Paraventricular Hypothalamic Nucleus; Rats; Rats, Wistar; Transfection

The link between obesity and diabetes is not fully understood but there is evidence to suggest that hypothalamic signalling pathways may be involved. The hypothalamic neuropeptides, pro-opiomelanocortin (POMC), neuropeptide Y (NPY) and agouti-related protein (AGRP) are central to the regulation of food intake and have been implicated in glucose homeostasis. Therefore, the expression of these genes was quantified in hypothalami from diabetic Zucker fatty (ZDF) rats and nondiabetic Zucker fatty (ZF) rats at 6, 8, 10 and 14 weeks of age. Although both strains are obese, only ZDF rats develop pancreatic degeneration and diabetes over this time period. In both ZF and ZDF rats, POMC gene expression was decreased in obese versus lean rats at all ages. By contrast, although there was the expected increase in both NPY and AGRP expression in obese 14-week-old ZF rats, the expression of NPY and AGRP was decreased in 6-week-old obese ZDF rats with hyperinsulinaemia and in 14-week-old rats with the additional hyperglycaemia. Therefore, candidate genes involved in glucose, and insulin signalling pathways were examined in obese ZDF rats over this age range. We found that expression of the ATP-sensitive potassium (K(ATP)) channel component, Kir6.2, was decreased in obese ZDF rats and was lower compared to ZF rats in each age group tested. Furthermore, immunofluorescence analysis showed that Kir6.2 protein expression was reduced in the dorsomedial and ventromedial hypothalamic nuclei of 6-week-old prediabetic ZDF rats compared to ZF rats. The Kir6.2 immunofluorescence colocalised with NPY throughout the hypothalamus. The differences in Kir6.2 expression in ZF and ZDF rats mimic those of NPY and AGRP, which could infer that the changes occur in the same neurones. Overall, these data suggest that chronic changes in hypothalamic Kir6.2 expression may be associated with the development of hyperinsulinaemia and hyperglycaemia in ZDF rats.

Topics: Agouti-Related Protein; Animals; Diabetes Mellitus; Gene Expression; Glucose; Hyperglycemia; Hyperinsulinism; Hypothalamus; Immunohistochemistry; Inflammation; Insulin; Leptin; Male; Neuropeptide Y; Obesity; Pancreas; Potassium Channels, Inwardly Rectifying; Pro-Opiomelanocortin; Rats; Rats, Wistar; Rats, Zucker; Signal Transduction

Gastric banding is thought to decrease appetite in addition to the mechanical effects of food restriction, although this has been difficult to demonstrate in human studies. Our aim was to investigate the changes in orexigenic signals in the obese Zucker rat after gastric banding.. Obese Zucker rats (fa/fa) were submitted to gastric banding (GBP), sham gastric banding fed ad libitum (sham), or sham operation with food restriction, pair-fed to the gastric banding group (sham-PF). Lean Zucker rats (fa/+) were used as additional controls. Body weight and food intake were daily recorded for 21 days after surgery when epididymal fat was weighed and fasting ghrelin and hypothalamic NPY mRNA expression were measured.. Gastric banding in obese Zucker rats resulted in a significant decrease of cumulative body weight gain and food intake. Furthermore, gastric banded rats were leaner than Sham-PF, as expressed by a significantly lower epididymal fat weight. Ghrelin levels of gastric banded rats were not increased when compared to sham-operated animals fed ad libitum and were significantly lower than the levels of weight matched sham-PF rats (1116.9 +/- 103.3 g GBP vs 963.2 +/- 54.3 g sham, 3,079.5 +/- 221.6 sham-PF and 2,969.9 +/- 150.9 g lean rats, p < 0.001); hypothalamic NPY mRNA expression was not increased in GBP when compared to sham-operated rats.. In obese Zucker rats, GBP prevents the increase in orexigenic signals that occur during caloric deprivation. Our data support the hypothesis that sustained weight loss observed after gastric banding does not depend solely on food restriction.

Topics: Adiposity; Animals; Blood Glucose; Body Weight; Caloric Restriction; Feeding Behavior; Gastrointestinal Hormones; Gastroplasty; Gene Expression; Ghrelin; Hypothalamus; Insulin; Leptin; Male; Neuropeptide Y; Obesity; Radioimmunoassay; Random Allocation; Rats; Rats, Zucker; RNA, Messenger; Triglycerides

Leptin-deficient ob/ob mice are more sensitive to exogenous leptin than lean mice and leptin treatment normalizes many of the phenotypic characteristics of ob/ob mice. The primary objective of this experiment was to investigate whether this altered leptin sensitivity in ob/ob mice was reflected in the hypothalamic mRNA profile.. Fifteen-week-old female ob/ob and lean mice were treated with 14 days of subcutaneous (sc) infusion of phosphate-buffered saline (PBS) or leptin (10 mug/d) using osmotic pumps. Real-time Taqman reverse transcription polymerase chain reaction (RT-PCR) (ABI Microfluidic cards) was used to quantitatively compare the mRNA levels of selected hypothalamic genes in these groups.. Hypothalamic mRNA levels for ob/ob control mice were higher for agouti-related protein (AGRP), neuropeptide Y (NPY), and arginine vasopressin (AVP), and lower for cocaine- and amphetamine-regulated transcript (CART), cAMP response element binding protein (CREB)-1, proopiomelanocortin (POMC)-1, and urocortin (UCN)-3 compared with lean controls. In leptin-treated ob/ob mice, hypothalamic mRNA levels were reduced for NPY, AGRP, AVP, and increased for suppressor of cytokine signaling 3 (SOCS3) compared with ob/ob controls. Leptin treatment dramatically up-regulated hypothalamic mRNA level of POMC1 in both lean and ob/ob mice. Strong correlations were observed between hypothalamic Janus kinase 2 (JAK2) and CREB1, STAT3 and CREB1, JAK2 and STAT3, NPY and AVP in all samples.. ob/ob and lean mice have different hypothalamic mRNA expression patterns (particularly those of feeding-related genes), and selected genes in ob/ob mice are more sensitive to exogenous leptin stimulation compared with lean mice.

Topics: Animals; Arginine Vasopressin; Body Weight; Cyclic AMP Response Element-Binding Protein; Disease Models, Animal; Eating; Female; Gene Expression Profiling; Hypothalamus; Injections, Subcutaneous; Janus Kinase 2; Leptin; Mice; Mice, Obese; Nerve Tissue Proteins; Neuropeptide Y; Obesity; Pro-Opiomelanocortin; RNA, Messenger; STAT3 Transcription Factor; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins; Thinness; Urocortins

Topics: Animals; Eating; Mice; Neuropeptide Y; Obesity; Stress, Physiological

Exposure to hypoxia induces anorexia in humans and rodents, but the role of leptin remains under discussion and that of orexigenic and anorexigenic hypothalamic neuropeptides remains unknown. The present study was designed to address this issue by using obese (Lepr(fa)/Lepr(fa)) Zucker rats, a rat model of genetic leptin receptor deficiency. Homozygous lean (Lepr(FA)/Lepr(FA)) and obese (Lepr(fa)/Lepr(fa)) rats were randomly assigned to two groups, either kept at ambient pressure or exposed to hypobaric hypoxia for 1, 2, or 4 days (barometric pressure, 505 hPa). Food intake and body weight were recorded throughout the experiment. The expression of leptin and vascular endothelial growth factor (VEGF) genes was studied in adipose tissue with real-time quantitative PCR and that of selected orexigenic and anorexigenic neuropeptides was measured in the hypothalamus. Lean and obese rats exhibited a similar hypophagia (38 and 67% of initial values at day 1, respectively, P < 0.01) and initial decrease in body weight during hypoxia exposure. Hypoxia led to increased plasma leptin levels only in obese rats. This resulted from increased leptin gene expression in adipose tissue in response to hypoxia, in association with enhanced VEGF gene expression. Increased hypothalamic neuropeptide Y levels in lean rats 2 days after hypoxia exposure contributed to accounting for the enhanced food consumption. No significant changes occurred in the expression of other hypothalamic neuropeptides involved in the control of food intake. This study demonstrates unequivocally that altitude-induced anorexia cannot be ascribed to anorectic signals triggered by enhanced leptin production or alterations of hypothalamic neuropeptides involved in anabolic or catabolic pathways.

Topics: Adipose Tissue; Animals; Body Weight; Eating; Gene Expression; Hematocrit; Hypoxia; Leptin; Male; Neuropeptide Y; Obesity; Rats; Rats, Zucker; Receptors, Cell Surface; Receptors, Leptin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Vascular Endothelial Growth Factor A

Melanin concentrating hormone (MCH) is a cyclic neuropeptide expressed in the lateral hypothalamus that plays an important role in energy homeostasis. To investigate the pharmacological consequences of inhibiting MCH signaling in murine obesity models, we examined the effect of acute and chronic administration of a selective MCH1 receptor antagonist (SCH-A) in diet-induced obese (DIO) and Lep(ob/ob) mice. Oral administration of SCH-A for 5 consecutive days (30 mg/kg q.d.) produced hypophagia, a loss of body weight and adiposity, and decreased plasma leptin levels in DIO mice, and hypophagia and reduced weight gain in Lep(ob/ob) mice. Chronic administration of SCH-A to DIO mice decreased food intake, body weight and adiposity, and plasma leptin and free fatty acids. These effects were accompanied by increases in several hypothalamic neuropeptides. Acute administration of SCH-A (30 mg/kg) prevented the decrease in energy expenditure associated with food restriction. These results indicate that MCH1 receptor antagonists may be effective in the treatment of obesity.

Topics: Adipose Tissue; Administration, Oral; Animals; Binding, Competitive; Body Weight; Brain; CHO Cells; Cricetinae; Cricetulus; Dietary Fats; Dose-Response Relationship, Drug; Eating; Energy Metabolism; Fatty Acids, Nonesterified; Female; Galanin; Gene Expression; Homeostasis; Hypothalamic Hormones; Hypothalamus; Insulin; Intracellular Signaling Peptides and Proteins; Iodine Radioisotopes; Leptin; Male; Melanins; Mice; Mice, Inbred C57BL; Mice, Obese; Neuropeptide Y; Neuropeptides; Nitriles; Obesity; Oligopeptides; Orexin Receptors; Orexins; Piperazines; Pituitary Hormones; Protein Binding; Receptors, G-Protein-Coupled; Receptors, Neuropeptide; Receptors, Somatostatin; Reverse Transcriptase Polymerase Chain Reaction; Triglycerides; Urea

Neuropeptide Y (NPY) is thought to have a major role in the physiological control of energy homeostasis. Among five NPY receptors described, the NPY Y5 receptor (Y5R) is a prime candidate to mediate some of the effects of NPY on energy homeostasis, although its role in physiologically relevant rodent obesity models remains poorly defined. We examined the effect of a potent and highly selective Y5R antagonist in rodent obesity and dietary models. The Y5R antagonist selectively ameliorated diet-induced obesity (DIO) in rodents by suppressing body weight gain and adiposity while improving the DIO-associated hyperinsulinemia. The compound did not affect the body weight of lean mice fed a regular diet or genetically obese leptin receptor-deficient mice or rats, despite similarly high brain Y5R receptor occupancy. The Y5R antagonist acts in a mechanism-based manner, as the compound did not affect DIO of Y5R-deficient mice. These results indicate that Y5R is involved in the regulation and development of DIO and suggest utility for Y5R antagonists in the treatment of obesity.

Topics: Adipose Tissue; Animals; Anti-Obesity Agents; Blood Glucose; Body Weight; Cyclohexanes; Diet; Insulin; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Neuropeptide Y; Obesity; Organ Size; Rats; Rats, Zucker; Receptors, Neuropeptide Y; Weight Gain; Xanthenes

Tub is a member of a small gene family, the tubby-like proteins (TULPs), with predominant expression in neurons. Mice carrying a mutation in Tub develop retinal and cochlear degeneration as well as late-onset obesity with insulin resistance. During behavioral and metabolic testing, we found that homozygous C57BL/6J-Tub(tub) mice have a lower respiratory quotient than C57BL/6J controls before the onset of obesity, indicating that tubby homozygotes fail to activate carbohydrate metabolism and instead rely on fat metabolism for energy needs. In concordance with this, tubby mice show higher excretion of ketone bodies and accumulation of glycogen in the liver. Quantitation of liver mRNA levels shows that, during the transition from light to dark period, tubby mice fail to induce glucose-6-phosphate dehydrogenase (G6pdh), the rate-limiting enzyme in the pentose phosphate pathway that normally supplies NADPH for de novo fatty acid synthesis and glutathione reduction. Reduced G6PDH protein levels and enzymatic activity in tubby mice lead accordingly to lower levels of NADPH and reduced glutathione (GSH), respectively. mRNA levels for the lipolytic enzymes acetyl-CoA synthetase and carnitine palmitoyltransferase are increased during the dark cycle and decreased during the light period, and several citric acid cycle genes are dysregulated in tubby mice. Examination of hypothalamic gene expression showed high levels of preproorexin mRNA leading to accumulation of orexin peptide in the lateral hypothalamus. We hypothesize that abnormal hypothalamic orexin expression leads to changes in liver carbohydrate metabolism and may contribute to the moderate obesity observed in tubby mice.

Topics: Acetate-CoA Ligase; Adaptor Proteins, Signal Transducing; Agouti-Related Protein; Animals; Brain Chemistry; Carbohydrate Metabolism; Carbon Dioxide; Carnitine O-Palmitoyltransferase; Circadian Rhythm; Citric Acid Cycle; Cochlear Diseases; Eating; Energy Metabolism; Enzyme Induction; Genes, Recessive; Glucosephosphate Dehydrogenase; Glutathione; Homozygote; Hypothalamus; Insulin Resistance; Intercellular Signaling Peptides and Proteins; Intracellular Signaling Peptides and Proteins; Lipid Metabolism; Lipolysis; Liver; Liver Glycogen; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Motor Activity; NADP; Neuropeptide Y; Neuropeptides; Obesity; Orexins; Oxygen; Oxygen Consumption; Pentose Phosphate Pathway; Proteins; Retinal Degeneration

Neuropeptide Y (NPY) is a key regulator of energy homeostasis and is implicated in the development of obesity and type 2 diabetes. Whereas it is known that hypothalamic administration of exogenous NPY peptides leads to increased body weight gain, hyperphagia, and many hormonal and metabolic changes characteristic of an obesity syndrome, the Y receptor(s) mediating these effects is disputed and unclear. To investigate the role of different Y receptors in the NPY-induced obesity syndrome, we used recombinant adeno-associated viral vector to overexpress NPY in mice deficient of selective single or multiple Y receptors (including Y1, Y2, and Y4). Results from this study demonstrated that long-term hypothalamic overexpression of NPY lead to marked hyperphagia, hypogonadism, body weight gain, enhanced adipose tissue accumulation, hyperinsulinemia, and other hormonal changes characteristic of an obesity syndrome. NPY-induced hyperphagia, hypogonadism, and obesity syndrome persisted in all genotypes studied (Y1(-/-), Y2(-/-), Y2Y4(-/-), and Y1Y2Y4(-/-) mice). However, triple deletion of Y1, Y2, and Y4 receptors prevented NPY-induced hyperinsulinemia. These findings suggest that Y1, Y2, and Y4 receptors under this condition are not crucially involved in NPY's hyperphagic, hypogonadal, and obesogenic effects, but they are responsible for the central regulation of circulating insulin levels by NPY.

Topics: Adipose Tissue; Animals; Blood Glucose; Body Weight; Female; Humans; Hyperinsulinism; Hyperphagia; Hypothalamus; Mice; Mice, Inbred C57BL; Neuropeptide Y; Obesity; Receptors, Neuropeptide Y

To investigate the concentration levels of leptin, orexins and neuropeptide Y (NPY) in the blood of obese children, and to analysed the relationship between these substances.. RIA methods were used to measure the concentrations of leptin, orexinA, orexinB, and NPY in the blood of 98 obese children [BMI: male (29.24 +/- 1.87) kg/mZ, female (28.12 +/- 2.30) kg/m2] and in 104 normal children [BMI: male (20.49 +/- 1.95) kg/m2, female (19.59 +/- 1.51) kg/m2] as the control group.. The leptin concentrations in obese children [male (26.00 +/- 14.66) ng/mL; female (33.59 +/- 14.63) ng/mL] were higher than those in the control group [male (6.65 +/- 44.49) ng/mL; female [10.48 +/- 5.52) ng/mL P < 0.013]. The concentrations of plasma orexinA in obes children [male (3.23 +/- 1.86) pg/mL; female (3.38 +/- 1.80) pg/mL] were lower than those in the control group [male (4.52 +/- 1.52) pg/mL; female (4.71 +/- 1.53) pg/mL P < 0.05]; Negative correlations between leptin and NPY were noted in the obesity group (r = -0.302) and the control group (r = -0.310, P < 0.01), while the slopes in the two groups were different (control group -2.969; obese group -0.809). A positive correlation between NPY and orexinA was noted (r = 0.207, P < 0.05). The fluctuation range of orexinA in obese children was markedly narrowed when compared with that in the control group.. The concentration level of peripheral orexinA and leptin in the obese and non-obese children change inversely. The obesity in children correlates with the concentrations of orexinA, leptin, NPY as well as with their interactions.

Topics: Adolescent; Child; Humans; Intracellular Signaling Peptides and Proteins; Leptin; Neuropeptide Y; Neuropeptides; Obesity; Orexins

Effects of amylin and pair feeding (PF) on body weight and metabolic parameters were characterized in diet-induced obesity-prone rats. Peripherally administered rat amylin (300 microg/kg.d, 22d) reduced food intake and slowed weight gain: approximately 10% (P<0.05), similar to PF. Fat loss was 3-fold greater in amylin-treated rats vs. PF (P<0.05). Whereas PF decreased lean tissue (P<0.05 vs. vehicle controls; VEH), amylin did not. During wk 1, amylin and PF reduced 24-h respiratory quotient (mean+/-se, 0.82+/-0.0, 0.81+/-0.0, respectively; P<0.05) similar to VEH (0.84+/-0.01). Energy expenditure (EE mean+/-se) tended to be reduced by PF (5.67+/-0.1 kcal/h.kg) and maintained by amylin (5.86+/-0.1 kcal/h.kg) relative to VEH (5.77+/-0.0 kcal/h.kg). By wk 3, respiratory quotient no longer differed; however, EE increased with amylin treatment (5.74+/-0.09 kcal/.kg; P<0.05) relative to VEH (5.49+/-0.06) and PF (5.38+/-0.07 kcal/h.kg). Differences in EE, attributed to differences in lean mass, argued against specific amylin-induced thermogenesis. Weight loss in amylin and pair-fed rats was accompanied by similar increases arcuate neuropeptide Y mRNA (P<0.05). Amylin treatment, but not PF, increased proopiomelanocortin mRNA levels (P<0.05 vs. VEH). In a rodent model of obesity, amylin reduced body weight and body fat, with relative preservation of lean tissue, through anorexigenic and specific metabolic effects.

Topics: Adipose Tissue; Agouti Signaling Protein; Amyloid; Animals; Anti-Obesity Agents; Body Composition; Body Weight; Calorimetry, Indirect; Diet, Atherogenic; Eating; Energy Metabolism; Gene Expression; Glycogen; Hypothalamic Hormones; In Situ Hybridization; Intercellular Signaling Peptides and Proteins; Islet Amyloid Polypeptide; Liver; Liver Glycogen; Male; Melanins; Mice; Muscle, Skeletal; Neuropeptide Y; Obesity; Pituitary Hormones; Pro-Opiomelanocortin; Rats; Thinness; Triglycerides

Both obesity and diabetes are associated with an increased incidence of gallstones. Recent animal and human data from our laboratory suggest that insulin resistance is associated with increased gallbladder volume and/or impaired gallbladder emptying. Pioglitazone is a thiazolidinedione that has been shown to improve insulin resistance. Therefore, we tested the hypothesis that pioglitazone would improve insulin resistance, decrease resting gallbladder volume and improve gallbladder response to neurotransmitters in insulin-resistant obese mice fed a 25% carbohydrate diet.. Twenty eight-week-old insulin-resistant obese (Lep(ob)) mice fed a 25% carbohydrate diet for 4 weeks. Half of the animals had 0.3 g/kg pioglitazone added to their diet. At 12 weeks all animals were fasted and underwent cholecystectomy. Gallbladder volume and weight were measured, and fresh gallbladders were placed in a muscle bath to assess response to acetylcholine (ACh 10(-5)M), neuropeptide Y (NPY 10(-8,-7,-6)M) and cholecystokinin (CCK 10(-10,-9,-8,-7)M). Serum glucose and insulin were measured, and HOMA Index, a measure of insulin resistance, was calculated.. Fasting serum insulin and HOMA Index were significantly decreased (P < 0.03), but gallbladder volume was significantly increased (P < 0.03) in the pioglitazone treated group. Pioglitazone did not alter gallbladder weight or response to ACh, NPY, or CCK.. These data suggest that in insulin-resistant obese mice pioglitazone 1) lowers insulin-resistance, 2) increases resting gallbladder volume, and 3) does not alter gallbladder response to neurotransmitters. Therefore, we conclude that pioglitazone, while improving insulin resistance, paradoxically increases gallbladder volume and, thereby, may increase the propensity for gallstone formation by enhancing gallbladder stasis.

Topics: Acetylcholine; Age Factors; Animals; Blood Glucose; Cholecystokinin; Cholinergic Agents; Dietary Carbohydrates; Female; Gallbladder; Gallstones; Hypoglycemic Agents; Insulin; Insulin Resistance; Leptin; Mice; Mice, Inbred C57BL; Mice, Obese; Neuropeptide Y; Obesity; Organ Size; Peptide Fragments; Pioglitazone; Thiazolidinediones

The binding of leptin to hypothalamic neurons elicits inhibition of orexigenic NPY/AgRP neurons and stimulation of anorexigenic POMC/CART neurons. Projections of serotonergic neurons onto POMC neurons suggest that leptin and serotonin converge onto POMC neurons to regulate body weight. We probed the interaction of these pathways by generating transgenic mice overexpressing leptin (LepTg) without 5HT2c receptors. On a chow diet, the lean phenotype of LepTg mice was unaffected by the absence of 5HT2c receptors, whereas on a high fat diet, LepTg/5HT2c receptors knockout mice showed an exacerbation of diet-induced obesity. POMC mRNA levels were low in LepTg, 5HT2c receptors knockout and LepTg/5HT2c receptors knockout mice, demonstrating that perturbations of the 5HT2c receptor and leptin pathways, either alone or in combination, negatively impact on POMC expression. Thus, on a chow diet, leptin action is independent of 5HT2c receptors whereas on a high fat diet 5HT2c receptors are required for the attenuation of obesity.

Topics: Agouti-Related Protein; Animals; Body Weight; Diet; Hypothalamus; Intercellular Signaling Peptides and Proteins; Leptin; Lipodystrophy; Male; Mice; Mice, Knockout; Neuropeptide Y; Neuropeptides; Obesity; Pro-Opiomelanocortin; Receptor, Serotonin, 5-HT2C; Receptors, Leptin

Neuropeptide Y (NPY) stimulates feeding and weight gain, but deletion of the NPY gene does not affect food intake and body weight in mice bred on a mixed genetic background. We reasoned that the orexigenic action of NPY would be evident in C57Bl/6J mice susceptible to obesity. NPY deficiency has no significant effect in mice fed a normal rodent diet. However, energy expenditure is elevated during fasting, and hyperphagia and weight gain are blunted during refeeding. Expression of agouti-related peptide (AGRP) in the hypothalamus is increased in NPY knockout (NPYko) than wild-type mice, but unlike wild type there is no further increase in AGRP when NPYko mice are fasted. Moreover, NPYko mice have higher oxygen consumption and uncoupling protein-1 expression in brown adipose tissue during fasting. The failure of an increase in orexigenic peptides and higher thermogenesis may contribute to attenuation of weight gain when NPYko mice are refed. C57Bl/6J mice lacking NPY are also less susceptible to diet-induced obesity (DIO) as a result of reduced feeding and increased energy expenditure. The resistance to DIO in NPYko mice is associated with a reduction in nocturnal feeding and increased expression of anorexigenic hypothalamic peptides. Insulin, leptin, and triglyceride levels increase with adiposity in both wild-type and NPYko mice.

Topics: Aging; Animals; Appetite; Blood Glucose; Body Weight; Corticosterone; Dietary Fats; Eating; Fasting; Female; Insulin; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Obese; Neuropeptide Y; Obesity; Oxygen Consumption; Thyroxine; Weight Gain

Topics: Animals; Humans; Neuropeptide Y; Obesity; Rats; Receptors, Neuropeptide Y

Serotonin (5-hydroxytryptamine; 5-HT) 2A receptors contribute to the effects of 5-HT on platelet aggregation and vascular smooth muscle cell proliferation, and are reportedly involved in decreases in plasma levels of adiponectin, an adipokine, in diabetic subjects. Here, we report that systemic administration of sarpogrelate, a 5-HT2A receptor antagonist, suppressed appetite and increased hypothalamic pro-opiomelanocortin and cocaine- and amphetamine-regulated transcript, corticotropin releasing hormone, 5-HT2C, and 5-HT1B receptor gene expression. A(y) mice, which have ectopic expression of the agouti protein, significantly increased hypothalamic 5-HT2A receptor gene expression in association with obesity compared with wild-type mice matched for age. Systemic administration of sarpogrelate suppressed overfeeding, body weight gain, and hyperglycemia in obese A(y) mice, whereas it did not increase plasma adiponectin levels. These results suggest that obesity increases hypothalamic 5-HT2A receptor gene expression, and pharmacologic inactivation of 5-HT2A receptors inhibits overfeeding and obesity in A(y) mice, but did not increase plasma adiponectin levels.

Topics: Adiponectin; Animals; Appetite; Body Weight; Eating; Gene Expression; Hypothalamus; Male; Mice; Mice, Obese; Nerve Tissue Proteins; Neuropeptide Y; Obesity; Pro-Opiomelanocortin; Receptor, Serotonin, 5-HT1B; Receptor, Serotonin, 5-HT2A; Receptor, Serotonin, 5-HT2C; Receptors, Corticotropin-Releasing Hormone; Serotonin 5-HT2 Receptor Antagonists; Serotonin Antagonists; Succinates

Neuropeptides play a pivotal role in the control of metabolic homeostasis. We aimed to evaluate the release of neuropeptides involved in the control of energy homeostasis in relation to metabolic status in aging humans. The study group consisted of 183 women: 75 centenarians (above 100 yrs old), 26 elderly women (below 70 yrs), 45 younger women (mean 26 yrs) and 37 obese women (mean 41.6 yrs). Fasting plasma concentration of leptin, adiponectin, ghrelin active, neuropeptide Y (NPY) and insulin were measured. Our results showed several differences in the metabolic and neurohormonal status in the centenarian group. The incidence of hypertension, glucose intolerance, insulin resistance and dyslipidemia was lower compared with obese women. Leptin and NPY concentrations were significantly lower than in elderly and obese subjects. Moreover, NPY level was higher than that in the younger group. Plasma adiponectin values were higher than in any of the other group. Insulin levels were significantly lower compared with the young and obese groups. Furthermore, a negative correlation was found between adiponectin and HOMA-IR, and adiponectin and insulin. Ghrelin active concentrations were significantly lower compared with the young subjects. However, ghrelin levels were higher than in obese subjects. We conclude that altered neuropeptide activity in centenarians may play a role in the mechanisms contributing to prolonged survival.

Topics: Adiponectin; Adult; Age Factors; Aged; Aged, 80 and over; Aging; Female; Ghrelin; Homeostasis; Humans; Insulin; Leptin; Longevity; Middle Aged; Neuropeptide Y; Neuropeptides; Neurosecretory Systems; Obesity; Peptide Hormones

Neuropeptide Y (NPY) and leptin are two peptides involved in the regulation of body weight, energy balance, and sympathetic tone. This study investigates the independent role of apneas and obesity on NPY and leptin plasma levels in patients with obstructive sleep apnea syndrome (OSAS). To this end we compared their values in 23 obese (body mass index > 30 kg/m2) and 24 nonobese (body mass index < 27 kg/m2) patients with OSAS, and in 19 obese and 18 nonobese control subjects without OSAS. Patients who used continuous positive airway pressure for more than 4 hours/night were reexamined 3 and 12 months later. We found that NPY levels were increased (p < 0.01) in patients with OSAS independently of obesity. Leptin levels were also increased in OSAS but this was mostly associated to obesity. Continuous positive airway pressure treatment reduced NPY levels in all patients and leptin levels only in nonobese patients (p < 0.01). We concluded that NPY and leptin plasma levels are increased in patients with OSAS. Yet, whereas the former appear independent of obesity, the latter are mostly associated with obesity.

Topics: Analysis of Variance; Biomarkers; Case-Control Studies; Continuous Positive Airway Pressure; Humans; Leptin; Male; Middle Aged; Neuropeptide Y; Obesity; Prospective Studies; Sleep Apnea, Obstructive; Statistics, Nonparametric

Otsuka Long-Evans Tokushima fatty (OLETF) rats lacking cholecystokinin-A receptors are hyperphagic, obese, and diabetic. Although exercise attenuates OLETF rats' obesity, the mechanisms underlying the effects of exercise are unclear. In this study, we determined the effects of running wheel activity on patterns of body weight gain, food intake, and hypothalamic gene expression. We demonstrate that voluntary running activity beginning at 8 wk of age normalized meal patterns, food intake, body weight, and plasma levels of glucose and leptin in OLETF rats. During the initial exercise period, corticotropin-releasing factor (CRF) mRNA expression was significantly elevated in the dorsomedial hypothalamus (DMH) but not in the paraventricular nucleus in both OLETF and control Long-Evans Tokushima rats. In response to long-term exercise, arcuate nucleus (Arc) neuropeptide Y (NPY), and proopiomelanocortin as well as DMH NPY and CRF mRNA expression were increased in Long-Evans Tokushima rats. In contrast, whereas exercising OLETF rats had increased Arc NPY and DMH CRF expression, Arc proopiomelanocortin and DMH NPY mRNA levels were not elevated. Finally, we demonstrate that the effects of exercise on body weight in OLETF rats were long lasting. Although food intake and body weight were increased in OLETF rats when running wheels were locked, weights did not return to those of sedentary OLETF rats. Together, these data suggest that the elevation of DMH CRF expression may mediate the short-term feeding inhibitory effects of exercise and that exercise limits the elevation of DMH NPY expression to account for the overall prevention of OLETF rats' obesity.

Topics: Animals; Blood Glucose; Body Weight; Corticotropin-Releasing Hormone; Eating; Hyperphagia; Hypothalamus; Leptin; Male; Neuropeptide Y; Obesity; Physical Conditioning, Animal; Pro-Opiomelanocortin; Rats; Rats, Inbred OLETF; Rats, Long-Evans; RNA, Messenger; Running; Signal Transduction

Early life nutrition impacts on subsequent risk of obesity and hypertension. Several brain chemicals responsible for both feeding and cardiovascular regulation are altered in obesity. We examined effects of early postnatal overnutrition on blood pressure, brain neuropeptide Y (NPY), and adiposity markers. Rat pup litters were adjusted to either 3 or 12 male animals (overnutrition and control, respectively) on day 1 of life. After weaning, rats were given either a palatable high-fat diet or standard chow. Smaller litter pups were significantly heavier by 17 days of age. By 16 wk, the effect of litter size was masked by that of diet, postweaning. Small and normal litter animals fed a high-fat diet had similar increases in body weight, plasma insulin, leptin, and adiponectin concentrations, leptin mRNA, and fat masses relative to chow-fed animals. An increase in 11beta-hydroxysteroid dehydrogenase-1 mRNA in white adipose tissue, and a decrease in uncoupling protein-1 mRNA in brown adipose tissue in both small litter groups at 16 wk of age, may represent a programming effect of the altered litter size. NPY concentration in the paraventricular nucleus of the hypothalamus was reduced in high fat-fed groups. Blood pressure was significantly elevated at 13 wk in high-fat-fed animals. This study demonstrates that overnourishment during early postnatal development leads to profound changes in body weight at weaning, which tended to abate with maturation. Thus the effects of long-term dietary intervention postweaning can override those of litter size-induced obesity.

Topics: 11-beta-Hydroxysteroid Dehydrogenase Type 1; Adiponectin; Adipose Tissue, Brown; Animals; Animals, Newborn; Blood Pressure; Blotting, Northern; Body Weight; Brain; Carrier Proteins; Dietary Fats; Female; Insulin; Intercellular Signaling Peptides and Proteins; Ion Channels; Leptin; Male; Membrane Proteins; Mitochondrial Proteins; Neuropeptide Y; Obesity; Rats; Rats, Sprague-Dawley; RNA, Messenger; Tumor Necrosis Factor-alpha; Uncoupling Protein 1

The anti-obesity effects of crude saponin (CS) of Korean red ginseng (KRG) were investigated in the rat fed a high-fat (HF) diet. Male Sprague-Dawley (SD) rats became obese by feeding the HF diet over 5 weeks, while the control rats were fed a normal diet, and then both groups were treated with CS (200 mg/kg, i.p.) for 3 weeks. The body weight, food consumption, adipose tissues, and expression of appetite peptides such as leptin and neuropeptide Y (NPY) were investigated in rats fed normal and HF diet after treatment of CS. Administration of CS reduced body weight, food intake, and fat content in HF diet rats in a manner similar to those of the normal diet fed rats. The hypothalamic NPY expression and serum leptin level were reduced in HF diet rats after CS treatment. Our results suggest that CS may be useful in the treatment of obesity and related disorders as anti-obesity agents.

Topics: Adipose Tissue; Animals; Body Weight; Dietary Fats; Disease Models, Animal; Drug Administration Schedule; Eating; Gene Expression; Hypothalamus; Injections, Intraperitoneal; Korea; Leptin; Male; Neuropeptide Y; Obesity; Panax; Plants, Medicinal; Rats; Rats, Sprague-Dawley; Saponins; Time Factors

To explore the cause of decreasing intake food of diet-induced obesity resistant (DIO-R) rats.. Fifty male Sprague-dawley (SD) rats were randomly divided into control group and high-fat group and they were fed with basic diet and high-fat diet respectively for 13 weeks. DIO-R and diet-induced obesity (DIO) rats were selected according to their body weight and the quantity of energy intake, then observing the changes of the total food intake, the level of serum leptin and plasma NPY were determined by radioimmunoassay and the contents of the melanocortin receptor-4 (MCR-4) in brain were determined by Western Blot.. The total food intake of DIO-R rats was (1 679.1 +/- 146.8) g. The total food intake of DIO rats was (1 818.4 +/- 148.9) g. The total food intake of DIO-R rats was lower than that of DIO rats (P < 0.05). The level of plasma NPY of DIO-R rats was (795.24 +/- 83.59) ng/L. The level of plasma NPY of DIO rats was (1 007.14 +/- 172.83) ng/L. The level of plasma NPY of DIO-R rats was lower than that of the DIO rats (P < 0.05). The levels of serum leptin of basic, DIO-R and DIO rats was (4.80 +/- 0.75) microg/L, (9.17 +/- 1.19) microg/L and (9.32 +/- 1.04) microg/L. The level of serum leptin of rats in high-fat diet group was increased as compared with the rats in basic diet group, but there was no significant difference between DIO-R and DIO rats (P > 0.05). The levels of brain MCR-4 of basic, DIO-R and DIO rats were (342 +/- 31) mm2, (455 +/- 33) mm2, (355 +/- 30) mm2. High fat diets increased the content of brain MCR-4 in DIO-R rats.. DIO-R rats decreased appetite by increasing expression of ob gene to reduce activity of NPY pathway and activate the MCR-4 pathway, and thus inhibit the increase body of weight.

Topics: Animals; Appetite; Blotting, Western; Body Weight; Brain; Dietary Fats; Disease Models, Animal; Energy Intake; Leptin; Male; Neuropeptide Y; Obesity; Radioimmunoassay; Random Allocation; Rats; Rats, Sprague-Dawley; Receptor, Melanocortin, Type 4

Leptin signaling in the brain regulates energy intake and expenditure. To test the degree of functional neuronal leptin signaling required for the maintenance of body composition, fertility, and cold tolerance, transgenic mice expressing Cre in neurons (CaMKIIalpha-Cre) were crossed to mice carrying a floxed leptin receptor (Lepr) allele to generate mice with neuron-specific deletion of Lepr in approximately 50% (C F/F mice) and approximately 75% (C Delta17/F mice) of hypothalamic neurons. Leptin receptor (LEPR)-deficient mice (Delta17/Delta17) with heat-shock-Cre-mediated global Lepr deletion served as obese controls. At 16 wk, male C F/F, C Delta17/F, and Delta17/Delta17 mice were 13.2 (P < 0.05), 45.0, and 55.9% (P < 0.001) heavier, respectively, than lean controls, whereas females showed 31.6, 68.8, and 160.7% increases in body mass (P < 0.001). Significant increases in total fat mass (C F/F: P < 0.01; C Delta17/F and Delta17/Delta17:P < 0.001 vs. sex-matched, lean controls), and serum leptin concentrations (P < 0.001 vs. controls) were present in proportion to Lepr deletion. Male C Delta17/F mice had significant elevations in basal serum insulin concentrations (P < 0.001 vs. controls) and were glucose intolerant, as measured by glucose tolerance test (AUC P < 0.01 vs. controls). In contrast with previous observations in mice null for LEPR signaling, C F/F and C Delta17/F mice were fertile and cold tolerant. These findings support the hypothesis that body weight, adiposity, serum leptin concentrations, and glucose intolerance are proportional to hypothalamic LEPR deficiency. However, fertility and cold tolerance remain intact unless hypothalamic LEPR deficiency is complete.

Topics: Adaptation, Physiological; Adipose Tissue, Brown; Animals; Arginine Vasopressin; Body Weight; Cold Temperature; Diabetes Mellitus, Experimental; DNA, Complementary; Eating; Female; Fertility; Hypothalamus; Male; Mice; Mice, Knockout; Mice, Transgenic; Neurons; Neuropeptide Y; Obesity; Pro-Opiomelanocortin; Receptors, Cell Surface; Receptors, Leptin

We previously reported a positive association among body mass index, single nucleotide polymorphisms (SNP) in the leptin and leptin receptor genes that are involved in body weight regulation, and non-Hodgkin lymphoma (NHL). Polymorphisms in the ghrelin (GHRL) and neuropeptide Y (NPY) genes were examined in the same population-based case-control study of NHL to further explore the role of genes involved in energy homeostasis and obesity in susceptibility to NHL. Ghrelin is an orexigenic hormone that induces NPY release and inhibits proinflammatory cytokines via its antagonistic relationship with leptin. NPY is a potent appetite stimulator controlled by ghrelin and leptin and also acts as a mediator of immune function. DNA from 458 cases and 812 controls was genotyped. Among genotyped GHRL SNPs, the variant allele for GHRL -4427G>A was inversely associated with all NHL [odds ratios (OR), 0.78; 95% confidence interval (95% CI), 0.59-1.0] and more specifically with diffuse large cell lymphoma (DLCL; homozygous variant: OR, 0.31; 95% CI, 0.13-0.74). Another SNP, GHRL 5179A>G, decreased the risk of DLCL (homozygous variant: OR, 0.35; 95% CI, 0.10-1.2). NPY -485T>C, 1258G>A, and 5671C>T were in total linkage disequilibrium (D' = 0.99) and the homozygous variants were associated with an increased risk of NHL in NPY SNPs -485T>C (OR, 1.7; 95% CI, 1.1-2.5), 1258G>A (OR, 1.7; 95% CI, 1.1-2.5), and 5671C>T (OR, 1.9; 95% CI, 1.3-2.8). When stratified by subtype, the variant allele for NPY 1128T>C was positively associated with follicular lymphoma (OR, 2.3; 95% CI, 1.1-4.9) as were homozygous variants for NPY SNPs -485T>C (OR, 2.4; 95% CI, 1.3-4.4), 1258G>A (OR, 2.0; 95% CI, 1.1-3.5), and 5671C>T (OR, 1.8; 95% CI, 1.1-3.0). These results add further support for the hypothesis that SNPs in energy-regulating genes affect risk of NHL.

Topics: Adult; Aged; Appetite; California; Case-Control Studies; DNA Primers; Energy Metabolism; Female; Genotype; Ghrelin; Homeostasis; Humans; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Non-Hodgkin; Male; Middle Aged; Neuropeptide Y; Obesity; Peptide Hormones; Polymorphism, Single Nucleotide

To understand mechanisms underlying a resistance to obesity, two obesity-resistant inbred mouse strains, SWR/J and A/J, were compared to 3 inbred "control" strains, C3H/HeJ, BALB/cByJ and C57L/J. These 5 strains, studied at 5 weeks of age when similar in body weight, were maintained for 3 weeks on a 3-diet feeding paradigm, with separate jars of carbohydrate, protein and fat, or for 1 week on a single high-fat or low-fat diet. The control strains each chose a balanced diet, with 50% carbohydrate and 15-25% fat, and they had a similar, normal range of scores for measures of body weight, adiposity, endocrine parameters and metabolic enzyme activity. Compared to these control strains, the obesity-resistant SWR/J and A/J strains consumed more total calories and selected a diet with significantly more fat (35-45%) and less carbohydrate (35%). Despite overeating, they weighed less and had significantly reduced adiposity. They also had lower levels of insulin and exhibited increased capacity of skeletal muscle to metabolize fat, as indicated by measures beta-hydroxyacyl-CoA dehydrogenase activity or its ratio to citrate synthase. Measurements of hypothalamic peptides via radioimmunoassay or real-time quantitative PCR revealed markedly enhanced galanin (GAL) in the paraventricular nucleus and reduced neuropeptide Y (NPY) expression in the arcuate nucleus of obesity-resistant mice. These patterns in SWR/J and A/J strains, seen on a low-fat as well as high-fat diet, may reflect mechanisms involving excess GAL and reduced NPY that contribute early, respectively, to the over-consumption of a high-fat diet and a resistance to the obesity-promoting effects of this diet.

Topics: 3-Hydroxyacyl CoA Dehydrogenases; Animals; Body Weight; Brain Chemistry; Citrate (si)-Synthase; Diet; Dietary Fats; Feeding Behavior; Galanin; Male; Mice; Mice, Inbred Strains; Muscle, Skeletal; Neuropeptide Y; Obesity; Phenotype; Reverse Transcriptase Polymerase Chain Reaction

Peg3 encodes a C2H2 type zinc finger protein that is implicated in a novel physiological pathway regulating core body temperature, feeding behavior, and obesity in mice. Peg3+/- mutant mice develop an excess of abdominal, subcutaneous, and intra-scapular fat, despite a lifetime of lower food intake than wild-type animals. However, they start life with reduced fat reserves and are slower to enter puberty. These mice maintain a lower core body temperature, fail to respond to a cold challenge, and have lower metabolic activity as measured by oxygen consumption. Plasma leptin levels are significantly higher than in wild types, and Peg3+/- mice appear to have developed leptin resistance. Administration of exogenous leptin resulted in a significant reduction in food intake in wild-type mice that was not observed in Peg3+/- mutants. This mutation, which is strongly expressed in hypothalamic tissue during development, has the capacity to regulate multiple events relating to energy homeostasis.

Topics: Adipose Tissue; Animals; Body Composition; Body Temperature; Body Weight; Eating; Energy Metabolism; Female; Hypothalamus; Kruppel-Like Transcription Factors; Leptin; Male; Mice; Motor Activity; Mutation; Neuropeptide Y; Obesity; Oxygen Consumption; Pro-Opiomelanocortin; Protein Kinases; RNA, Messenger; Sexual Maturation; Transcription Factors

It has been reported that the peptides such as orexins, neuropeptide Y (NPY) and leptin may play an important role in the regulation of appetite and energy metabolism. The interaction between leptin, orexins and NPY, as well as between peptides and insulin and cortisol in the different nutritional states have been investigated in animals. However, at present this relationship is poorly understood in humans.. Material consisted of 36 obese women and 16 lean women. Plasma orexin A, orexin B, neuropeptide Y (NPY), leptin, insulin concentrations were measured with RIA methods.. Plasma orexin A concentrations were significantly lower in obese women as compared with control group. Plasma orexin A was significantly lower in severe obesity (BMI > 40 kg/m2) than that in moderate obesity (BMI < 40 kg/m2). Plasma orexin B concentrations did not change. However, plasma NPY, leptin and insulin levels were markedly higher in obese women, especially in severe obesity.. Our results confirmed the thesis that orexin A, NPY, leptin play an important role in the regulation of energy metabolism in humans. In obesity the activity of these peptides is disturbed.

Topics: Adult; Energy Metabolism; Female; Humans; Insulin; Intracellular Signaling Peptides and Proteins; Leptin; Middle Aged; Neuropeptide Y; Neuropeptides; Obesity; Orexins; Radioimmunoassay

The interaction of high-fat diet and the peptide YY (PYY) gene expression in diet-induced obesity and the mechanisms which predisposed some individuals to become obese on high-fat diet were explored. Thirty-six male SD rats were randomly divided into high-fat diet group (n=27) and chow fed control group (n=9). After 15 weeks of either a high-fat diet or chew fed diet, the high-fat diet group was subdivided into dietary induced obesity (DIO) and dietary induced obesity resistant (DIR) group according to the final body weight. Then the DIO rats were subdivided into two groups for a 8-week secondary dietary intervention. One of the group was switched to chew fed diet, whereas the other DIO and DIR rats continued on the initial high-fat diet. Weight gain and food intake were measured, food efficiency was calculated, and the concentrations of plasma neuropeptide Y (NPY) and PYY were assayed. Hypothalamic NPY mRNA expression and PYY mRNA expression in ileum and colon was detected by RT-PCR. The results showed that at the end of 15th week, the levels of body weight and caloric intake were significantly higher in DIO group than in DIR or control group (P<0. 01), while no significant difference was found between DIR and control group (P>0.05). The concentration of plasma PYY was significantly higher in DIR group than in DIO and CF group, while no significant difference was found between DIO and CF group (P <0.01). After switching the DIO rats to chow fed diet, their body weight gains were significantly lower than that of the DIO-HF group. The expression of PYY mRNA was increased in DIO-HF/ CF rats than in DIO-HF rats, and the expression of hypothalamic NPY mRNA was decreased in DIO-HF/CF rats than in DIO-HF group. It was concluded that both dietary composition and PYY gene expression could potently alter the hypothalamic NPY expression and result in different susceptibility to obese and overeating. The decreased PYY was associated with the increased NPY expression and their predisposal to obese and overeating in rats.

Topics: Animals; Dietary Fats; Eating; Energy Metabolism; Genetic Predisposition to Disease; Male; Neuropeptide Y; Obesity; Peptide YY; Random Allocation; Rats; Rats, Sprague-Dawley; RNA, Messenger

Age-related obesity is associated with impaired hypothalamic pro-opiomelanocortin (Pomc) gene expression. We assessed whether overproduction of POMC in the hypothalamus ameliorates age-related obesity in rats.. Recombinant adeno-associated virus (rAAV) encoding Pomc (rAAV-Pomc) or control vector was delivered bilaterally into the basomedial hypothalamus of aged obese rats with coordinates targeting the arcuate nucleus. Energy balance, glucose metabolism, brown adipose tissue thermogenesis and mRNA levels of hypothalamic neuropeptides and melanocortin receptors were assessed.. Forty-two days after Pomc gene delivery, hypothalamic Pomc expression increased 12-fold while agouti-related protein and neuropeptide Y mRNA levels remained unchanged. Using a punch technique, we detected the highest Pomc RNA level in the arcuate nucleus. Pomc overexpression reduced food consumption from day 10 after vector injection, but this anorexic effect abated by day 30. In contrast, there was a steady decrease in body weight without apparent attenuation. Pomc gene delivery decreased visceral adiposity and induced uncoupling protein 1 in brown adipose tissue in aged rats. Serum NEFA and triglyceride levels were also diminished by rAAV-Pomc treatment. Improved glucose metabolism and insulin sensitivity were observed on day 36 but not day 20 after Pomc gene delivery. The expression of hypothalamic melanocortin 3 and 4 receptor decreased by 17% and 25%, respectively in rAAV-Pomc rats.. This study demonstrates that targeted Pomc gene therapy in the hypothalamus reduces body weight and visceral adiposity, and improves glucose and fat metabolism in aged obese rats. Thus long-term activation of the central melanocortin system may be a viable strategy to combat age-related obesity and diabetes.

Topics: Adipose Tissue, Brown; Aging; Agouti-Related Protein; Animals; Body Weight; Cholesterol; Dependovirus; Eating; Fatty Acids, Nonesterified; Genetic Therapy; Genetic Vectors; Glucose; Glucose Intolerance; Glucose Tolerance Test; Hypothalamus; Intercellular Signaling Peptides and Proteins; Leptin; Male; Neuropeptide Y; Obesity; Peptide Hormones; Pro-Opiomelanocortin; Rats; Rats, Inbred F344; Receptor, Melanocortin, Type 3; Receptor, Melanocortin, Type 4; Triglycerides

We have generated mice that carry a neuron-specific leptin receptor (LEPR) transgene whose expression is driven by the rat synapsin I promoter synapsin-LEPR B (SYN-LEPR-B). We have also generated mice that are compound hemizygotes for the transgenes SYN-LEPR-B and neuron-specific enolase-LEPR B (NSE-LEPR-B). We observed a degree of correction in db/db mice that are hemizygous (Syn db/db) and homozygous (Syn/Syn db/db) for the SYN-LEPR-B transgene similar to that previously reported for the NSE-LEPR-B transgene. We also show complete correction of the obesity and related phenotypes of db/db mice that are hemizygous for both NSE-LEPR-B and SYN-LEPR-B transgenes (Nse+Syn db/db). Body composition, insulin sensitivity, and cold tolerance were completely normalized in Nse+Syn db/db mice at 12 weeks of age compared with lean controls. In situ hybridization for LEPR B isoform expression in Nse+Syn db/db mice showed robust expression in the energy homeostasis-relevant regions of the hypothalamus. Expression of 3 neuropeptide genes, agouti-related peptide (Agrp), neuropeptide Y (Npy), and proopiomelanocortin (Pomc), was fully normalized in dual transgenic db/db mice. The 2 transgenes in concert conferred normal fertility to male and female db/db mice. Male mice with partial peripheral deletion of Lepr, induced in the periweaning phase, did not show alterations in body composition or mass. In summary, we show that brain-specific leptin signaling is sufficient to reverse the obesity, diabetes, and infertility of db/db mice.

Topics: Agouti-Related Protein; Alleles; Animals; Blood Glucose; Body Composition; Body Weight; Cold Temperature; Diabetes Mellitus; DNA, Complementary; Female; Fertility; Gene Expression Regulation; Genetic Therapy; Genotype; Glucose; Homeostasis; Homozygote; Hypothalamus; In Situ Hybridization; Infertility; Infertility, Female; Infertility, Male; Insulin; Intercellular Signaling Peptides and Proteins; Male; Mice; Mice, Transgenic; Neurons; Neuropeptide Y; Obesity; Peptides; Phenotype; Phosphopyruvate Hydratase; Polymerase Chain Reaction; Pro-Opiomelanocortin; Promoter Regions, Genetic; Protein Isoforms; Proteins; Rats; Receptors, Cell Surface; Receptors, Leptin; Signal Transduction; Synapsins; Time Factors; Tissue Distribution; Transgenes

To observe effects of acupuncture on BMI, WHR and serum levels of leptin and neuropeptide Y in simple obesity Uigur patients to research the mechanism of acupuncture in slimming.. Thirty simple obesity Uigur patients were treated with body acupuncture combined with electroacupuncture. Two courses later, their therapeutic effects were observed. And the above indexes were determined before and after treatment.. The clinical total effective rate was 80.00%, and BMI, WHR, and the serum leptin level decreased (P < 0. 001).. Uigur patients of simple obesity possibly exist resistance of leptin and acupuncture can decrease the peripheral leptin content.

Topics: Acupuncture Therapy; Electroacupuncture; Humans; Leptin; Neuropeptide Y; Obesity

Neuropeptide Y (NPY) is a powerful orexigenic neurotransmitter. The NPY Y1 and Y5 receptors have been implicated in mediating the appetite-stimulating activity of NPY. To further investigate the importance of these two receptors in NPY-induced hyperphagia after chronic central administration, we used mice lacking either Npy1r or Npy5r expression. NPY infusion into the lateral ventricle of wild-type mice stimulated food intake and induced obesity over a 7-d period. Fat pad weight as well as plasma insulin, leptin, and corticosterone levels were strongly increased in NPY-treated mice. In addition, NPY infusion resulted in a significant decrease in hypothalamic NPY and proopiomelanocortin expression. Interestingly, the lack of either Npy1r or Npy5r expression in knockout mice did not affect such feeding response to chronic NPY infusion. Moreover, the obesity syndrome that developed in these animals was similar to that in wild-type animals. Taken together, these data strongly suggest biological redundancies between Y1 and Y5 receptor signaling in the NPY-mediated control of food intake.

Topics: Adipose Tissue; Animals; Body Weight; Corticosterone; Drinking; Eating; Feeding Behavior; Hyperphagia; Injections, Intraventricular; Insulin; Lateral Ventricles; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Neuropeptide Y; Obesity; Pro-Opiomelanocortin; Receptors, Neuropeptide Y; RNA, Messenger

The effects of diet and adiposity have been implicated in disturbances of female reproductive function. In an effort to better elucidate the relationship between obesity and female fertility, we analyzed the effect of increasing dietary fat content on body composition, insulin sensitivity, and pregnancy rates in two common inbred mouse strains, DBA/2J and C57BL/6J. After 16 wk, females of both strains on the high fat diet developed glucose intolerance and insulin resistance, but only the female DBA/2J mice developed dietary-induced obesity and hyperleptinemia. The high fat diet was associated with more than a 60% decrease in natural pregnancy rates of female DBA/2J mice, whereas the fertility of female C57BL/6J mice was unaffected. Despite developing a similar degree of obesity, insulin resistance, and hyperleptinemia, male DBA/2J mice did not manifest diminished fertility. Obese female DBA/2J mice achieved normal ovulatory responses and pregnancy rates after exogenous gonadotropin stimulation, suggesting their fertility defect to be central in origin. Real-time PCR quantification of hypothalamic cDNA revealed a 100% up-regulation of neuropeptide Y and a 50% suppression of GnRH expression accompanied by a 95% attenuation of leptin receptor type B expression in obese female DBA/2J mice. These findings suggest that obesity-associated hyperleptinemia, and not insulin resistance or increased dietary fat per se, gradually induces central leptin resistance, increases hypothalamic neuropeptide Y-ergic tone, and ultimately causes hypothalamic hypogonadism. The data establish high fat-fed female DBA/2J mice as a wild-type murine model of obesity-related infertility.

Topics: Animals; Body Composition; Dietary Fats; Female; Gene Expression; Hyperinsulinism; Hypothalamus; Infertility, Female; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Neuropeptide Y; Obesity; Pregnancy; Receptors, Cell Surface; Receptors, Leptin; Repressor Proteins; Species Specificity; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins; Transcription Factors

Dietary fatty acid profile, independent of caloric percent of fat, is a major regulator of body adiposity. This study examined the effects of dietary fat amount and types on fat storage and hypothalamic gene expression in the mouse model of chronic diet-induced obesity.. The dietary interventions were in twofold: (1) the obesity was induced by a 13-week obesogenic fat diet compared with a low-fat (LF) diet, and (2) the reversibility was tested by using high n-3 polyunsaturated fat (PUFA) and LF diets. Fifty-four C57Bl/6 mice were fed a high-fat (59% in kcal) diet for 13 weeks and then classified as diet-induced obese (DIO) or diet-resistant (DR) mice according to upper and lower tertiles of body weight gain. The DIO mice were then subdivided into three groups for a 6-week secondary dietary intervention. Two of the groups were switched to either a high n-3 PUFA (DIO-n3) or a low-fat (10% in kcal, DIO-LF) diet, whereas the third (controls) and DR mice continued on the initial high-fat diet. Food efficiency was calculated as weekly body weight gain per gram of food intake.. After switching the DIO mice to the n-3 PUFA or LF diet, their body weights were reduced to the level of the DR and LF mice. The food efficiencies were, from the highest to lowest, in the order: DIO>LF>DR>DIO-LF>DIO-n3. Using quantitative in situ hybridization, we found that the DIO mice had higher levels of leptin receptor (LR, +290%, p<0.005) and neuropeptide Y (NPY, +25%, p<0.05) mRNA expression in the hypothalamic arcuate nucleus (Arc) than the DR mice, whereas the level of pro-opiomelanocortin (POMC) mRNA expression was significantly reduced (-45%, p<0.01). All effects that were essentially returned to DR levels by the change to the n-3 PUFA diet and, with the exception of a failure to normalize Arc NPY mRNA levels, by the change to LF diet.. Taken together, the present results show that both change in level and quality of dietary fat can potently alter hypothalamic neuropeptide expression and result in effective amelioration of diet-induced obesity. Interestingly, the n-3 PUFA diet when fed to already obese mice produced a pattern of hypothalamic gene expression similar to that in obesity resistant (DR) mice. It remains to be determined if the effects of n-3 fatty acids on brain neuropeptide gene expression are direct or indirect.

Topics: Adipose Tissue; Animals; Arcuate Nucleus of Hypothalamus; Diet; Dietary Fats; Energy Intake; Energy Metabolism; Fatty Acids, Omega-3; Fatty Acids, Unsaturated; Gene Expression Regulation; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Neuropeptide Y; Obesity; Pro-Opiomelanocortin; Receptors, Cell Surface; Receptors, Leptin; RNA, Messenger; Triglycerides; Weight Gain

The effects of running wheel exercise and caloric restriction on the regulation of body weight, adiposity, and hypothalamic neuropeptide expression were compared in diet-induced obese male rats over 6 wk. Compared with sedentary controls, exercising rats had reduced body weight gain (24%), visceral (4 fat pads; 36%) and carcass (leptin; 35%) adiposity but not insulin levels. Hypothalamic arcuate nucleus (ARC) proopiomelanocortin (POMC) mRNA expression was 25% lower, but ARC neuropeptide Y (NPY), agouti- related peptide, dorsomedial nucleus (DMN) NPY, and paraventricular nucleus (PVN) corticotropin- releasing hormone (CRH) expression was comparable to controls. Sedentary rats calorically restricted to 85% of control body weight reduced their visceral adiposity (24%), leptin (64%), and insulin (21%) levels. ARC NPY (23%) and DMN NPY (60%) were increased, while ARC POMC (40%) and PVN CRH (14%) were decreased. Calorically restricted exercising rats an half as much as ad libitum-fed exercising rats and had less visceral obesity than comparably restricted sedentary rats. When sedentary restricted rats were refed after 4 wk, they increased intake and regained the weight gain and adiposity of sedentary controls. While refed exercising rats and sedentary rats ate comparable amounts, refed exercising rats regained weight and adiposity only to the level of ad libitum-fed exercising rats. Thus exercise lowers the defended level of weight gain and adiposity without a compensatory increase in intake and with a very different profile of hypothalamic neuropeptide expression from calorically restricted rats. This may be due to exercise-related factors other than plasma insulin and leptin.

Topics: Adipose Tissue; Agouti-Related Protein; Animals; Autoradiography; Corticotropin-Releasing Hormone; Diet; Energy Intake; Energy Metabolism; Insulin; Leptin; Male; Motor Activity; Neuropeptide Y; Obesity; Peptide Fragments; Physical Exertion; Pro-Opiomelanocortin; Rats; Rats, Sprague-Dawley; Receptors, Cell Surface; Receptors, Leptin; RNA, Messenger; Weight Gain

Hormone-sensitive lipase (HSL) plays a crucial role in the hydrolysis of triacylglycerol and cholesteryl ester in various tissues including adipose tissues. To explore the role of HSL in the metabolism of fat and carbohydrate, we have generated mice lacking both leptin and HSL (Lep(ob/ob)/HSL(-/-)) by cross-breeding HSL(-/-) mice with genetically obese Lep(ob/ob) mice. Unexpectedly, Lep(ob/ob)/HSL(-/-) mice ate less food, gained less weight, and had lower adiposity than Lep(ob/ob)/HSL(+/+) mice. Lep(ob/ob)/HSL(-/-) mice had massive accumulation of preadipocytes in white adipose tissues with increased expression of preadipocyte-specific genes (CAAT/enhancer-binding protein beta and adipose differentiation-related protein) and decreased expression of genes characteristic of mature adipocytes (CCAAT/enhancer-binding protein alpha, peroxisome proliferator activator receptor gamma, and adipocyte determination and differentiation factor 1/sterol regulatory element-binding protein-1). Consistent with the reduced food intake, hypothalamic expression of neuropeptide Y and agouti-related peptide was decreased. Since HSL is expressed in hypothalamus, we speculate that defective generation of free fatty acids in the hypothalamus due to the absence of HSL mediates the altered expression of these orexigenic neuropeptides. Thus, deficiency of both leptin and HSL has unmasked novel roles of HSL in adipogenesis as well as in feeding behavior.

Topics: Adipocytes; Agouti-Related Protein; Animals; Blotting, Northern; Blotting, Western; Corticosterone; Crosses, Genetic; Feeding Behavior; Female; Hypothalamus; Immunoblotting; Immunohistochemistry; Intercellular Signaling Peptides and Proteins; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Mice, Transgenic; Neuropeptide Y; Neuropeptides; Obesity; Oxygen Consumption; Proteins; Sterol Esterase; Temperature; Time Factors

1. Neuropeptide Y (NPY) profoundly enhances feeding when injected intracerebroventricularly, or directly into hypothalamic nuclei, such as the paraventricular nucleus (PVN). Paradoxically, NPY has a reduced action on feeding in obese Zucker rats relative to lean Zucker rats, although the obese rats have much higher levels of hypothalamic NPY expression. GABAergic inputs to a subpopulation of medial parvocellular PVN (mpPVN) neurons are sensitive to NPY. Here, we tested the hypothesis that the blunted eating response to NPY observed in obese Zucker rats will be reflected in a reduced NPY action at mpPVN GABAergic synapses. 2. 'Blind' whole-cell patch-clamp recordings made from mpPVN neurons in acute brain slices of lean and obese Zucker rats revealed GABAergic inhibitory postsynaptic currents (IPSC) responses which were inhibited by NPY. While the maximum response in the obese Zucker rats was significantly less than in lean Zucker or Sprague-Dawley rats, there was no difference in the EC(50). 3. Experiments using blocking concentrations of Y(1)- or Y(5)-receptor antagonists revealed no differences between lean and obese Zucker rats in the contributions of either of these receptors to the total NPY response in mpPVN. 4. NPY is less effective at the mpPVN GABA synapse in obese than in lean Zucker rats. This is not associated with a change in the proportion of Y(1) or Y(5) receptors mediating the NPY response, and is consistent with the downregulation of NPY receptors or a reduction in receptor-effector coupling, and with the reduced sensitivity of obese rats to NPY.

Topics: Animals; Eating; Electrophysiology; Female; In Vitro Techniques; Membrane Potentials; Neurons; Neuropeptide Y; Obesity; Paraventricular Hypothalamic Nucleus; Rats; Rats, Sprague-Dawley; Rats, Zucker; Receptors, GABA-A; Receptors, Neuropeptide Y; Synapses

Neuropeptide Y (NPY) and galanin have both been implicated in the regulation of body weight, yet mice bearing deletions of either of these molecules have unremarkable metabolic phenotypes. To investigate whether galanin and NPY might compensate for one another, we produced mutants lacking both neuropeptides (GAL(-/-)/NPY(-/-)). We found that male GAL(-/-)/NPY(-/-) mice ate significantly more and were much heavier (30%) than wild-type (WT) controls. GAL(-/-)/NPY(-/-) mice responded to a high-fat diet by gaining more weight than WT mice gain, and they were unable to regulate their weight normally after a change in diet. GAL(-/-)/NPY(-/-) mice had elevated levels of leptin, insulin, and glucose, and they lost more weight than WT mice during chronic leptin treatment. Galanin mRNA was increased in the hypothalamus of NPY(-/-) mice, providing evidence of compensatory regulation in single mutants. The disruption of energy balance observed in GAL(-/-)/NPY(-/-) double knockouts is not found in the phenotype of single knockouts of either molecule. The unexpected obesity phenotype may result from the dysregulation of the leptin and insulin systems that normally keep body weight within the homeostatic range.

Topics: Animals; Body Weight; Circadian Rhythm; Dietary Fats; Dorsomedial Hypothalamic Nucleus; Eating; Endocrine System; Galanin; Hormones; Insulin; Leptin; Male; Mice; Mice, Inbred Strains; Mice, Knockout; Motor Activity; Neuropeptide Y; Obesity; Phenotype

To test the hypothesis that genital prolapse may be related to peripheral nerve abnormalities, we examined the changes occurring to peptide-containing nerve processes supplying the periurethral muscles in women with stress urinary incontinence associated with prolapse.. Thirty patients with genital prolapse and 10 age-matched control subjects entered the study. All patients were evaluated by urodynamic investigations. Ten of 30 patients had pure stress urinary incontinence; none of the control subjects was incontinent. During surgery, four biopsy samples were obtained from each woman from the periurethral and perirectal muscles. The muscle sections were processed for immunohistochemistry using specific antibodies to glial (S-100 protein) and general neuronal markers (neuron-specific enolase) and neuropeptides, including neuropeptide Y, vasoactive intestinal polypeptide, and substance P. The evaluation of immunolabeled nerves was based on a semiquantitative analysis that allowed for a four-point ordinate scale score.. S-100 and neuron-specific enolase immunoreactive nerve fibers, running either singly or in small bundles, along with a dense network of neural processes containing neuropeptide Y, vasoactive intestinal polypeptide, and substance P, were found throughout the connective tissue and striated muscle of the control specimens. In contrast, in the muscle specimens from those with genitourinary prolapse, both the density and the intensity of neuropeptide Y, vasoactive intestinal polypeptide, and substance P immunoreactive nerves were markedly reduced compared with the control specimens.. The evidence of a reduced peptide-containing nerve supply to the perineal muscles provides a morphologic basis suggesting that neural abnormalities contribute to the pathogenesis of genital prolapse and urinary incontinence.

Topics: Aged; Biomarkers; Biopsy; Birth Weight; Connective Tissue; Denervation; Female; Humans; Middle Aged; Models, Neurological; Muscle, Skeletal; Nerve Tissue Proteins; Neurons; Neuropeptide Y; Neuropeptides; Obesity; Parity; Pelvic Floor; Peripheral Nervous System Diseases; Phosphopyruvate Hydratase; Postmenopause; Rectum; S100 Proteins; Substance P; Urethra; Urinary Incontinence, Stress; Uterine Prolapse; Vasoactive Intestinal Peptide

Inactivating mutations of the pro-opiomelanocortin (POMC) gene in both mice and humans leads to hyperphagia and obesity. To further examine the mechanisms whereby POMC-deficiency leads to disordered energy homeostasis, we have generated mice lacking all POMC-derived peptides. Consistent with a previously reported model, Pomc(-/-) mice were obese and hyperphagic. They also showed reduced resting oxygen consumption associated with lowered serum levels of thyroxine. Hypothalami from Pomc(-/-) mice showed markedly increased expression of melanin-concentrating hormone mRNA in the lateral hypothalamus, but expression of neuropeptide Y mRNA in the arcuate nucleus was not altered. Provision of a 45% fat diet increased energy intake and body weight in both Pomc(-/-) and Pomc(+/-) mice. The effects of leptin on food intake and body weight were blunted in obese Pomc(-/-) mice whereas nonobese Pomc(-/-) mice were sensitive to leptin. Surprisingly, we found that Pomc(-/-) mice maintained their acute anorectic response to peptide-YY(3-36) (PYY(3-36)). However, 7 days of PYY(3-36) administration had no effect on cumulative food intake or body weight in wild-type or Pomc(-/-) mice. Thus, POMC peptides seem to be necessary for the normal response of energy balance to high-fat feeding, but not for the acute anorectic effect of PYY(3-36) or full effects of leptin on feeding. The finding that the loss of only one copy of the Pomc gene is sufficient to render mice susceptible to the effects of high fat feeding emphasizes the potential importance of this locus as a site for gene-environment interactions predisposing to obesity.

Topics: Animals; Appetite Depressants; Base Sequence; Body Weight; Dietary Fats; DNA Primers; Energy Intake; Hypothalamic Hormones; Hypothalamus; Kinetics; Leptin; Melanins; Mice; Mice, Knockout; Mutagenesis, Site-Directed; Neuropeptide Y; Obesity; Peptide Fragments; Peptide YY; Phenotype; Pituitary Hormones; Polymerase Chain Reaction; Pro-Opiomelanocortin; Transcription, Genetic

Leptin regulates energy homeostasis and reproduction as evidenced by dysfunctions characterized in several genetic models of leptin pathway deficiency, such as the ob/ob and db/db mice and fa/fa Zucker rat. An additional model, the obese (f/f) Koletsky rat with a nonsense leptin receptor mutation has not been fully characterized. These rats are obese, hyperphagic, diabetic, and infertile; however, little else is known about the effects of the mutation. We have characterized alterations in hypothalamic appetite regulating neuropeptides as well as energy expenditure, metabolic hormones, and the reproductive axis of obese f/f rats. As expected, obese rats of both sexes were hyperinsulinemic, hyperglycemic, and hyperleptinemic. They exhibited reduced uncoupling protein-1 mRNA expression in brown fat, indicating reduced energy expenditure. In addition, hypothalamic expression of orexigenic neuropeptide Y and agouti-related peptide mRNA levels was upregulated while the anorexigenic cocaine and amphetamine regulated transcript and proopiomelanocortin mRNA levels were reduced. We also observed reproductive axis perturbations including reduced hypothalamic luteinizing hormone releasing hormone, serum estradiol and testosterone, and increased serum progesterone levels. In conclusion, obese Koletsky rats are phenotypically similar to other leptin pathway deficiency models with reduced energy expenditure and hypothalamic neuropeptidergic alterations that could account for their obesity and infertility.

Topics: Adipose Tissue, Brown; Agouti-Related Protein; alpha-MSH; Amphetamines; Animals; Body Weight; Carrier Proteins; Cocaine; Diabetes Mellitus, Experimental; Disease Models, Animal; Female; Genotype; Hypothalamus; Intercellular Signaling Peptides and Proteins; Ion Channels; Male; Membrane Proteins; Mitochondrial Proteins; Mutation; Neuropeptide Y; Neuropeptides; Obesity; Oligonucleotides; Peptides; Phenotype; Proteins; Rats; Receptors, Cell Surface; Receptors, Leptin; Reproduction; Reverse Transcriptase Polymerase Chain Reaction; Uncoupling Protein 1; Up-Regulation

Disturbances in insulin signaling have been shown to induce obesity and/or hyperphagia in brain insulin receptor or insulin receptor substrate-2 (IRS-2) knockout (KO) mice. This study aimed to examine the central and peripheral mechanisms underlying the phenotype in IRS-2 KO mice.. We measured the histological characterization of adipose tissues, mRNA levels of pro-opiomelanocortin, agouti-related protein, and neuropeptide Y in the hypothalamus and uncoupling proteins (UCPs) in peripheral tissues of IRS-2 KO mice.. Female IRS-2 KO mice showed increased daily food intake. Body weight and adiposity were increased in both sexes, although these differences were more pronounced in female than in male IRS-2 KO mice. Both male and female IRS-2 KO mice showed decreased UCP1 mRNA expression in brown adipose tissue with defective thermoregulation, and UCP2 mRNA expression was increased in the white adipose tissue of female knockout mice. Furthermore, arcuate nucleus mRNA expression of pro-opiomelanocortin, was decreased in both male and female IRS-2 KO mice, whereas expression of agouti-related protein and neuropeptide Y were increased in female IRS-2 KO mice.. In IRS-2 KO mice, disrupted control of hypothalamic neuropeptide levels and UCP mRNA expression may contribute to the development of obesity.

Topics: Adipose Tissue; Agouti-Related Protein; Animals; Arcuate Nucleus of Hypothalamus; Blood Glucose; Body Composition; Eating; Fatty Acids, Nonesterified; Female; Gene Expression; Gene Expression Regulation; Hypothalamus; Insulin; Insulin Receptor Substrate Proteins; Intercellular Signaling Peptides and Proteins; Intracellular Signaling Peptides and Proteins; Ion Channels; Liver; Male; Membrane Transport Proteins; Mice; Mice, Inbred C57BL; Mice, Knockout; Mitochondrial Proteins; Muscle, Skeletal; Neuropeptide Y; Neuropeptides; Obesity; Phosphoproteins; Pro-Opiomelanocortin; Proteins; RNA, Messenger; Sex Characteristics; Triglycerides; Uncoupling Protein 2; Weight Gain

The incidence of obesity, with its associated health risks, is on the increase throughout the western world affecting all age groups, including children. The typical western diet is high in fat and sugar and low in complex carbohydrates. This study looks at the effects of feeding an equivalent high-energy (HE) diet to growing rats. Juvenile male Sprague-Dawley rats that were fed an HE (18.9 kJ/g) diet starting approximately 10 d after weaning gained less weight than littermates fed a nonpurified (14 kJ/g) diet. Despite an initial hyperphagia following the change in diet, HE rats also consumed less energy. Although they exhibited reduced weight gain, HE rats were relatively obese; fat pad weights were elevated for all 4 dissected depots. HE-fed rats exhibited symptoms of developing metabolic syndrome with elevated plasma concentrations of glucose, triglycerides, nonesterified fatty acids, insulin, and leptin. In addition, leptin receptor gene expression in the hypothalamic arcuate nucleus (ARC) and ventromedial nucleus of HE rats was reduced. Consistent with the elevated serum leptin and other peripheral signals in HE rats, hypothalamic gene expression for the orexigenic neuropeptides, neuropeptide Y (ARC and dorsomedial nucleus), and agouti-related peptide (AgRP), was reduced. This reduction in orexigenic signaling and decline in energy intake is consistent with an apparent attempt to counter the further development of an obese state in rats consuming an energy-dense diet. The juvenile Sprague-Dawley rat has potential in the development of a model of childhood diet-induced obesity.

Topics: Agouti-Related Protein; Animals; Animals, Newborn; Body Weight; Energy Intake; Gene Expression; Hypothalamus; Intercellular Signaling Peptides and Proteins; Leptin; Male; Metabolic Syndrome; Neuropeptide Y; Obesity; Proteins; Rats; Rats, Sprague-Dawley; Receptors, Cell Surface; Receptors, Leptin

We examined the galanin-like peptide (GALP) gene expression in the arcuate nucleus (ARC) and posterior pituitary (PP) in 6- and 18-week-old male obese fa/fa rats. GALP mRNA in the ARC in fa/fa rats was significantly decreased in 6- and 18-week-old and GALP mRNA in the PP in fa/fa rats was significantly increased in 18-week-old compared to lean Fa/? rats. Insulin treatment in hyperglycemic fa/fa rats partially reversed those changes. These results suggest that the GALP gene expression in fa/fa rats might be regulated in part by leptin-independent mechanisms.

Topics: Animals; Arcuate Nucleus of Hypothalamus; Blood Glucose; Galanin-Like Peptide; Gene Expression Regulation; Hyperglycemia; Insulin; Leptin; Male; Neuropeptide Y; Obesity; Pituitary Gland, Posterior; Pro-Opiomelanocortin; Rats; Rats, Mutant Strains; RNA, Messenger

Obesity, inactivity and being overweight are leading causes of morbidity and mortality in the United States. The relationship between eating, overeating, and addiction have been discussed, debated and more recently investigated. We have hypothesized that drugs of abuse compete with food for brain reward sites. Overeating and obesity may act as protective factors reducing drug reward and addiction.. In the first part of this study, 374 charts of all active weight management patients in a 12-month period were examined. Demographic information, laboratory testing, psychiatric diagnostic interview, alcohol and drug history were reviewed. A detailed alcohol use, abuse, dependence history was present in 298 charts as part of the pre-bariatric evaluation. The relationship between BMI and alcohol use among female patients (n = 298) was then analyzed.. We found a significant (p <.05) inverse relationship between BMI and alcohol consumption. The more obese the patient was, the less alcohol they consumed. The percentage of women who consumed alcohol in the past year decreased as BMI level increased. These results confirmed our surgeons' perception that it is rare to find a morbidly obese patient excluded for bariatric surgery because of excessive alcohol consumption.. Obese patients have lower rates of alcohol use than found in the general population of women. As BMI increases, lower rates of alcohol consumption are found. Overeating may compete with alcohol for brain reward sites, making alcohol ingestion less reinforcing.

Topics: Adolescent; Adult; Alcoholism; Behavior, Addictive; Body Mass Index; Brain; Comorbidity; Female; gamma-Aminobutyric Acid; Humans; Middle Aged; Neuropeptide Y; Obesity; Positron-Emission Tomography; United States

Galanin-like peptide (GALP) is a 60-amino-acid peptide with structural similarities to galanin and a high affinity for galanin receptors. GALP is expressed by a discrete population of neurons in the arcuate nucleus (ARC) and median eminence of the hypothalamus of several species, including the rat. GALP neurons express leptin receptors and GALP mRNA levels are decreased slightly in fasted rats and stimulated significantly by acute leptin treatment in combination with fasting. In studies to further explore the leptin dependence of GALP expression, we examined GALP mRNA levels in the hypothalamus of obese Zucker and streptozotocin-induced diabetic (STZ-DM) rats. In leptin receptor-deficient obese Zucker rats, with 75% higher body weight than lean littermates, GALP mRNA levels in the ARC were decreased by 75%, while neuropeptide Y (NPY) mRNA levels were increased 7-fold (n = 5, p < 0.001), consistent with earlier reports. In hypoleptinemic diabetic rats with 4.5-fold higher blood glucose and 15% lower body weight than controls, GALP mRNA levels in the ARC were decreased by 90%, while NPY mRNA levels were increased 9-fold (n = 5, p < 0.001). GALP is also expressed by pituicytes in the neural lobe of the rat pituitary gland and GALP expression is increased by osmotic stimulation such as dehydration and salt loading. Thus, in STZ-DM rats that are in a hyperosmotic state with elevated plasma vasopressin levels, GALP mRNA levels were increased by approximately 20-fold in the neural lobe relative to control (n = 4, p < 0.001). The current findings are consistent with a strong tonic influence of leptin receptor signalling on hypothalamic GALP expression under normal conditions, and possible abnormalities in GALP neuronal signalling and their putative targets, thyrotropin-releasing hormone and gonadotropin hormone-releasing hormone neurons, under pathophysiological conditions such as diabetes and obesity. Our data in STZ-DM rats also clearly demonstrate that GALP gene expression is differentially regulated in neurons and pituicytes.

Topics: Analysis of Variance; Animals; Arcuate Nucleus of Hypothalamus; Arginine Vasopressin; Blood Glucose; Body Weight; Diabetes Mellitus, Experimental; Galanin-Like Peptide; Hypothalamus; In Situ Hybridization; Male; Neuropeptide Y; Obesity; Pituitary Gland; Rats; Rats, Sprague-Dawley; Rats, Zucker; Receptors, Cell Surface; Receptors, Leptin; RNA, Messenger

It has been suggested that certain cells in the brain, like pancreatic beta-cells, use glucose transporter-2 (GLUT-2), glucokinase and glucagon-like peptide-1 receptor (GLP-1R) to sense glucose in the service of multiple aspects of energy balance. The obese Zucker rat displays numerous disturbances in energy homeostasis and may provide a model of dysfunctional expression of genes related to nutrient control systems. Using real-time RT-PCR we measured gene expression for three of the pancreatic glucose-sensing markers and neuropeptide Y (NPY) in the medial, lateral hypothalamus and hindbrain of lean and obese Zucker rats of both genders. Additionally, we measured circulating levels of glucose, leptin, insulin, corticosterone and glucagon. The results indicate that GLUT-2 mRNA expression is decreased, whereas glucokinase is increased in the hindbrain of obese rats. NPY mRNA level is significantly higher, whereas GLP-1R is significantly lower in the medial hypothalamus in obese individuals. Gender-related differences were found in the hindbrain and medial hypothalamus for GLUT-2 and in the lateral hypothalamus for GLP-1R and they may be related to the fact that the female Zucker rats do not develop diabetes as readily as males. Furthermore, the hindbrain may be an important site for glucose-sensing where major phenotypic changes occur for glucose-sensing genes expression.

Topics: Animals; Blood Glucose; Corticosterone; Energy Metabolism; Female; Gene Expression Regulation; Glucagon; Glucagon-Like Peptide-1 Receptor; Glucokinase; Glucose; Glucose Transporter Type 2; Hypothalamus; Insulin; Leptin; Male; Monosaccharide Transport Proteins; Neuropeptide Y; Obesity; Rats; Rats, Zucker; Receptors, Glucagon; Rhombencephalon; RNA, Messenger; Sex Characteristics; Transcription, Genetic

NPY is the most potent orexigenic agent known to man, with NPY Y1 and NPY Y5 being the receptor subtypes that are most likely responsible for centrally-mediated NPY-induced feeding responses. Based on the aforementioned, novel hydrazide derivatives were prepared for the purpose of searching new NPY Y5 receptor antagonists. Many of the compounds exhibited nanomolar binding affinity for this receptor, affording trans-N-(4-[N'-(3,4-dichlorophenyl)hydrazinocarbonyl]cyclohexylmethyl)-4-fluorobenzenesulfonamide, which showed the best activity (IC(50)=0.43nM).

Topics: Animals; Anti-Obesity Agents; Binding, Competitive; Cell Line; Humans; Hydrazines; Inhibitory Concentration 50; Neuropeptide Y; Obesity; Receptors, Neuropeptide Y; Structure-Activity Relationship; Sulfonamides

Beta2-adrenergic receptor gene and neuropeptide Y gene may potentially influence lipid metabolism and overall energy balance. Therefore, we examined associations of these genes with lipid fractions and obesity-related phenotypes in hypertensive subjects. A total of 638 white individuals from 212 Polish families with clustering of essential hypertension were phenotyped for cardiovascular risk determinants. Each subject was genotyped for functional polymorphisms of beta2-adrenergic receptor gene (Arg16Gly and Gln27Glu) and neuropeptide Y (Leu7Pro). Of 3 common haplotypes of beta2-adrenergic receptor gene, Arg16Gln27 was overtransmitted to offspring with elevated levels of total cholesterol (Z=2.2; P=0.026) and LDL-cholesterol (Z=3.2; P=0.002). Individually, Leu7Pro was not associated with any of the metabolic phenotypes in family-based tests or case-control analyses. However, in the presence of Arg allele of Arg16Gly and Gln allele of Gln27Glu, homozygosity for Leu variant of the Leu7Pro polymorphism was associated with 2.1-increased odds ratio (confidence interval, 1.10 to 3.81; P=0.024) of elevated LDL in hypertensive subjects, independent of age, gender, body mass index, adjusted blood pressures, antihypertensive therapy, and use of nonselective beta-blockers and diuretics. Consistently, there was a significant multilocus association among variants of Arg16Gly, Gln27Glu, and Leu7Pro in hypertensive probands with elevated LDL (cases; P=0.028) but not in hypertensive subjects with normal LDL (controls). This study revealed an association of LDL-cholesterol with beta2-adrenergic receptor gene haplotype and provided evidence for epistatic interaction between beta2-adrenergic receptor gene and neuropeptide Y gene in determination of LDL-cholesterol in patients with essential hypertension.

Topics: Cholesterol, LDL; Female; Haplotypes; Humans; Hypertension; Logistic Models; Male; Neuropeptide Y; Obesity; Pedigree; Phenotype; Polymorphism, Single Nucleotide; Receptors, Adrenergic, beta-2

Anorexia-associated malnutrition is a severe complication that increases mortality in peritoneal dialysis (PD) patients. Ghrelin is a recently-discovered orexigenic hormone with actions in brain and stomach. We analyzed, in 42 PD patients, the possible relationship between ghrelin and appetite regulation with regard to other orexigens [neuropeptide Y (NPY), NO3] and anorexigens [cholecystokinin (CCK), leptin, glucose-dependent insulinotropic peptide (GIP), tumor necrosis factor alpha (TNFalpha)]. All orexigens and anorexigens were determined in plasma. Eating motivation was evaluated using a visual analog scale (VAS). The patients were divided into three groups: those with anorexia (n = 12), those with obesity associated with high intake (n = 12), and those with no eating behavior disorders (n = 18). A control group of 10 healthy volunteers was also evaluated. Mean plasma levels of ghrelin were high (3618.6 +/- 1533 mg/mL), with 36 patients showing values above the normal range (< 2600 mg/mL). Patients with anorexia had lower ghrelin and NPY levels and higher peptide-C, CCK, interleukin-1 (IL-1), TNFalpha, and GIP levels than did the other patients. Patients with anorexia also had an early satiety score and low desire and pleasure in eating on the VAS and diet survey. We observed significant positive linear correlations between ghrelin and albumin (r = 0.43, p < 0.05), prealbumin (r = 0.51, p < 0.05), transferrin (r = 0.4, p < 0.05), growth hormone (r = 0.66, p < 0.01), NO3 (r = 0.36, p < 0.05), and eating motivation (VAS). At the same time, negative relationships were observed between blood ghrelin and GIP (r = -0.42, p < 0.05), insulin (r = -0.4, p < 0.05), leptin (r = -0.45, p < 0.05), and creatinine clearance [r = -0.33, p = 0.08 (nonsignificant)]. Ghrelin levels were not related to Kt/V or to levels of CCK and cytokines. Ghrelin plasma levels are elevated in PD patients. Uremic patients with anorexia show relatively lower ghrelin plasma levels than the levels seen in obese patients or in patients with normal appetite. The role of ghrelin in appetite modulation is altered in uremic PD patients, and that alteration is possibly associated with disorders in insulin and growth hormone metabolism.

Topics: Adult; Aged; Anorexia; Appetite Regulation; Blood Proteins; Cholecystokinin; Cytokines; Eating; Female; Gastric Inhibitory Polypeptide; Ghrelin; Humans; Leptin; Male; Middle Aged; Neuropeptide Y; Nitric Oxide; Nutritional Status; Obesity; Peptide Hormones; Peritoneal Dialysis

Rats that develop diet-induced obesity (DIO) on a 31% fat [high-energy (HE)] diet have defective sensing and responding to altered glucose levels compared with diet-resistant (DR) rats. Thus we postulated that they would also have defective counterregulatory responses (CRR) to insulin-induced hypoglycemia (IIH). Chow-fed selectively bred DIO and DR rats underwent three sequential 60-min bouts of IIH separated by 48 h. Glucose levels fell comparably, but DIO rats had 22-29% lower plasma epinephrine (Epi) levels during the first two bouts than DR rats. By the third trial, despite comparable Epi levels, DIO rats had lower 30-min glucose levels and rebounded less than DR rats 85 min after intravenous glucose. Although DIO rats gained more carcass and fat weight after 4 wk on an HE diet than DR rats, they were unaffected by prior IIH. Compared with controls, DR rats with prior IIH and HE diet had higher arcuate nucleus neuropeptide Y (50%) and proopiomelanocortin (POMC; 37%) mRNA and an inverse correlation (r = 0.85; P = 0.004) between POMC expression and body weight gain on the HE diet. These data suggest that DIO rats have a preexisting defect in their CRR to IIH but that IIH does not affect the expression of their hypothalamic neuropeptides or weight gain as it does in DR rats.

Topics: Adipose Tissue; Animals; Arcuate Nucleus of Hypothalamus; Blood Glucose; Body Composition; Catecholamines; Diet; Homeostasis; Hypoglycemia; Hypoglycemic Agents; Hypothalamus; In Situ Hybridization; Insulin; Lactic Acid; Male; Neuropeptide Y; Obesity; Organ Size; Pro-Opiomelanocortin; Rats; RNA, Messenger; Weight Gain

Disruption of melanocortin (MC) signaling, such as by ectopic Agouti overexpression, leads to an obesity syndrome with hyperphagia, obesity, and accelerated body weight gain during high-fat diet. To investigate where in the brain disruption of MC signaling results in obesity, long-term Agouti expression was induced after local injections of recombinant adeno-associated viral particles in selected brain nuclei of adult rats. Agouti expression in the paraventricular nucleus, a hypothalamic region with a high density of MC receptors, induced acute onset hyperphagia and rapid weight gain that persisted for at least 6 weeks. In contrast, obesity and hyperphagia developed with a 3 week delay when Agouti was expressed in the dorsal medial hypothalamus. Agouti expression in the lateral hypothalamus (LH) did not affect food intake and body weight during regular diet, despite the presence of MC receptors in this region. However, during exposure to a high-fat diet, animals with Agouti expression in the LH exhibited a marked increase in body weight. Here we show that the LH is important for the protection against diet-induced obesity by controlling caloric intake during consumption of a high-fat diet. Together, this study provides evidence that different aspects of the Agouti-induced obesity syndrome, such as hyperphagia and diet responsiveness, are mediated by distinct brain regions and opens challenging opportunities for further understanding of pathophysiological processes in the development of the obesity syndrome.

Topics: Agouti Signaling Protein; Agouti-Related Protein; Animals; Cell Line; Dietary Fats; Energy Intake; Humans; Hyperphagia; Hypothalamus; Hypothalamus, Middle; Intercellular Signaling Peptides and Proteins; Male; Neuropeptide Y; Obesity; Organ Specificity; Paraventricular Hypothalamic Nucleus; Proteins; Rats; Rats, Wistar; Receptors, Melanocortin; Recombinant Fusion Proteins; RNA, Messenger; Weight Gain

Effects of Roux-en-Y gastric bypass (RYGB) on hypothalamic food intake regulation have not been investigated. The hypothalamic arcuate nucleus (ARC) and the magnocellular (m) and parvocellular (p) parts of the paraventricular nucleus (PVN) regulate hunger and satiety, and are under control of the orexigenic neuropeptide Y (NPY), and the anorexigenic alpha-melanocyte stimulating hormone (alpha-MSH) and serotonin (5-HT). We hypothesized that after RYGB, weight loss is associated with hypothalamic down regulation of NPY and up regulation of 5-HT and alpha-MSH.. Obesity was induced in 12 Sprague Dawley rats using a high-energy diet for 7 weeks, and then the rats were divided into three groups (n = 4/group): RYGB, sham-operated pair-fed (PF), and sham-operated ad libitum (obese control). Ten days after operation, immunohistochemical quantification of NPY, alpha-MSH, and 5-HT(1B)-receptors in ARC and PVN was performed. Data were analyzed using ANOVA and Tukey's test.. Body weight decreased in RYGB (417 +/- 21 g; mean +/- SE) and in PF (436 +/- 14 g) rats 10 days after operation compared with obese control rats (484 +/- 15 g; p < 0.05 for each comparison). NPY in ARC, pPVN, and mPVN decreased by 43%, 43%, and 61%, respectively in RYGB and by 55%, 42%, and 71% in PF, respectively, compared with obese controls (p < 0.05 for each pairwise comparison). RYGB versus PF did not show differences. alpha-MSH in ARC, pPVN and mPVN increased by 35%, 175%, and 67%, respectively in RYGB and by 29%, 162%, and 116% in PF, respectively, compared with obese controls (each p < 0.05). In mPVN, alpha-MSH significantly decreased by 23% in RYGB versus PF (p < 0.05). 5-HT-(1B)-receptor in pPVN increased by 58% in RYGB and by 26% in PF, compared with obese controls (p < 0.05). Compared with obese controls, 5HT-(1B)-receptor in mPVN increased by 39% in RYGB (p < 0.05) and by 9% in PF (p > 0.05). An increase of 5-HT-(1B)-receptor in pPVN and mPVN occurred in RYGB versus PF (p < 0.05).. Obese rats that undergo weight loss after RYGB demonstrate changes in hypothalamic down regulation of NPY and up regulation of alpha-MSH and serotonin.

Topics: Anastomosis, Roux-en-Y; Animals; Arcuate Nucleus of Hypothalamus; Down-Regulation; Gastric Bypass; Male; Melanocyte-Stimulating Hormones; Neuropeptide Y; Obesity; Paraventricular Hypothalamic Nucleus; Rats; Rats, Sprague-Dawley; Serotonin; Up-Regulation; Weight Loss

This study was aimed to investigate the changes of orexin-A (OXA) and neuropeptide Y (NPY) expression in the hypothalamus of the fasted and high-fat diet fed rats. For the experiments, the male Sprague-Dawley (SD) rats were used as the model of high-fat diet-induced obesity. The mean loss of body weight (MLBW) did not show the linear pattern during the fasting; from 24 h to 84 h of fastings, the MLBW was not significantly changed. The numbers of OXA-immunoreactive (IR) neurons were decreased at 84 h of fasting compared with those in other five fasting subgroups. The NPY immunoreactivities in the arcuate nucleus (ARC) and the suprachiasmatic nucleus (SCN) observed at 84 h of fasting were higher than that observed at 24 h of fasting. The number of OXA-IR neurons of the LHA (lateral hypothalamic area) in the high-fat (HF) diet fed group was more increased than that of the same area in the normal-fat (NF) diet fed group. The NPY immunoreactivities of the ARC and the SCN were higher in HF group than those observed in the same areas of NF group. Based on these results, it is noteworthy that the decrease of the body weight during the fast was not proportionate to the time-course, implicating a possible adaptation of the body for survival against starvation. The HF diet might activate the OXA and the NPY in the LHA to enhance food intake.

Topics: Adaptation, Physiological; Animals; Arcuate Nucleus of Hypothalamus; Dietary Fats; Eating; Fasting; Hypothalamic Area, Lateral; Hypothalamus; Immunohistochemistry; Intracellular Signaling Peptides and Proteins; Male; Neuropeptide Y; Neuropeptides; Obesity; Orexins; Rats; Rats, Sprague-Dawley; Suprachiasmatic Nucleus

Orlistat is an inhibitor of lipase which splits triglycerides into free fatty acides and glycerol. This drug, by inhibiting hydrolysis of triglycerides, is the cause of significant loss of fat in the faeces. 13 obese and 15 nonobese subjects were examined. Obese subjects received orlistat (Xenical, F. Hoffmann La Roche Ltd, Switzerland) 3 x 120 mg/d. Treatment with orlistat for 16 weeks was followed by a significant fall of BMI and MAP, insulinemia, insulin/glucose ratio, leptinemia, serum total cholesterol, triglycerides, HDL-cholesterol and 25-OH-D concentration respectively. Orlistat did not influence significantly serum LDL-cholesterol concentration but unexpectedly increased plasma levels of folic acid, vitamin B12 and NPY.. (1) Monitoring of plasma 25-OH-D levels in obese patients on orlistat therapy seems to be mandatory. (2) In spite of significant changes (in opposite direction) in leptinemia and serum NPY level observed in obese subjects treated with orlistat, presence of a functional relationship between these hormones could not be confirmed.

Topics: Adult; Anti-Obesity Agents; Blood Glucose; Carbohydrates; Case-Control Studies; Cholesterol, HDL; Cholesterol, LDL; Enzyme Inhibitors; Female; Hormones; Humans; Hypercholesterolemia; Hyperlipidemias; Insulin; Lactones; Leptin; Lipase; Lipids; Male; Neuropeptide Y; Obesity; Orlistat; Poland; Time Factors; Treatment Outcome; Triglycerides; Vitamins; Weight Loss

Neuropeptide Y (NPY) is a strong orexigenic neurotransmitter also known to modulate several neuroendocrine axes. alpha-Melanocyte-stimulating hormone (MSH) is an essential anorectic neuropeptide, acting on hypothalamic MC3/4 receptor subtypes. When given as an intracerebroventricular bolus injection, Melanotan-II (MT-II), a non selective MC receptor agonist, inhibits feeding, suppresses the NPY orexigenic action, and reduces basal insulinaemia. We evaluated the effects of a 7-day central infusion of MT-II (15 nmol/day) given either alone or in association with NPY (5 nmol/day) in male Sprague-Dawley rats. MT-II produced almost full anorexia for 1-2 days but then feeding gradually returned to normal despite continued MT-II infusion. When coinfused with NPY, MT-II also produced the same initial anorectic episode but then maintained feeding to upper normal levels, thus cancelling the hyperphagia driven by NPY. Whereas NPY infusion produced a doubling of fat pad weight, MT-II reduced adiposity by a factor of two compared to pair-fed rats, and vastly curtailed the NPY-driven increase in fat pad weight. MT-II infusion also significantly curtailed the NPY-induced rise in insulin and leptin secretions. NPY infusion significantly inhibited hypothalamic pro-opiomelanocortin mRNA expression, most likely cancelling the alpha-MSH anorectic activity. As expected from previous studies, chronic NPY infusion strongly inhibited both the gonadotropic and somatotropic axes, and coinfusion of MT-II did not reverse these NPY-driven effects, in sharp contrast with that seen for the metabolic data. MT-II infusion alone had little effect on these axes. In conclusion, chronic MT-II infusion generated a severe but transient reduction in feeding, suggesting an escape phenomenon, and clearly reduced fat pad size. When coinfused with NPY, MT-II was able to cancel most of the NPY effects on feeding, but not those on the neuroendocrine axes. It appears therefore that, as expected, NPY and alpha-MSH closely interact in the control of feeding, whereas the neural pathways by which NPY affects growth and reproduction are distinct and not sensitive to MC peptide modulation.

Topics: Adipocytes; Adipose Tissue; alpha-MSH; Animals; Carrier Proteins; Drinking; Drug Interactions; Eating; Gene Expression; Gonadal Steroid Hormones; Growth Hormone-Releasing Hormone; Hypothalamus; Insulin; Insulin-Like Growth Factor I; Intracellular Signaling Peptides and Proteins; Leptin; Male; Neuropeptide Y; Neuropeptides; Obesity; Orexins; Peptides, Cyclic; Pro-Opiomelanocortin; Rats; Rats, Sprague-Dawley; Weight Gain

Topics: Agouti-Related Protein; alpha-MSH; Animals; Anti-Obesity Agents; Appetite; Arcuate Nucleus of Hypothalamus; Body Weight; Brain; Caloric Restriction; Fatty Acids; Ghrelin; Humans; Insulin; Intercellular Signaling Peptides and Proteins; Leptin; Longevity; Mice; Neurons; Neuropeptide Y; Obesity; Peptide Hormones; Peptide YY; Pro-Opiomelanocortin; Protein Tyrosine Phosphatase, Non-Receptor Type 1; Protein Tyrosine Phosphatases; Proteins; Receptor, Insulin; Receptors, Pituitary Hormone; Stearoyl-CoA Desaturase

Topics: Agouti-Related Protein; alpha-MSH; Animals; Anti-Obesity Agents; Appetite; Arcuate Nucleus of Hypothalamus; Ciliary Neurotrophic Factor; Clinical Trials as Topic; Cyclobutanes; Energy Intake; Ghrelin; Humans; Hunger; Intercellular Signaling Peptides and Proteins; Lactones; Leptin; Mice; Nerve Tissue Proteins; Neurons; Neuropeptide Y; Obesity; Orlistat; Peptide Fragments; Peptide Hormones; Peptide YY; Phentermine; Proteins; Receptors, Corticotropin; Receptors, Melanocortin; Weight Loss

Neuropeptide Y (NPY) is an orexigenic (appetite-stimulating) peptide that plays an important role in regulating energy balance. When administered directly into the central nervous system, animals exhibit an immediate increase in feeding behavior, and repetitive injections or chronic infusions lead to obesity. Surprisingly, initial studies of Npy(-/-) mice on a mixed genetic background did not reveal deficits in energy balance, with the exception of an attenuation in obesity seen in ob/ob mice in which the NPY gene was also deleted. Here, we show that, on a C57BL/6 background, NPY ablation is associated with an increase in body weight and adiposity and a significant defect in refeeding after a fast. This impaired refeeding response in Npy(-/-) mice resulted in a deficit in weight gain in these animals after 24 h of refeeding. These data indicate that genetic background must be taken into account when the biological role of NPY is evaluated. When examined on a C57BL/6 background, NPY is important for the normal refeeding response after starvation, and its absence promotes mild obesity.

Topics: Adipose Tissue; Animals; Body Composition; Diet; Eating; Fasting; Feeding Behavior; Female; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Motor Activity; Neuropeptide Y; Obesity; Oxygen Consumption; Pulmonary Gas Exchange; Sex Characteristics

Regulation of proopiomelanocortin (POMC) is an important means of controlling the central melanocortin system. It has never been established whether the spectrum of POMC-derived peptides synthesized and secreted from the hypothalamus is altered in response to changes in energy homeostasis in vivo. To monitor secretion, we analyzed peptide content of rat cerebrospinal fluid. Strikingly, both the POMC precursor and ACTH were readily detected. Moreover, levels of both were lower in samples from obese Zucker rats (fa/fa) vs. lean Zucker rats (+/+, fa/+) and from fasted vs. fed rats, whereas alpha MSH could not be detected. POMC levels were also decreased in hypothalamic extracts from obese and fasted animals. In contrast, despite being the most predominant peptide in extracts, alpha MSH levels were not significantly changed in any of the rat models. The ratio of precursor to derived peptides in cerebrospinal fluid was significantly higher in obese vs. lean and fed vs. fasted rats, indicating that secretion of POMC-derived peptides is differentially down-regulated during negative energy balance. In contrast to peptide analysis, we found that POMC gene expression was not significantly decreased in fasted rat hypothalami. We conclude that regulation of peptide secretion is an important mechanism by which the POMC system is controlled.

Topics: Adrenocorticotropic Hormone; Agouti-Related Protein; alpha-MSH; Animals; Aspartic Acid Endopeptidases; Energy Metabolism; Gene Expression; Hypothalamus; Intercellular Signaling Peptides and Proteins; Male; Neuropeptide Y; Obesity; Pro-Opiomelanocortin; Proprotein Convertase 2; Proprotein Convertases; Proteins; Rats; Rats, Wistar; Rats, Zucker; Reverse Transcriptase Polymerase Chain Reaction; Subtilisins

Secretion of leptin from adipocytes communicates body energy status to the brain by activating the leptin receptor long form (LRb). LRb regulates energy homeostasis and neuroendocrine function; the absence of LRb in db/db mice results in obesity, impaired growth, infertility and diabetes. Tyr 1138 of LRb mediates activation of the transcription factor STAT3 during leptin action. To investigate the contribution of STAT3 signalling to leptin action in vivo, we replaced the gene encoding the leptin receptor (lepr) in mice with an allele coding for a replacement of Tyr 1138 in LRb with a serine residue (lepr(S1138)) that specifically disrupts the LRb-STAT3 signal. Here we show that, like db/db mice, lepr(S1138) homozygotes (s/s) are hyperphagic and obese. However, whereas db/db mice are infertile, short and diabetic, s/s mice are fertile, long and less hyperglycaemic. Furthermore, hypothalamic expression of neuropeptide Y (NPY) is elevated in db/db mice but not s/s mice, whereas the hypothalamic melanocortin system is suppressed in both db/db and s/s mice. LRb-STAT3 signalling thus mediates the effects of leptin on melanocortin production and body energy homeostasis, whereas distinct LRb signals regulate NPY and the control of fertility, growth and glucose homeostasis.

Topics: Alleles; alpha-MSH; Animals; Blood Glucose; Body Weight; Cell Line; Diabetes Mellitus; DNA-Binding Proteins; Energy Metabolism; Estrous Cycle; Female; Homeostasis; Humans; Infertility; Leptin; Male; Mice; Neuropeptide Y; Obesity; Phenotype; Receptors, Cell Surface; Receptors, Leptin; Reproduction; RNA, Messenger; Signal Transduction; STAT3 Transcription Factor; Trans-Activators

The present study was designed to define how dietary fat type regulates body adiposity in dietary obesity-susceptible (DOS) Sprague-Dawley (SD) rats. Eighty-three SD rats received a purified diet containing 50 g maize oil (MO)/kg for 3 weeks and then thirty-nine of the rats, designated as the DOS rats, were allotted to diets containing 160 g MO (DOS-MO), beef tallow (DOS-BT) or fish oil (DOS-FO)/kg for 9 weeks. As a result of the experiment, the DOS-FO rats had significantly (P<0.05) reduced weight gain and abdominal and epididymal fat-pad mass than the DOS-MO and DOS-BT rats. Serum leptin level was also significantly (P<0.05) lower in the DOS-FO rats; however, hypothalamic leptin receptor (a and b) mRNA and neuropeptide Y expressions were not altered by dietary fat sources. A lower acetyl-CoA carboxylase mRNA expression in the liver was observed in the DOS-FO group, whereas hepatic peroxisome proliferator-activated receptor-gamma mRNA and protein expressions were markedly elevated in the DOS-FO group compared with those in the other groups. We did not observe differences in acetyl-CoA carboxylase and peroxisome proliferator-activated receptor-gamma expressions in epididymal fat of the DOS rats consuming MO, BT or FO. It is concluded from our present observations that dietary fat type, especially that rich in FO, plays a potential role in down-regulation of adiposity by altering hepatic lipogenic genes, rather than feeding behaviour, in the DOS-SD rats.

Topics: Acetyl-CoA Carboxylase; Adipose Tissue; Animals; Cattle; Corn Oil; Dietary Fats; Disease Susceptibility; Eating; Fish Oils; Gene Expression Regulation; Leptin; Liver; Male; Neuropeptide Y; Obesity; Rats; Rats, Sprague-Dawley; Receptors, Cell Surface; Receptors, Cytoplasmic and Nuclear; Receptors, Leptin; Transcription Factors; Weight Gain

Previous studies on mice with melanocortin-4 receptor gene (MC4r) knockout have focused on obese adults. Because humans with functional MC4r mutations show early-onset obesity, we determined the onset of excessive fat deposition in 10- to 56-day-old mice, taking into account sex and litter influences. Total body fat content of MC4r-/- on day 35 and MC4r+/- on day 56 significantly exceeds that of MC4r+/+. Plasma leptin levels increase in proportion to fat mass. According to cumulative food intake and energy expenditure measurements from day 21 to 35, onset of excessive fat deposition in MC4r-/- is fueled by hyperphagia and counteracted partially by hypermetabolism. In 35- to 56-day-old mice, arcuate nucleus neuropeptide Y (NPY) mRNA decreases and pro-opiomelanocortin (POMC) mRNA increases with fat content and plasma leptin levels independently of genotype. Taking into account fat content by ANCOVA reveals, however, increases in both NPY mRNA and POMC mRNA due to melanocortin-4 receptor (MC4R) deficiency. We conclude that hyperphagia, not hypometabolism, is the primary disturbance initiating excessive fat deposition in MC4R-deficient mice at weaning and that the overall changes in NPY and POMC expression tend to antagonize the onset of excessive fat deposition.

Topics: Adipose Tissue; Animals; Body Composition; Eating; Energy Intake; Energy Metabolism; Female; Genotype; Hyperphagia; Leptin; Male; Mice; Mice, Knockout; Neuropeptide Y; Obesity; Peptide Fragments; Pro-Opiomelanocortin; Receptor, Melanocortin, Type 4; Receptors, Corticotropin

A common Leu7Pro polymorphism in the signal peptide of neuropeptide Y has been associated with increased plasma cholesterol and accelerated atherosclerosis in the Finnish population.. A cross-sectional design was carried out in 1,000 individuals from the Mediterranean Spanish population to estimate its prevalence. Two independently collected samples consisting of 486 subjects (sample 1) and 514 subjects (sample 2) were studied. The Leu7Pro polymorphism was determined.. We found only one individual carrying the Leu7Pro variant (0.1%). The allele frequency of the Pro7 allele was extremely low: 0.005 (95% CI,0.0001-0.0015).. This low prevalence suggests that the Pro7 allele is not one of the genetic determinant factors affecting obesity, plasma lipids or alcoholism in this population.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Child; Cross-Sectional Studies; Female; Humans; Leucine; Lipids; Male; Middle Aged; Neuropeptide Y; Obesity; Polymorphism, Genetic; Prevalence; Proline; Protein Precursors; Spain

Proopiomelanocortin (POMC) neurons in the hypothalamus are direct targets of the adipostatic hormone leptin and contribute to energy homeostasis by integrating peripheral and central information. The melanocortin and beta-endorphin neuropeptides are processed from POMC and putatively coreleased at axon terminals. Melanocortins have been shown by a combination of pharmacological and genetic methods to have inhibitory effects on appetite and body weight. In contrast, pharmacological studies have generally indicated that opioids stimulate food intake. Here we report that male mice engineered to selectively lack beta-endorphin, but that retained normal melanocortin signaling, were hyperphagic and obese. Furthermore, beta-endorphin mutant and wild-type mice had identical orexigenic responses to exogenous opioids and identical anorectic responses to the nonselective opioid antagonist naloxone, implicating an alternative endogenous opioid tone to beta-endorphin that physiologically stimulates feeding. These genetic data indicate that beta-endorphin is required for normal regulation of feeding, but, in contrast to earlier reports suggesting opposing actions of beta-endorphin and melanocortins on appetite, our results suggest a more complementary interaction between the endogenously released POMC-derived peptides in the regulation of energy homeostasis.

Topics: Animals; beta-Endorphin; Eating; Energy Metabolism; Glucose; Homeostasis; Hyperinsulinism; Hyperphagia; Leptin; Male; Mice; Mice, Knockout; Naloxone; Narcotic Antagonists; Neuropeptide Y; Obesity; Reference Values

To clarify the role of the neuropeptide Y (NPY) Y5 receptor subtype in energy homeostasis, the effect of the intracerebroventricular infusion of a selective Y5 agonist, D-Trp(34)NPY, was investigated in C57BL/6J mice. Intracerebroventricular infusion of D-Trp(34)NPY (5 and 10 microg/d) produced hyperphagia and body weight gain, accompanied by increased adipose tissue weight, hypercholesterolemia, hyperinsulinemia, and hyperleptinemia. Oral administration of a selective Y5 antagonist at a dose of 100 mg/kg twice a day completely suppressed all of these D-Trp(34)NPY-induced changes, indicating that chronic activation of the Y5 receptor produces hyperphagia and obesity. In addition, D-Trp(34)NPY still resulted in an increase in adipose tissue weight accompanied by hyperleptinemia and hypercholesterolemia, although D-Trp(34)NPY-induced food intake was restricted by pair-feeding. Under the pair-fed condition, D-Trp(34)NPY decreased hormone-sensitive lipase activity in white adipose tissue and uncoupling protein-1 mRNA expression in brown adipose tissue. These findings indicate that Y5-mediated obesity may involve metabolic changes, such as decreased lipolysis and thermogenesis, as well as hyperphagia. Therefore, the Y5 receptor can play a key role in regulating energy homeostasis.

Topics: Animals; Binding, Competitive; Carrier Proteins; CCAAT-Enhancer-Binding Proteins; DNA-Binding Proteins; Drug Administration Schedule; Energy Metabolism; Glycogen; Homeostasis; Hyperphagia; Injections, Intraventricular; Ligands; Lipoprotein Lipase; Male; Mice; Mice, Inbred C57BL; Neuropeptide Y; Obesity; Receptors, Neuropeptide Y; RNA, Messenger; Sterol Esterase; Sterol Regulatory Element Binding Protein 1; Transcription Factors; Triglycerides

The aim of the present work was to describe the effects of sibutramine on body weight and adiposity and to establish the potential involvement of neuropeptide Y (NPY) and orexins in the anorectic action of this drug. Male obese Zucker rats were daily administered with sibutramine (10 mg/kg, intraperitoneal) for two weeks. Carcass composition was assessed using the official methods of the Association of Official Analytical Chemists. Total body oxygen consumption was measured daily for 60 min before sibutramine or saline injection and for 30 min (from 60 to 90 min) after drug or saline injection. Hypothalamic arcuate and paraventricular nuclei, and the lateral hypothalamic area were immunostained for NPY, orexin A and orexin B. Commercial kits were used for serum determinations. Reductions in body weight and adipose tissue weights were observed after sibutramine treatment in obese Zucker rats. No changes in NPY immunostaining in the arcuate and paraventricular nuclei were found. Orexin A and orexin B immunostaining was not modified in the lateral hypothalamic area in treated rats. The reduction in body weight and adiposity induced by sibutramine was achieved by both a reduction in food intake and an increase in energy expenditure. NPY and orexins do not seem to be involved in the anorectic effect of sibutramine.

Topics: Adipose Tissue; Animals; Appetite Depressants; Body Composition; Carrier Proteins; Cyclobutanes; Drinking; Eating; Energy Metabolism; Hypothalamus; Intracellular Signaling Peptides and Proteins; Male; Neuropeptide Y; Neuropeptides; Obesity; Orexins; Organ Size; Oxygen Consumption; Rats; Rats, Zucker; Weight Gain

Pancreatic polypeptide (PP) belongs to a family of peptides including neuropeptide Y and peptide YY. We examined the role of PP in the regulation of body weight as well as the therapeutic potential of PP.. We measured food intake, gastric emptying, oxygen consumption, and gene expression of hypothalamic neuropeptides, gastric ghrelin, and adipocytokines in mice after administering PP intraperitoneally. Peptide gene expression was also examined in PP-overexpressing mice. Vagal and sympathetic nerve activities were recorded after intravenous administration in rats. Effects of repeated administrations of PP on energy balance and on glucose and lipid metabolism were examined in both ob/ob obese mice and fatty liver Shionogi (FLS)-ob/ob obese mice.. Peripherally administered PP induced negative energy balance by decreasing food intake and gastric emptying while increasing energy expenditure. The mechanism involved modification of expression of feeding-regulatory peptides (decrease in orexigenic neuropeptide Y, orexin, and ghrelin along with an increase in anorexigenic urocortin) and activity of the vagovagal or vagosympathetic reflex arc. PP reduced leptin in white adipose tissue and corticotropin-releasing factor gene expression. The expression of gastric ghrelin and hypothalamic orexin was decreased in PP-overexpressing mice. Repeated administrations of PP decreased body weight gain and ameliorated insulin resistance and hyperlipidemia in both ob/ob obese mice and FLS-ob/ob obese mice. Liver enzyme abnormalities in FLS-ob/ob obese mice were also ameliorated by PP.. These observations indicate that PP may influence food intake, energy metabolism, and the expression of hypothalamic peptides and gastric ghrelin.

Topics: Animals; Body Weight; Carrier Proteins; Disease Models, Animal; Eating; Energy Metabolism; Gastric Emptying; Gene Expression; Ghrelin; Hypothalamus; Injections, Intraperitoneal; Intracellular Signaling Peptides and Proteins; Male; Mice; Neuropeptide Y; Neuropeptides; Obesity; Orexins; Oxygen Consumption; Pancreatic Polypeptide; Peptide Hormones; Peptide YY

Outbred Sprague-Dawley rats selectively bred for their propensity to develop diet-induced obesity (DIO) become heavier on low-fat diet than those bred to be diet resistant (DR) beginning at approximately 5 wk of age. Here we assessed the development of metabolic and neural functions for insights into the origins of their greater weight gain. From week 5 to week 10, chow-fed DIO rats gained 15% more body weight and ate approximately 14% more calories but had only slightly greater adiposity and plasma leptin than DR rats. From day 3 through week 10, DIO and DR rats had similar mRNA expression of arcuate nucleus neuropeptide Y, proopiomelanocortin, agouti-related peptide, and all splice variants of the leptin receptor (OB-R). When fed a high-energy (HE; 31% fat) diet, 7-wk-old DIO rats had a 240% increase in plasma leptin levels after only 3 days. Despite this early leptin rise, they maintained a persistent hyperphagia and became more obese than chow-fed DIO rats and DR rats fed chow or HE diet. Their failure to reduce caloric intake, despite high levels of leptin, suggests that selectively bred DIO rats might have reduced leptin sensitivity similar to that seen in the outbred DIO parent strain.

Topics: Adipose Tissue; Agouti-Related Protein; Animal Feed; Animals; Arcuate Nucleus of Hypothalamus; Breeding; Disease Models, Animal; Energy Intake; Energy Metabolism; Female; Insulin; Intercellular Signaling Peptides and Proteins; Leptin; Male; Neuropeptide Y; Obesity; Pro-Opiomelanocortin; Proteins; Rats; Rats, Sprague-Dawley; Receptors, Cell Surface; Receptors, Leptin; RNA, Messenger

An increased action of hypothalamic neuropeptide Y (NPY) has been proposed as a major factor in the pathophysiology of the obesity syndrome in Zucker (fa/fa) rats. Using a developmental strategy to test this hypothesis, we showed previously that significantly more arcuate NPY was expressed in fa/fa pups than in lean littermates on postnatal day (P) 2 and throughout the preweaning period [Physiol. Behav. 67 (1999) 521], and that hyperphagia first appeared on P12 [Am. J. Physiol. 275 (1998) R1106]. To test the hypothesis further, we used a specific radioimmunoassay to measure the concentration of hypothalamic NPY peptide in lean (+/+ and +/fa) and obese fa/fa Zucker rat pups on P9, P10, and P12. The concentration of NPY in fa/fa pups was not significantly different from that of the other genotypes. There was, however, a significant decrease in NPY concentration from P9 to P12 in fa/fa pups, but not in lean pups. The combination of increased NPY message and decreasing concentration of NPY peptide in fa/fa pups with age is consistent with, but does not prove, increased release of hypothalamic NPY in fa/fa pups just before and on P12 when hyperphagia emerges. These results provide further support for the importance of hypothalamic NPY in the phenotypic expression of hyperphagia in the fa/fa pups during the second postnatal week.

Topics: Aging; Animals; Female; Genotype; Hyperphagia; Hypothalamus; Male; Neuropeptide Y; Obesity; Phenotype; Rats; Rats, Zucker

Some mice become obese whereas others remain lean when raised on a high-energy diet. This study examined the levels of neuropeptide Y (NPY), and of Y1, Y2, Y5 and leptin receptor mRNA expression in the hypothalamic arcuate nucleus (Arc) of chronic high-energy diet-induced obese (DIO) and resistant (DR) mice. Forty mice were divided into two groups and fed either a high-fat (HF: 40% of calories from fat, 20% of calories from saturated fat; n=34) or low-fat (LF: 10% of calories from fat, 1% from saturated fat; n=6) diet. After 22 weeks of feeding, visceral fat accumulation was 69% higher in DIO mice compared with DR mice, and the former showed a moderate level of glucose intolerance. In DIO mice, the levels of NPY and leptin receptor mRNA expressions were significantly higher than in LF mice (+32 and +14%, P<0.001 and 0.05 respectively), indicating central leptin resistance, whereas the DR and LF groups did not differ. The level of Y2 receptor mRNA expression was similar between the DIO and LF groups but, importantly, was reduced approximately 20% in DR mice (P<0.005). The level of Y5 receptor mRNA was 36% lower in DR mice than DIO mice (P<0.05). The differences between DIO and DR mice identified by this study may assist in a better understanding of genetic predisposition to an increased fat deposition induced by a chronic high-fat diet. A low level of Y2 and Y5 receptor mRNA expression may contribute to the prevention of chronic high-energy diet-induced obesity in DR mice.

Topics: Adipose Tissue; Animals; Arcuate Nucleus of Hypothalamus; Blood Glucose; Body Constitution; Body Weight; Down-Regulation; Energy Intake; Food, Formulated; Gene Expression Regulation; Genetic Predisposition to Disease; Hypothalamus; Immunity, Innate; Male; Mice; Mice, Inbred C57BL; Neuropeptide Y; Obesity; Organ Size; Receptors, Cell Surface; Receptors, Leptin; Receptors, Neuropeptide Y; RNA, Messenger

Topics: Adult; Agouti-Related Protein; alpha-MSH; Animals; Appetite Depressants; Cholecystokinin; Colon; Controlled Clinical Trials as Topic; Ghrelin; Homeostasis; Humans; Hypothalamus; Intercellular Signaling Peptides and Proteins; Intestine, Small; Leptin; Models, Biological; Neuropeptide Y; Obesity; Peptide Fragments; Peptide Hormones; Peptide YY; Pro-Opiomelanocortin; Proteins; Rats; Satiety Response

To study the blood hormone level between diet-induced obesity-resistant (DIO-R) rats and diet-induced obesity(DIO) rats in blood hormone.. Fifty male Sprague-dawley (SD) rats were randomly divided into control group and high-fat group and they were fed with basic diet and high-fat diet respectively for 13 weeks. DIO-R and DIO rats were selected according to their body weight, then the intake of diet and body fat contents, the level of serum insulin, serum leptin and plasma NPY were determined by radioimmunoassay. The results showed that the weight, diet intake and body fat of DIO-R rats were significantly lower than those of DIO rats(P < 0.05). The level of serum insulin and plasma NPY of DIO-R rats were lower than those of DIO rats(P < 0.05). The level of serum leptin of rats in high-fat diet group was higher than that of the rat in basic diet group, but there was no significant difference between DIO-R and DIO rats(P > 0.05).. High fat diets can induce SD rat to develop obesity and obesity-resistance. The balance of insulin-leptin-NPY feedback may play a partial of role in resisting diet-induced obesity of rats.

Topics: Animals; Diet; Dietary Fats; Insulin; Leptin; Male; Neuropeptide Y; Obesity; Random Allocation; Rats; Rats, Sprague-Dawley

Obesity is a polygenic disorder that is associated with gallstone disease. We have previously shown that leptin deficiency in obese mice correlates with decreased gallbladder motility, suggesting that leptin plays a role in the link between gallstone disease and obesity. However, most obese humans are leptin-resistant, and relatively few are leptin-deficient. To confirm that leptin dysfunction is responsible for impaired gallbladder motility in obese mice, we hypothesized that leptin-resistant obese mice (Lep(db)) would have abnormal gallbladder motility while obese mice with intact leptin function (Agouti Yellow, A(y)) would have normal gallbladder motility.. Eighteen lean control (C57BL/6J), 10 A(y) and 12 Lep(db) female mice were fasted overnight, weighed, and livers and gallbladders were harvested. Liver weights and gallbladder volumes were measured. Gallbladder contractile responses (N/cm(2)) to acetylcholine (10(-5)M), neuropeptide Y (10(-8,-7,-6) M) and cholecystokinin (10(-10,-9,-8,-7)M) were determined in muscle bath chambers. Results were analyzed by analysis of various (ANOVA) and with the Mann-Whitney Rank Sum Test.. Both Agouti yellow (A(y)) and leptin-resistant (Lep(db)) obese mice had body weights, liver weights and gallbladder volumes that were significantly greater (P < 0.01) than lean control mice. Leptin-resistant obese mice had gallbladder responses to acetylcholine, neuropeptide Y and cholecystokinin that were significantly less (P < 0.01) than both lean control and Agouti yellow obese mice.. These data suggest that (1). leptin-resistant obese mice (Lep(db)) have abnormal gallbladder motility and (2). obese mice with normal leptin metabolism (A(y)) have normal gallbladder response to neurotransmitters. We conclude that leptin represents a link between obesity, gallbladder motility and gallstone formation.

Topics: Acetylcholine; Animals; Cholecystokinin; Female; Gallbladder Emptying; Leptin; Mice; Mice, Obese; Neuropeptide Y; Neurotransmitter Agents; Obesity

The objective of this study was to determine if central overexpression of leptin could overcome the leptin resistance caused by 100 days of high-fat feeding. Three-month old-F344XBN male rats were fed either control low fat chow (Chow), which provides 15% of energy as fat, or a high-fat/high-sucrose diet (HF), which provides 59% of energy as fat. Over several weeks, the HF-fed animals spontaneously split into two groups of animals: those that became obese on the HF diet (DIO) and those that did not gain extra weight on the HF diet [diet resistant (DR)]. After 100 days of HF feeding, animals were given a single intracerebroventricular injection containing 5.75E10 particles of rAAV encoding leptin (rAAV-leptin) or control virus (rAAV-con). Chow animals responded robustly to rAAV-leptin, including significant anorexia, weight loss, and lipopenia. In contrast, DIO were completely unresponsive to rAAV-leptin. DR rats responded to rAAV-leptin, but in a more variable fashion than Chow. Unlike what was observed in Chow, the anorectic response to rAAV-leptin rapidly attenuated and was no longer significant by day 14 postvector delivery. Both DIO and DR animals were found to have reduced long-form leptin receptor expression and enhanced basal P-STAT-3 in the hypothalamus with respect to Chow. rAAV-leptin caused an increase in STAT3 phosphorylation and proopiomelanocortin expression in the hypothalamus and an increase in uncoupling protein-1 in brown adipose tissue in both Chow and DR animals, but failed to do so in DIO. This suggests that central overexpression of leptin is not a viable strategy to reverse diet-induced obesity.

Topics: Adipose Tissue, Brown; Animals; Body Weight; Carrier Proteins; Dietary Fats; DNA-Binding Proteins; Eating; Fatty Acids, Nonesterified; Gene Expression; Genetic Therapy; Ion Channels; Leptin; Male; Membrane Proteins; Mitochondrial Proteins; Neuropeptide Y; Obesity; Oxygen Consumption; Pro-Opiomelanocortin; Rats; Rats, Inbred BN; Rats, Inbred F344; Receptors, Cell Surface; Receptors, Leptin; STAT3 Transcription Factor; Trans-Activators; Transgenes; Treatment Failure; Uncoupling Protein 1

In young (35- to 56-day-old) and middle-aged (9-mo-old) wild-type (+/+) and melanocortin-4 receptor (MC4R)-deficient (+/-, -/-) mice, expressions of neuropeptide Y (NPY), agouti-related protein (AGRP), pro-opiomelanocortin (POMC), and cocaine-and-amphetamine-regulated transcript (CART) were analyzed in the arcuate nucleus (ARC) and adjacent regions comprising the dorsomedial (DMN) and ventromedial (VMN) nucleus. In the ARC of young mice, NPY and AGRP expression increased and POMC and CART expression decreased with body fat content. Adjusting for the influence of body fat content by ANCOVA showed that the levels of NPY, POMC, and CART were highest and of AGRP lowest in young -/- mice. In the middle-aged mice, feedback from body fat content was weakened. For -/- mice ANCOVA revealed higher NPY and AGRP, lower POMC, and unchanged CART expression levels relative to young -/- mice. In the DMN and VMN, POMC and AGRP signals were absent at each age. CART was expressed in the DMN independent of age, fat content, and genotype. For NPY expression, an age-dependent induction was found in the DMN and VMN; it was absent in the young but present in the middle-aged mice, showing close positive correlations between body fat content and the numbers of NPY-labeled cells which were further enhanced in -/- mice. Thus MC4R deficiency augments age-induced NPY expression in the DMN and VMN with no feedback from body fat content. Negative feedback control by body fat content on ARC neuropeptide expression is present in young animals but vanishes with age and is modulated by MC4R deficiency.

Topics: Adipose Tissue; Aging; Agouti-Related Protein; Animals; Arcuate Nucleus of Hypothalamus; Gene Deletion; Genotype; Hypothalamus; Intercellular Signaling Peptides and Proteins; Leptin; Mice; Mice, Knockout; Models, Animal; Nerve Tissue Proteins; Neuropeptide Y; Neuropeptides; Obesity; Pro-Opiomelanocortin; Proteins; Receptor, Melanocortin, Type 4

Leptin regulates feeding behavior and energy metabolism by affecting hypothalamic neuromodulators. The present study was designed to examine hypothalamic neuronal histamine, a recently identified mediator of leptin signaling in the brain, in genetic obese animals. Concentrations of hypothalamic histamine and tele-methylhistamine (t-MH), a major histamine metabolite, were significantly lower in obese (ob/ob) and diabetic (db/db) mice, and Zucker fatty (fa/fa) rats, leptin-deficient and leptin-receptor defective animals, respectively, relative to lean littermates (P < 0.05 for each). A bolus infusion of leptin (1.0 microg) into the lateral ventricle (ilvt) significantly elevated the turnover rate of hypothalamic neuronal histamine, as assessed by pargyline-induced accumulation of t-MH, in ob/ob mice compared with phosphate-buffered saline (PBS) infusions (P < 0.05). However, this same treatment did not affect hypothalamic histamine turnover in db/db mice. In agouti yellow (A(y)/a) mice, animals defective in pro-opiomelanocortin (POMC) signaling, normal levels of histamine, and t-MH were seen in the hypothalamus at 4 weeks of age when obesity had not yet developed. These amine levels in A(y)/a mice showed no change until 16 weeks of age, although the mice were remarkably obese by this time. Infusions of corticotropin releasing hormone (CRH), one of neuropeptide related to leptin signaling, into the third ventricle (i3vt) increased histamine turnover in the hypothalamus of Wistar King A rats (P < 0.05 versus PBS infusion). Infusion of neuropeptide Y (NPY) or alpha-melanocyte stimulating hormone (MSH), a POMC-derived peptide failed to increase histamine turnover. These results indicate that lowered activity of hypothalamic neuronal histamine in ob/ob and db/db mice, and fa/fa rats may be due to insufficiency of leptin action in the brains of these animals. These results also suggest that disruption of POMC signaling in A(y)/a mice may not impact on neuronal histamine. Moreover, CRH but neither POMC-derived peptide nor NPY may act as a signal to neuronal histamine downstream of the leptin signaling pathway.

Topics: alpha-MSH; Animals; Corticotropin-Releasing Hormone; Disease Models, Animal; Histamine; Hypothalamus; Injections, Intraventricular; Leptin; Male; Methylhistamines; Mice; Mice, Inbred C57BL; Mice, Obese; Neuropeptide Y; Obesity; Pro-Opiomelanocortin; Rats; Rats, Wistar; Rats, Zucker; Third Ventricle

The gene GAD2 encoding the glutamic acid decarboxylase enzyme (GAD65) is a positional candidate gene for obesity on Chromosome 10p11-12, a susceptibility locus for morbid obesity in four independent ethnic populations. GAD65 catalyzes the formation of gamma-aminobutyric acid (GABA), which interacts with neuropeptide Y in the paraventricular nucleus to contribute to stimulate food intake. A case-control study (575 morbidly obese and 646 control subjects) analyzing GAD2 variants identified both a protective haplotype, including the most frequent alleles of single nucleotide polymorphisms (SNPs) +61450 C>A and +83897 T>A (OR = 0.81, 95% CI [0.681-0.972], p = 0.0049) and an at-risk SNP (-243 A>G) for morbid obesity (OR = 1.3, 95% CI [1.053-1.585], p = 0.014). Furthermore, familial-based analyses confirmed the association with the obesity of SNP +61450 C>A and +83897 T>A haplotype (chi(2) = 7.637, p = 0.02). In the murine insulinoma cell line betaTC3, the G at-risk allele of SNP -243 A>G increased six times GAD2 promoter activity (p < 0.0001) and induced a 6-fold higher affinity for nuclear extracts. The -243 A>G SNP was associated with higher hunger scores (p = 0.007) and disinhibition scores (p = 0.028), as assessed by the Stunkard Three-Factor Eating Questionnaire. As GAD2 is highly expressed in pancreatic beta cells, we analyzed GAD65 antibody level as a marker of beta-cell activity and of insulin secretion. In the control group, -243 A>G, +61450 C>A, and +83897 T>A SNPs were associated with lower GAD65 autoantibody levels (p values of 0.003, 0.047, and 0.006, respectively). SNP +83897 T>A was associated with lower fasting insulin and insulin secretion, as assessed by the HOMA-B% homeostasis model of beta-cell function (p = 0.009 and 0.01, respectively). These data support the hypothesis of the orexigenic effect of GABA in humans and of a contribution of genes involved in GABA metabolism in the modulation of food intake and in the development of morbid obesity.

Topics: Adult; Aged; Alleles; Autoantibodies; Case-Control Studies; Catalysis; Cell Line; Chromosome Mapping; Chromosomes, Human, Pair 10; Eating; Family Health; Feeding Behavior; Female; gamma-Aminobutyric Acid; Genetic Linkage; Genotype; Glutamate Decarboxylase; Haplotypes; Humans; Hunger; Insulin; Insulin Secretion; Insulin-Secreting Cells; Isoenzymes; Lod Score; Luciferases; Male; Middle Aged; Molecular Sequence Data; Neuropeptide Y; Obesity; Obesity, Morbid; Odds Ratio; Paraventricular Hypothalamic Nucleus; Plasmids; Polymorphism, Single Nucleotide; Promoter Regions, Genetic; Risk; Surveys and Questionnaires

It has been reported that neuropeptides may play a role in the control of appetite and in the mechanism of hormone release. Neuropeptides such as beta-endorphin, neuropeptide Y (NPY), galanin and leptin may affect hormones release, on the other hand the hormonal status may modulate neuropeptide activity.. The material consisted of 90 obese women, 30 women with Anorexia Nervosa, and 30 healthy, lean women of control group. Plasma beta-endorphin, NPY, leptin, somatostatin and serum pituitary and gonadal hormones concentrations were measured with RIA methods.. We observed the highest plasma NPY levels in obese hypertensive and diabetic patients. After carbohydrate administration (OGTT) a marked increase of insulin, beta-endorphin and NPY was found. The blunted response of GH to GH-RH may be connected with increased somatostatin activity and hyperinsulinemia. The abnormal response of LH to opioid blockade may be a result of disturbed opioid and NPY activities in obese patients. However in patients with anorexia nervosa, plasma leptin and NPY concentrations were low. The disturbances in beta-endorphin release are also observed.. The neuroendocrine disturbances in obesity and in anorexia nervosa are opposite. The feedback mechanism between leptin and NPY is disturbed in both in obesity and in anorexia nervosa. An abnormal activity of neuropeptides may lead to disturbed control of appetite and hormonal dysregulation in eating disorders.

Topics: Adult; Anorexia Nervosa; Appetite; beta-Endorphin; Diabetes Mellitus; Feedback, Physiological; Female; Glucose Tolerance Test; Human Growth Hormone; Humans; Hypertension; Leptin; Luteinizing Hormone; Neuropeptide Y; Neuropeptides; Obesity; Somatostatin

Targeted deletion of the gene encoding the neuronal and neuroendocrine secreted polypeptide VGF (nonacronymic) produces a lean, hypermetabolic mouse. Consistent with this phenotype, VGF mRNA levels are regulated in the hypothalamic arcuate nucleus in response to fasting. To gain insight into the site(s) and mechanism(s) of action of VGF, we further characterized VGF expression in the hypothalamus. Double-label studies indicated that VGF and pro-opiomelanocortin were coexpressed in lateral arcuate neurons in the fed state, and that VGF expression was induced after fasting in medial arcuate neurons that synthesize neuropeptide Y (NPY). Like NPY, VGF mRNA induction in this region of the hypothalamus in fasted mice was inhibited by exogenous leptin. In leptin-deficient ob/ob and receptor-mutant db/db mice, VGF mRNA levels in the medial arcuate were elevated. To identify neural pathways that are functionally compromised by Vgf ablation, VGF mutant mice were crossed with obese A(y)/a (agouti) and ob/ob mice. VGF deficiency completely blocked the development of obesity in A(y)/a mice, whereas deletion of Vgf in ob/ob mice attenuated weight gain but had no impact on adiposity. Hypothalamic levels of NPY and agouti-related polypeptide mRNAs in both double-mutant lines were dramatically elevated 10- to 15-fold above those of wild-type mice. VGF-deficient mice were also found to resist diet- and gold thioglucose-induced obesity. These data and the susceptibility of VGF mutant mice to monosodium glutamate-induced obesity are consistent with a role for VGF in outflow pathways, downstream of hypothalamic and/or brainstem melanocortin 4 receptors, that project via the autonomic nervous system to peripheral metabolic tissues and regulate energy homeostasis.

Topics: Agouti Signaling Protein; Animals; Arcuate Nucleus of Hypothalamus; Aurothioglucose; Diet; Disease Models, Animal; Energy Metabolism; Fasting; Gene Targeting; Immunohistochemistry; In Situ Hybridization; Intercellular Signaling Peptides and Proteins; Leptin; Male; Mice; Mice, Knockout; Mice, Mutant Strains; Nerve Growth Factors; Neural Pathways; Neurons; Neuropeptide Y; Neuropeptides; Obesity; Pro-Opiomelanocortin; Proteins; Rats; Rats, Sprague-Dawley; RNA, Messenger; Satiety Response; Sodium Glutamate

Neuronal responses to neuropeptide Y and dopamine were recorded in brain slices of hypothalamic paraventricular (PVH) and ventromedial (VMH) nuclei in normal and hyperphagic overweight rats reared in small litters of three pups. NPY significantly activated PVH neurons of normal rats, but inhibited neurons of overweight rats. In the VMH, a significantly higher coincidence of inhibition induced by NPY and dopamine was found in overweight rats. Similar neuronal responses were evoked by a NPY Y5 receptor agonist. Effects of NPY could be blocked by a Y1 receptor antagonist. The altered response of PVH neurons to the feeding-inducing NPY and the increased inhibition by NPY and dopamine in the VMH might contribute to the persisting hyperphagia and overweight of postnatally overnourished rats.

Topics: Action Potentials; Animals; Animals, Outbred Strains; Dopamine; Hyperphagia; Male; Neuropeptide Y; Obesity; Organ Culture Techniques; Paraventricular Hypothalamic Nucleus; Rats; Rats, Wistar; Ventromedial Hypothalamic Nucleus

On low-fat chow diet, rats prone to diet-induced obesity (DIO) have increased arcuate nucleus neuropeptide Y (NPY) expression but similar leptin levels compared with diet-resistant (DR) rats (19). Here, body weight and leptin levels rose in DIO rats, and they defended their higher body weight after only 1 wk on a 31% fat high-energy (HE) diet. However, DIO NPY expression did not fall to DR levels until 4 wk when plasma leptin was 168% of DR levels. When switched to chow, DIO rats lost carcass fat (18). By 10 wk, leptin levels fell to 148% and NPY expression again rose to 150% of DR levels. During 4 wk of food restriction, DIO leptin fell by approximately 50% while NPY increased by 30%. While both returned to control levels by 8 wk, DIO rats still regained all lost weight when fed ad libitum. Finally, the anorexic effect of intracerebroventricular leptin (10 microg) was inversely correlated with subsequent 3-wk weight gain on HE diet. Thus NPY expression and food intake are less sensitive to the leptin's suppressive effects in DIO rats. While this may predispose them to develop DIO, it does not fully explain their defense of a higher body weight on HE diet.

Topics: Animals; Anorexia; Arcuate Nucleus of Hypothalamus; Body Weight; Brain; Dietary Fats; Energy Intake; Food Deprivation; Injections, Intraventricular; Leptin; Male; Neuropeptide Y; Obesity; Rats; Rats, Sprague-Dawley; RNA, Messenger

We previously demonstrated that C75, a specific and potent inhibitor of fatty acid synthase (FAS), reduced food intake and decreased body weight in mice. In the present study, we determined that these effects were not due to conditioned taste aversion. To investigate the mechanism of C75 action, we examined FAS brain expression. FAS was expressed in a number of brain regions, including arcuate and paraventricular nuclei (PVN) within regions that comprise the arcuate-PVN pathway in mouse and human. Although C75 and fasting significantly downregulated liver FAS, FAS levels remained high in hypothalamus, indicating that FAS levels were regulated differently in brain from those in liver. Double fluorescence in situ for FAS and neuropeptide Y (NPY) showed that FAS co-localized with NPY in neurons in the arcuate nucleus. NPY immnuoreactivity after C75 treatment was decreased in axon terminals that innervate the PVN and lateral hypothalamus. Collectively, these results demonstrate that FAS is present and active in neurons and suggests that C75 may alter food intake via interactions within the arcuate-PVN pathway mediated by NPY.

Topics: 4-Butyrolactone; Acetyl-CoA Carboxylase; Adult; Aged; Amino Acid Sequence; Animals; Appetite; Arcuate Nucleus of Hypothalamus; Carboxy-Lyases; Conditioning, Psychological; Eating; Enzyme Inhibitors; Fasting; Fatty Acid Synthases; Female; Gene Expression Regulation, Enzymologic; Humans; Immunohistochemistry; Liver; Male; Mice; Mice, Inbred BALB C; Middle Aged; Molecular Sequence Data; Neurons; Neuropeptide Y; Obesity; Paraventricular Hypothalamic Nucleus; RNA, Messenger; Taste

This study was designed to investigate whether dietary fat and genetic background might differentially alter the expression of hypothalamic genes involved in food intake.. Three-month-old Osborne-Mendel (OM) and S5B/Pl rats were fed either a high-fat or a low-fat diet for 14 days. mRNA for neuropeptide Y (NPY), corticotrophin-releasing hormone, NPY Y-1 receptor and Y-5 receptor, and serotonin 2c (5-HT2c) receptors were measured using Northern blotting or ribonuclease protection assays.. OM rats showed an increased expression of NPY and corticotrophin-releasing hormone compared with S5B/Pl rats. The expression of NPY-Y1 and -Y5 receptor mRNA was significantly higher in the hypothalamus of OM rats compared with S5B/Pl rats. The expression of 5HT-2c receptor mRNA was significantly reduced in both strains of rats eating a high-fat diet when compared with the animals eating the low-fat diet.. These data suggest that over activity of the NPY system may contribute to the development of obesity in OM rats and that expression of the 5HT-2c receptor gene may be modulated by dietary fat.

Topics: Animals; Corticosterone; Corticotropin-Releasing Hormone; Dietary Fats; Eating; Gene Expression; Hypothalamus; Insulin; Leptin; Male; Neuropeptide Y; Obesity; Organ Size; Rats; Receptor, Serotonin, 5-HT2C; Receptors, Neuropeptide Y; Receptors, Serotonin; RNA, Messenger; Species Specificity; Weight Gain

Sprague-Dawley rats selectively bred for diet-induced obesity (DIO) or diet resistance (DR) were characterized on diets of differing energy content and palatability. Over 10 wk, DR rats on a high-energy (HE) diet (31% fat) gained weight similarly to DR rats fed chow (4.5% fat), but they became obese on a palatable liquid diet (Ensure). DIO rats gained 22% more weight on an HE diet and 50% more on Ensure than chow-fed DIO rats. DIO body weight gains plateaued when switched from HE diet to chow. But, Ensure-fed DIO rats switched to chow spontaneously reduced their intake and weight to that of rats switched from HE diet to chow. They also reduced their hypothalamic proopiomelanocortin and dynorphin but not neuropeptide Y mRNA expression by 17-40%. When reexposed to Ensure after 7 wk, they again overate and matched their body weights to rats maintained on Ensure throughout. All Ensure-fed rats had a selective reduction in dynorphin mRNA in the ventromedial hypothalamic nucleus. Thus genetic background, diet composition, and palatability interact to produce disparate levels of defended body weight and central neuropeptide expression.

Topics: Adipose Tissue; Animal Feed; Animals; Arcuate Nucleus of Hypothalamus; Body Weight; Diet; Dietary Sucrose; Dynorphins; Eating; Food, Formulated; Gene Expression; Leptin; Male; Neuropeptide Y; Obesity; Pro-Opiomelanocortin; Rats; Rats, Sprague-Dawley; RNA, Messenger

Orexins (forms A and B) belong to a new family of peptides that, as neuropeptide Y (NPY), stimulate food intake when centrally injected. The ob/ob mouse is a well-characterized model of hyperphagia and obesity associated with strong metabolic disturbances and a central dysregulation of peptides involved in the control of feeding. In the present report, we investigated the hypocretin (Hcrt)/orexin (OX) peptide pathway in lean and ob/ob mice. Prepro-Hcrt/OX mRNA expression, measured by in situ hybridization was restricted to the lateral hypothalamus area. It was significantly decreased in ob/ob mice (-18%; p<0.01). When estimated by real time RT-PCR in the whole hypothalamus, this decrease amounted to 65% (p<0.001). Hcrt-1/OX-A peptide concentrations, measured by RIA in microdissected hypothalamic nuclei were high in the lateral hypothalamus (LH) and lower in the arcuate (ARC) and paraventricular nuclei (PVN). In ob/ob mice, OX-A levels were significantly lower than in lean mice in the LH (-34%; p<0.02) and in the PVN (-72%; p<0.005). Acute intracerebroventricular injection of Hcrt-1/OX-A (1-10 nmol) stimulated feeding in lean, but not in ob/ob mice, whereas Hcrt-2/OX-B (1-10 nmol) had the opposite effect. Acute third ventricle (i3vt) injections of Hcrt/OX peptides in ob/ob mice transiently increased their metabolic rate and stimulated lipid substrate utilization. These findings provide direct evidence that Hcrt/OX peptides are down-regulated in the hypothalamus of ob/ob mice, contrary to the NPY system. The present data argues that Hcrt/OX peptides are not primarily responsible for the metabolic syndrome of the ob/ob mice. The diminution in the OX tone might participate in a counterregulatory system necessary to limit the adverse effects of NPY on food intake and body weight.

Topics: Animals; Carrier Proteins; Eating; Energy Metabolism; Feeding Behavior; Gene Expression; Hypothalamic Area, Lateral; In Situ Hybridization; Injections, Intraventricular; Intracellular Signaling Peptides and Proteins; Male; Mice; Mice, Inbred C57BL; Mice, Inbred Strains; Neuropeptide Y; Neuropeptides; Obesity; Orexins; Radioimmunoassay; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

Animal studies have demonstrated the importance of orexigenic NPY and agouti-related protein (AGRP) hypothalamic neurons, which are inhibited by the adipocyte hormone leptin, in the regulation of body weight and neuroendocrine secretion. We have examined NPY and AGRP neurons in postmortem human hypothalami from controls, Prader-Willi syndrome and other obese subjects, using quantitative immunocytochemistry (ICC) and in situ hybridization, to identify causes of leptin resistance in human obesity. Using combined ICC and in situ hybridization, AGRP, but not POMC, was colocalized with NPY in infundibular nucleus neurons. Infundibular nucleus (including median eminence) NPY ICC staining or mRNA expression, and AGRP ICC staining, increased with premorbid illness duration. NPY ICC staining and mRNA expression were reduced in obese subjects, but AGRP ICC staining was unchanged, correcting for illness duration. This suggests normal responses of NPY and AGRP neurons to peripheral signals, such as leptin and insulin, in human illness and obesity. The pathophysiology of obesity and illness-associated anorexia appear to lie in downstream or separate neuronal circuits, but the infundibular neurons may mediate neuroendocrine responses to illness. The implications for pharmacological treatment of human obesity are discussed.

Topics: Adult; Aged; Aged, 80 and over; Aging; Agouti-Related Protein; Cadaver; Female; Humans; Hypothalamus; Intercellular Signaling Peptides and Proteins; Male; Middle Aged; Neuropeptide Y; Obesity; Postmortem Changes; Prader-Willi Syndrome; Preservation, Biological; Proteins; RNA, Messenger; Sex Characteristics; Tissue Distribution; Tissue Fixation

Acute central nervous system administration of neuropeptide Y (NPY) elicits variable hemodynamic responses. Chronic intracerebroventricular (ICV) administration of NPY produces obesity in rats. Obesity has been shown to increase arterial pressure.. In this study we examined the chronic hemodynamic effects of NPY-induced obesity. Sprague-Dawley rats were implanted with radiotelemetry transmitters to continuously record heart rate and arterial pressure in the conscious state. Neuropeptide Y or vehicle was delivered into the third cerebral ventricle by osmotic minipumps over 2 weeks. Three groups were studied: vehicle, NPY-treated (free-fed), and NPY-treated (pair-fed to vehicle-treated rats).. Neuropeptide Y increased food intake and body weight in free-fed animals, and substantially augmented visceral adiposity in both free- and pair-fed rats. Despite increased adiposity, chronic ICV administration of NPY in conscious unstressed rats did not increase arterial pressure. Neuropeptide Y decreased heart rate, suggesting a sympathoinhibitory effect.. Obesity induced by 2-week ICV administration of NPY does not increase arterial pressure, perhaps indicating inhibition of sympathetic outflow that may oppose the pressor effect of adiposity.

Topics: Adipose Tissue; Animals; Blood Pressure; Body Weight; Eating; Heart Rate; Hemodynamics; Injections, Intraventricular; Male; Neuropeptide Y; Obesity; Rats; Rats, Sprague-Dawley; Viscera

Melanin-concentrating hormone (MCH) is a cyclic 19-aa hypothalamic neuropeptide derived from a larger prohormone precursor of MCH (Pmch), which also encodes neuropeptide EI (NEI) and neuropeptide GE (NGE). Pmch-deficient (Pmch-/-) mice are lean, hypophagic, and have an increased metabolic rate. Transgenic mice overexpressing Pmch are hyperphagic and develop mild obesity. Consequently, MCH has been implicated in the regulation of energy homeostasis. The MCH 1 receptor (MCH1R) is one of two recently identified G protein-coupled receptors believed to be responsible for the actions of MCH. We evaluated the physiological role of MCH1R by generating MCH1R-deficient (Mch1r-/-) mice. Mch1r-/- mice have normal body weights, yet are lean and have reduced fat mass. Surprisingly, Mch1r-/- mice are hyperphagic when maintained on regular chow, and their leanness is a consequence of hyperactivity and altered metabolism. Consistent with the hyperactivity, Mch1r-/- mice are less susceptible to diet-induced obesity. Importantly, chronic central infusions of MCH induce hyperphagia and mild obesity in wild-type mice, but not in Mch1r-/- mice. We conclude that MCH1R is a physiologically relevant MCH receptor in mice that plays a role in energy homeostasis through multiple actions on locomotor activity, metabolism, appetite, and neuroendocrine function.

Topics: Agouti-Related Protein; Animals; Appetite Stimulants; Body Composition; Corticotropin-Releasing Hormone; Dietary Fats; Eating; Energy Metabolism; Female; Gene Expression; Growth; Hyperkinesis; Hyperphagia; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Motor Activity; Neuropeptide Y; Neurosecretory Systems; Obesity; Peptide Fragments; Receptors, Pituitary Hormone

Otsuka Long-Evans Tokushima Fatty (OLETF) rat lacking CCK-A receptors are hyperphagic and obese. Previous work has demonstrated alterations in neuropeptide Y (NPY) and proopiomelanocortin (POMC) mRNA expression in ad libitum fed OLETF rats compared to lean Long-Evans Tokushima Otsuka (LETO) controls. In order to determine whether alterations in sensitivity to central peptides involved in overall feeding control may contribute to the hyperphagia and obesity in OLETF rats, we assessed OLETF and LETO rats feeding responses to lateral ventricular infusions of NPY (1 and 3.2 nmol), the melanocortin 3/4 agonist MTII (0.1 and 0.32 nmol) and the melanocortin receptor antagonist SHU-9119 (0.25 and 0.5 nmol). At a 3-h time point, NPY increased food intake in both OLETF and LETO rats. OLETF rats were more sensitive, having significant increases at both NPY doses and a greater increase at the higher dose. The melanocortin agonist MTII decreased intake in both LETO and OLETF rats. At the 20-h time point, the magnitude of suppression was greater in OLETF rats. SHU-9119 increased food intake in both groups. OLETF rats were more sensitive with larger relative increase and longer-lasting effects at the lower dose. These results are consistent with demonstrated alterations in neuropeptide gene expression in OLETF rats and indicate that alterations in responsivity to NPY and melanocortin signaling are unlikely to contribute to their hyperphagia and obesity.

Topics: Animals; Appetite Stimulants; Body Weight; Injections, Intraventricular; Male; Melanocyte-Stimulating Hormones; Neuropeptide Y; Obesity; Pro-Opiomelanocortin; Rats; Rats, Inbred OLETF; Receptor, Cholecystokinin A; Receptors, Cholecystokinin

Immunohistochemistry and Western blotting were used to determine the distribution of orexin receptors in the rat brain. Strong orexin receptor 1 (OX1R) immunoreactivity was detected in the hypothalamus including the arcuate, ventromedial, and tuberomammillary nuclei that are involved in feeding regulation. The neuropeptide Y- and proopiomelanocortin-containing neurons of the arcuate nucleus, which act to stimulate or to inhibit feeding, respectively, displayed intense OX1R immunoreactivity by double immunostaining. Western blotting analysis yielded a 50-kDa major band of OX1R.

Topics: Animals; Antibody Specificity; Appetite Regulation; Arcuate Nucleus of Hypothalamus; Carrier Proteins; Hypothalamic Area, Lateral; Hypothalamus; Immunohistochemistry; Intracellular Signaling Peptides and Proteins; Male; Neurons; Neuropeptide Y; Neuropeptides; Obesity; Orexin Receptors; Orexins; Pro-Opiomelanocortin; Rats; Rats, Sprague-Dawley; Receptors, G-Protein-Coupled; Receptors, Neuropeptide; Ventromedial Hypothalamic Nucleus

A subset of Sprague-Dawley rats developed persistent obesity when maintained on a high-fat diet for 6 months followed by a low-fat diet for 1 month, while another subset from the same cohort of rats remained lean on the same diet regimens. The diet-induced obese (DIO) rats had higher energy intake than expenditure, while diet-resistant (DR) rats maintained energy balance. DIO rats also had an increased respiratory quotient and higher levels of plasma leptin, insulin and cholesterol. In the hypothalamic areas, DIO rats had elevated NPY and AGRP mRNA, but not MCH mRNA. Our data suggest that the increase in hypothalamic expression of NPY and AGRP may contribute to the development of persistent obesity in DIO rats.

Topics: Agouti-Related Protein; Animals; Cell Respiration; Cholesterol; Dietary Fats; Disease Models, Animal; Eating; Energy Metabolism; Food, Formulated; Genetic Predisposition to Disease; Homeostasis; Hypothalamic Hormones; Hypothalamus; Insulin; Intercellular Signaling Peptides and Proteins; Leptin; Melanins; Neuropeptide Y; Obesity; Pituitary Hormones; Predictive Value of Tests; Proteins; Rats; Rats, Sprague-Dawley; RNA, Messenger; Up-Regulation

The aim of this work was to study the potential involvement of neuropeptide Y (NPY) and orexins in the anorexigenic mechanism of fluoxetine in obese Zucker rats, assessing the effects of chronic fluoxetine treatment on NPY and orexin immunostaining in several hypothalamic regions.. Male obese Zucker (fa/fa) rats were administered fluoxetine (10 mg/kg intraperitoneally) daily for 2 weeks. The control group was administered 0.9% NaCl solution. Carcass composition was assessed using the official methods of the Association of Official Analytical Chemists. To test the potential thermogenic effect of fluoxetine administration, total body oxygen consumption was measured daily for 60 minutes before fluoxetine or saline injection and for 30 minutes after drug or saline injection. Hypothalamic arcuate and paraventricular nuclei, and the lateral hypothalamic area were immunostained for NPY, orexin A, and orexin B. Commercial kits were used for serum determinations.. Chronic fluoxetine administration in obese Zucker rats generated a reduction in body weight gain, food intake, adipocyte size, fat mass, and body protein. A decrease in NPY immunostaining in the paraventricular nucleus, without changes in the arcuate, was observed. However, no changes were observed in the number of neural cells immunostained for orexin A or orexin B in the lateral hypothalamic area.. Due to the hyperphagic effect of NPY in the paraventricular nucleus, these results suggest that NPY, but not orexins, could be involved in the anorexigenic effect of fluoxetine in obese Zucker rats.

Topics: Adipocytes; Adipose Tissue; Animals; Blood Glucose; Body Composition; Body Weight; Carrier Proteins; Cell Size; Drinking; Eating; Fluoxetine; Hypothalamus; Immunoenzyme Techniques; Intracellular Signaling Peptides and Proteins; Leptin; Male; Neuropeptide Y; Neuropeptides; Obesity; Orexins; Organ Size; Oxygen Consumption; Rats; Rats, Zucker; Selective Serotonin Reuptake Inhibitors; Thyroid Hormones; Triglycerides

A single nucleotide polymorphism (SNP) T1128C, which causes an amino acid change from leucine(7) to proline(7) in the signal peptide of neuropeptide Y (NPY), has been found to be associated with multiple clinical parameters or disease. However, this SNP was not identified in the Japanese population. We asked if this is also true in the Korean population.. Genotyping was conducted by pyrosequencing, a newly developed real-time high-throughput SNP scoring technique.. All 242 Korean subjects showed T1128/T1128 genotype.. The T1128C SNP does not appear to exist in this Korean population.

Topics: Adult; Base Sequence; Genetics, Population; Genotype; Humans; Korea; Leucine; Neuropeptide Y; Obesity; Polymorphism, Single Nucleotide; Proline; Protein Sorting Signals

A dysregulation in the hypothalamic neuropeptide systems involved in the control of appetite has previously been shown in models of diet-induced obesity. In the present study, male Sprague-Dawley rats were rendered obese by a highly palatable cafeteria-style diet over 20 weeks, while control rats had access to standard laboratory chow. Feeding responses to alpha-melanocyte stimulating hormone (alpha-MSH), an anorectic peptide and neuropeptide Y (NPY), a potent orexigenic agent were investigated in diet-induced obese and control animals. In addition, endogenous hypothalamic peptide levels were determined in these animals. Intracerebroventricular injections of either 4 nmol alpha-MSH or saline vehicle were given 10 min prior to the onset of the dark phase. Diet-induced obese rats had significantly enhanced nocturnal inhibitory feeding responses to alpha-MSH (P<0.05). The orexigenic feeding response induced by 1 nmol NPY was similar for both groups. At sacrifice, both alpha-MSH and NPY peptide content were selectively reduced in the paraventricular nucleus (PVN) of these animals (P<0.05). Although diet-induced obesity had no effect on responses to NPY, the significantly greater inhibition of nocturnal feeding by alpha-MSH and reduction in PVN alpha-MSH peptide level, suggests melanocortinergic signalling may be reduced in obesity which may account for the hyperphagia of these animals when presented with a palatable diet.

Topics: Adipose Tissue; alpha-MSH; Animals; Appetite; Body Weight; Cerebral Ventricles; Circadian Rhythm; Diet; Feeding Behavior; Humans; Hypothalamus; Injections, Intraventricular; Male; Neuropeptide Y; Obesity; Rats; Rats, Sprague-Dawley; Weight Gain

The inheritance of adiposity levels has been investigated in an intercross of the obese, diabetes-prone NZO and the small, lean SM mouse strains. Adiposity index (AI) was defined as the sum of four fat pad weights divided by body weight. DNA pools from fat and lean mice were analyzed with microsatellite variants to screen the genome for quantitative trait loci (QTLs) affecting AI. Ten significant QTLs affecting AI were identified on Chromosome (Chr) 1 (three loci), Chr 2, Chr 5 (two loci), Chr 6 (two loci), Chr 7, and Chr 17. Most of the QTLs appear to be novel. Several QTLs differentially affect specific fat depots. Thus, Chr 2 and Chr 7 QTLs affect gonadal more than inguinal fat, while the converse is true for the Chr 17 QTL. Gender influences the expression of several of the QTLs. For example, effects of the proximal Chr 1 QTL (Obq7) on AI appears to be primarily in males. The proximal AI QTL on Chr 6 (Obq13) maps near the neuropeptide Y (Npy) locus. Sequence analysis of the Npy gene revealed a 1-nucleotide deletion within a highly conserved portion of the 3' untranslated region in strain NZO. However, the deletion is polymorphic among mouse strains. Furthermore, lack of association between this same variant and AI in previously analyzed crosses raises doubt that it is the basis of Obq13. The present cross is the fourth in a series of intercrosses among 10 inbred strains arranged such that each strain is crossed with each adjacent strain within a circle. This design affords multiple opportunities to analyze each segregating QTL.

Topics: 3' Untranslated Regions; Adipose Tissue; Animals; Base Sequence; Body Constitution; Body Weight; Conserved Sequence; Crosses, Genetic; Female; Genotype; Glucose; Male; Mice; Mice, Inbred Strains; Mice, Obese; Microsatellite Repeats; Molecular Sequence Data; Neuropeptide Y; Obesity; Polymorphism, Genetic; Quantitative Trait, Heritable; Reverse Transcriptase Polymerase Chain Reaction; Sequence Deletion

The primary role of the orexins was originally believed to be appetite regulation, but is now believed to be the regulation of sleep, arousal and locomotor activity. Orexin A immunoreactivity (orexin A-IR) and prepro-orexin mRNA were measured in the CNS of obese and lean Zucker rats. There were no differences in orexin A-IR or prepro-orexin mRNA levels between obese and lean Zucker rats. The orexins are therefore unlikely to be important in this model of obesity. Levels of orexin A-IR and prepro-orexin mRNA were measured in the CNS of Wistar-Kyoto (WKY) rats, which are hypoactive and have abnormal sleep architecture. Compared to Wistar rats, WKY rats had significantly lower orexin A-IR (with differences of up to 100% in some brain regions) and prepro-orexin mRNA levels. These observations suggest that the sleep and activity phenotype of the WKY strain may be related to orexin deficiency and that this strain may be a useful model of partial orexin deficiency.

Topics: Animals; Antibodies; Brain Chemistry; Carrier Proteins; Disease Models, Animal; Gene Expression; Hypothalamus; Intracellular Signaling Peptides and Proteins; Locomotion; Male; Neuropeptide Y; Neuropeptides; Obesity; Orexins; Protein Precursors; Rats; Rats, Inbred WKY; Rats, Wistar; Rats, Zucker; RNA, Messenger; Sleep; Species Specificity

The purpose of this study was to test the continuing validity of the hypothesis that neuropeptide Y (NPY) produced in the brain controls food intake through an interaction with the NPY Y(5) receptor subtype.. The hypothesis was tested using CGP 71683A a potent and highly selective non-peptide antagonist of the NPY Y(5) receptor which was administered into the right lateral ventricle of obese Zucker fa/fa rats.. Intraventricular injection of 3.4 nmol/kg NPY increased food intake during a 2 h test period. Doses of CGP 71683A in excess of 15 nmol/kg (i.cv.) resulted in blockade of the increase in food intake produced by NPY. Repeated daily injection of CGP 71683A (30--300 nmol/kg, i.cv.) immediately before the dark phase produced a dose-dependent and slowly developing decrease in food intake. CGP 71683A has a low affinity for NPY Y(1), Y(2) and Y(4) receptors but a very high affinity for the NPY Y(5) receptor (Ki, 1.4 nM). Surprisingly, CGP 71683A had similarly high affinity for muscarinic receptors (Ki, 2.7 nM) and for the serotonin uptake recognition site (Ki, 6.2 nM) in rat brain. Anatomic analysis of the brain after treatment with CGP 71683A demonstrated an inflammatory response associated with the fall in food intake.. While the fall in food intake in response to CGP 71683A may have a Y(5) component, interactions with other receptors or inflammatory mediators may also play a role. It is concluded that CGP 71683A is an imprecise tool for investigating the role of the NPY Y(5) receptor in the control of physiological processes including food intake. International Journal of Obesity (2001) 25, 84-94

Topics: Animals; Dose-Response Relationship, Drug; Eating; Encephalitis; Energy Intake; Injections, Intraventricular; Male; Naphthalenes; Neuropeptide Y; Obesity; Pyrimidines; Rats; Rats, Wistar; Rats, Zucker; Receptors, Muscarinic; Receptors, Neuropeptide Y; Receptors, Serotonin; Time Factors

Melanin concentrating hormone (MCH) and the orexins (A and B) have been identified as neuropeptides localized to the lateral hypothalamic area (LHA) and are potential regulators of energy homeostasis. Potential factors regulating expression of both MCH and the orexins include fasting and leptin. Previous studies have generated conflicting data and, as there is little leptin receptor expressed in the lateral hypothalamus, it is likely that any observed leptin effects on these peptides are indirect. In this study, we examined MCH and preproorexin expression in mice in physiological states of starvation, with or without leptin administration, in addition to characterizing MCH and preproorexin expression in well-known obesity models, including ob/ob and UCP-DTA mice. Neuropeptide Y (NPY) expression in the arcuate nucleus was used as a positive control. After a 60-h fast, expression of both NPY and MCH mRNA was increased (by 148 and 33%, respectively) while preproorexin expression in the murine LHA did not change. Leptin administration to fasted mice blunted the rise in MCH and NPY expression towards control levels. In contrast, there was a 78% increase in preproorexin expression in fasted mice in response to peripheral leptin administration. MCH expression was increased (by 116%) in ob/ob mice at baseline, as we have previously reported. In addition, leptin treatment of ob/ob mice blunted the increase in MCH expression. In contrast, preproorexin expression did not differ in the leptin-deficient ob/ob mice or in the obese hyperleptinemic brown adipose tissue deficient (UCP-DTA) mice in comparison with controls. In summary, MCH expression is increased in two states of decreased leptin, fasting and ob/ob mice, and leptin replacement blunts MCH expression in both paradigms. Thus, MCH expression appears to be regulated by leptin. In contrast, preproorexin expression does not respond acutely to fasting, although it is acutely increased by leptin treatment during fasting. These preproorexin responses are in contrast to those seen with well-characterized orexigenic neuropeptides, such as NPY and AgRP, suggesting that appetite regulation may not be a significant physiological role of orexins. This conclusion is further supported by the observation that orexin ablated mice have arousal and not feeding deficits.

Topics: Animals; Eating; Gene Expression Regulation; Hypothalamic Area, Lateral; Hypothalamic Hormones; Intracellular Signaling Peptides and Proteins; Leptin; Male; Melanins; Mice; Mice, Inbred C57BL; Mice, Knockout; Neurons; Neuropeptide Y; Neuropeptides; Obesity; Orexins; Pituitary Hormones; Protein Precursors; RNA, Messenger

We studied the effects of the novel noradrenaline and serotonin (5-HT) reuptake inhibitor sibutramine on feeding and body weight in a rat model of dietary obesity, and whether it interacts with hypothalamic neuropeptide Y (NPY) neurones. Chow-fed and dietary-obese (DIO) male Wistar rats were given sibutramine (3 mg kg(-1) day(-1) p.o.) or deionized water for 21 days. Sibutramine decreased food intake throughout the treatment period in both dietary-obese rats (P<0.0001) and lean rats (P<0.0001). Weight gain was reduced so that final body weight was 10% lower in dietary-obese (P<0.005) and 8% lower in lean (P<0.05) rats versus their untreated controls. Plasma leptin concentration was lower in sibutramine-treated dietary-obese rats (P<0.05), and in treated lean rats (P<0.05). Using the homeostasis model assessment (HOMA) as a measure of insulin resistance, untreated DIO rats were significantly more insulin resistant than controls (P<0.005), and this was corrected by sibutramine treatment (P<0.05). Neither hypothalamic NPY mRNA nor NPY peptide levels in a number of hypothalamic nuclei were significantly altered by sibutramine compared to untreated controls. The hypophagic and anti-obesity effects of sibutramine in dietary-obese Wistar rats appear not to be mediated by inhibition of ARC NPY neurones.

Topics: Adipose Tissue; Animals; Appetite Depressants; Body Weight; Cyclobutanes; Diet; Feeding Behavior; Hypothalamus; Insulin Resistance; Leptin; Male; Neurons; Neuropeptide Y; Obesity; Rats; Rats, Wistar; RNA, Messenger

Neuropeptide Y (NPY), one of the most abundant peptide transmitters in the mammalian brain, is assumed to play an important role in feeding and body weight regulation. However, there is little genetic evidence that overexpression or knockout of the NPY gene leads to altered body weight regulation. Previously, we developed NPY-overexpressing mice by using the Thy-1 promoter, which restricts NPY expression strictly within neurons in the central nervous system, but we failed to observe the obese phenotype in the heterozygote. Here we report that in the homozygous mice, overexpression of NPY leads to an obese phenotype, but only after appropriate dietary exposure. NPY-overexpressing mice exhibited significantly increased body weight gain with transiently increased food intake after 50% sucrose--loaded diet, and later they developed hyperglycemia and hyperinsulinemia without altered glucose excursion during 1 year of our observation period.

Topics: Aging; Animals; Arginine; Brain; Cyclohexanes; Dietary Sucrose; Energy Intake; Homozygote; Humans; Mice; Mice, Knockout; Mice, Transgenic; Neuropeptide Y; Obesity; Phenotype; Promoter Regions, Genetic; Receptors, Neuropeptide Y; Reference Values; Thy-1 Antigens; Xanthenes

Topics: Adipocytes; Animals; Arcuate Nucleus of Hypothalamus; Carrier Proteins; Eating; Energy Metabolism; Hypothalamus; Ion Channels; Membrane Proteins; Mice; Mice, Knockout; Mitochondrial Proteins; Neuropeptide Y; Obesity; Peptides; Receptor, Melanocortin, Type 4; Receptors, Corticotropin; Uncoupling Protein 1

We developed a new hypothesis claiming that natriuresis of fasting is not only caused by diminished insulin resistance and hyperinsulinaemia with the subsequent reduction of renal sodium retention but it can also be attributed to the function of the leptin-NPY system. Each element of this concept has been substantiated by convincing experimental evidences as follows:1. Leptin, the adipocyte-derived peptide hormone conveys information to the central nervous system about the size of body energy stores and it reciprocally regulates the hypothalamic expression of NPY, the major mediator of its metabolic and neuroendocrine actions.2. NPY has been demonstrated to be intimately involved in the regulation of renal functions; under various experimental conditions it increased urine flow rate and urinary sodium excretion presumably through stimulating the synthesis and/or release of other natriuretic factors.3. Fasting-induced suppression of tissue expression of leptin mRNA and circulating plasma leptin levels is associated with simultaneous activation of NPY system.4. This sequence of events implies that NPY contributes to natriuresis that occurs in response to fasting.

Topics: Fasting; Humans; Kidney; Leptin; Natriuresis; Neuropeptide Y; Obesity; Sodium

Vanadium, a potent nonselective inhibitor of protein tyrosine phosphatases, has been shown to mimic many of the metabolic actions of insulin both in vivo and in vitro. The mechanism(s) of the effect of vanadium on the decrease in appetite and body weight in Zucker fa/fa rats, an insulin-resistant model, is still unclear. Because insulin may inhibit hypothalamic neuropeptide Y (NPY), which is known to be related to appetite, and increase leptin secretion in adipose tissue, we studied the possibility that the changes in appetite produced by vanadium may be linked to altered NPY levels in the hypothalamus. We also examined effects of vanadium on leptin. Zucker lean and fatty rats were chronically treated with bis(maltolato)oxovanadium(IV) (BMOV), an organic vanadium compound, in the drinking water. Plasma and adipose tissue leptin levels were measured by radioimmunoassay and immunoblotting, respectively. Hypothalamic NPY mRNA and peptide levels were measured using in situ hybridization and immunocytochemistry, respectively. BMOV treatment significantly reduced food intake, body fat, body weight, plasma insulin levels, and glucose levels in fatty Zucker rats. Fifteen minutes after insulin injection (5 U/kg, intravenous [IV]), circulating leptin levels (+100%) and adipose leptin levels (+60%) were elevated in BMOV-treated fatty rats, although these effects were not observed in untreated fatty rats. NPY mRNA levels in the arcuate nucleus (ARC) (-29%), NPY peptide levels in ARC (-31%), as well as in the paraventricular nucleus (PVN) (-37%) were decreased with BMOV treatment in these fatty rats. These data indicate that BMOV may increase insulin sensitivity in adipose tissue and decrease appetite and body fat by decreasing NPY levels in the hypothalamus. BMOV-induced reduction in appetite and weight gain along with normalized insulin levels in models of obesity, suggest its possible use as a therapeutic agent in obesity.

Topics: Adipose Tissue; Animals; Appetite; Arcuate Nucleus of Hypothalamus; Blood Glucose; Cell Nucleus; Disease Models, Animal; Hypoglycemic Agents; Hypothalamus; Immunohistochemistry; In Situ Hybridization; Insulin; Leptin; Male; Neuropeptide Y; Obesity; Pyrones; Rats; Rats, Zucker; RNA, Messenger; Vanadates; Vanadium

This study used a hypothalamo-pituitary disconnected (HPD) sheep model to investigate the central regulation of long-term cycles in voluntary food intake (VFI) and body weight (BW). VFI, BW, and circulating concentrations of metabolic hormones [alpha-melanocyte-stimulating hormone (alpha-MSH), insulin-like growth factor-1 (IGF-1), insulin, and leptin] were measured in HPD and control Soay rams exposed to alternating 16 weekly periods of long and short days for 80 wk. In the controls, the physiology was cyclical with a 32-wk periodicity corresponding to the lighting regimen. VFI and BW increased under long days to a maximum early into short days, and there were associated increases in blood concentrations of alpha-MSH, insulin, and leptin. In the HPD rams, there were no significant photoperiod-induced changes in any of the parameters. VFI increased after surgery for 8 wk and then gradually declined, although BW increased progressively and the HPD rams became obese. Concentrations of alpha-MSH, insulin, and leptin in peripheral blood were permanently increased (>200%), and levels of IGF-1 decreased (<55%). The HPD lesion effectively destroyed the entire median eminence [no nerve terminals immunostained for tyrosine hydroxylase (TH) and gonadotropin-releasing hormone] and the adjacent arcuate nucleus (no perikarya immunostained for proopiomelanocortin or TH, and no cells expressed neuropeptide Y mRNA). The results support the conclusion that arcuate hypothalamic systems generate long-term rhythms in VFI, BW, and energy balance.

Topics: Adaptation, Physiological; Adipose Tissue; alpha-MSH; Animals; Appetite; Arcuate Nucleus of Hypothalamus; Body Weight; Denervation; Eating; Energy Metabolism; Glucose; Gonadotropin-Releasing Hormone; Hypoglycemic Agents; Hypothalamo-Hypophyseal System; Immunohistochemistry; Insulin; Insulin-Like Growth Factor I; Leptin; Male; Neuropeptide Y; Obesity; Photoperiod; Pro-Opiomelanocortin; RNA, Messenger; Seasons; Sheep; Tyrosine 3-Monooxygenase

Otsuka Long-Evans Tokushima Fatty (OLETF) rats lacking CCK-A receptors are hyperphagic, obese, and diabetic. We have previously demonstrated that these rats have a peripheral satiety deficit resulting in increased meal size. To examine the potential role of hypothalamic pathways in the hyperphagia and obesity of OLETF rats, we compared patterns of hypothalamic neuropeptide Y (NPY), proopiomelanocortin (POMC), and leptin receptor mRNA expression in ad libitum-fed Long-Evans Tokushima (LETO) and OLETF rats and food-restricted OLETF rats that were pair-fed to the intake of LETO controls. Pair feeding OLETF rats prevented their increased body weight and elevated levels of plasma insulin and leptin and normalized their elevated POMC and decreased NPY mRNA expression in the arcuate nucleus. In contrast, NPY expression was upregulated in the dorsomedial hypothalamus (DMH) in pair-fed OLETF rats. A similar DMH NPY overexpression was evident in 5-wk-old preobese OLETF rats. These findings suggest a role for DMH NPY upregulation in the etiology of OLETF hyperphagia and obesity.

Topics: Age Factors; Animals; Body Composition; Carrier Proteins; Dorsomedial Hypothalamic Nucleus; Eating; Energy Metabolism; Gene Expression; Hyperphagia; In Situ Hybridization; Insulin; Leptin; Male; Neuropeptide Y; Obesity; Pro-Opiomelanocortin; Rats; Rats, Inbred OLETF; Receptor, Cholecystokinin A; Receptors, Cell Surface; Receptors, Cholecystokinin; Receptors, Leptin; RNA, Messenger; Satiation

We investigated whether pair-feeding to prevent hyperphagia would potentiate the insulin-sensitizing effect of rosiglitazone in chow-fed and insulin-resistant dietary obese rats, and studied the role of leptin and hypothalamic neuropeptide Y as mediators of weight gain during treatment.. Dietary obese and chow-fed rats (575 +/- 10 vs. 536 +/- 7 g; p < 0.01) were given rosiglitazone (30 mg/kg p.o.) or vehicle daily for 14 days.. Energy intake and weight gain were greater in rosiglitazone-treated ad-lib-fed rats (body weight: chow + 24 +/- 2 g, rosiglitazone-treated + 55 +/- 2 g, p < 0.001; dietary obese + 34 +/- 2 g, rosiglitazone-treated + 74 +/- 7 g, p < 0.001). Half of each rosiglitazone-treated group were pair-fed to vehicle-treated controls. Rosiglitazone normalized circulating free fatty acids (FFAs) and insulin sensitivity in dietary obese rats (homeostasis model assessment (HOMA): chow-fed controls, 3.9 +/- 0.3; dietary obese controls, 6.7 +/- 0.7; rosiglitazone-treated, ad lib-fed dietary obese, 4.2 +/- 0.5; both p < 0.01). Insulin sensitivity improved further with pair-feeding (HOMA: 2.9 +/- 0.4; p < 0.05 vs. rosiglitazone-treated, ad lib-fed dietary obese), despite unchanged FFAs. Qualitatively similar findings were made in chow-fed rats. Pair-feeding prevented rosiglitazone-related weight gain in chow-fed, but not dietary obese rats (body weight: + 49 +/- 5 g, p < 0.001 vs. untreated dietary obese controls). Adipose tissue OB mRNA was elevated in dietary obese rats, reduced 49% (p < 0.01) by rosiglitazone treatment, and further (by 16%) with pair-feeding (p < 0.0001). Plasma leptin, however, only fell in the pair-fed group. Hypothalamic neuropeptide Y mRNA was unchanged throughout, suggesting that weight gain associated with high-dose rosiglitazone treatment is independent of hypothalamic neuropeptide Y.. Food restriction potentiates the insulin-sensitizing effect of rosiglitazone in rats, and this effect is independent of a fall in FFAs.

Topics: Animals; Body Weight; Carrier Proteins; Eating; Food Deprivation; Hyperphagia; Hypoglycemic Agents; Hypothalamus; Insulin Resistance; Ion Channels; Leptin; Male; Mitochondrial Proteins; Neuropeptide Y; Obesity; Rats; Rats, Wistar; RNA, Messenger; Rosiglitazone; Thiazoles; Thiazolidinediones; Uncoupling Protein 3

Many hyothalamic neuropeptides are involved in the regulation of food intake and body weight. The orexins (OX) which are synthesized in the lateral hypothalamus are among the most recently characterized whereas neuropeptide Y (NPY) belongs to a group of "older" peptides extensively studied for their effects on feeding behavior. Both stimulate food ingestion in rodents. In this experiment, we measured the expressions of these peptides as well as of their receptors (OX1-R and OX2-R, Y1 and Y5) in the hypothalamus of obese hyperphagic and lean Zucker rats by real-time RT-PCR using the TaqMan apparatus. NPY mRNA expression in the obese rats was significantly increased by a factor of 10 (P < 0.002) whereas expressions of the Y1 and Y5 receptors were decreased by 25% (P < 0.01) and 50% (P < 0.002), respectively. Their prepro-orexin mRNA expression was more than twofold decreased (P < 0.01) and expressions of their OX receptors 1 and 2 mRNA were five- and fourfold increased (P < 0.05), respectively. An inverse phenomenon was therefore noted between the two peptides: for NPY, increased levels and downregulation of receptors; and for OX, diminished levels with upregulation of receptors. The reasons for these changes might be linked to the absence of leptin signaling as similar profiles are found in the ob/ob mice. For orexins at least, other factors such as hyperglycemia might be involved. Based on anatomical considerations, a direct effect of NPY or of other brain peptides such as CRH cannot be excluded. We conclude that the diminution in the OX tone might participate in a counterregulatory system necessary to limit the noxious effects of NPY on food intake and body weight.

Topics: Animals; Body Weight; Carrier Proteins; Eating; Hypothalamus; Intracellular Signaling Peptides and Proteins; Leptin; Male; Neuropeptide Y; Neuropeptides; Obesity; Orexin Receptors; Orexins; Peptides; Protein Precursors; Rats; Rats, Zucker; Receptors, G-Protein-Coupled; Receptors, Neuropeptide; Receptors, Neuropeptide Y; RNA, Messenger

Brain-derived neurotrophic factor has been associated previously with the regulation of food intake. To help elucidate the role of this neurotrophin in weight regulation, we have generated conditional mutants in which brain-derived neurotrophic factor has been eliminated from the brain after birth through the use of the cre-loxP recombination system. Brain-derived neurotrophic factor conditional mutants were hyperactive after exposure to stressors and had higher levels of anxiety when evaluated in the light/dark exploration test. They also had mature onset obesity characterized by a dramatic 80-150% increase in body weight, increased linear growth, and elevated serum levels of leptin, insulin, glucose, and cholesterol. In addition, the mutants had an abnormal starvation response and elevated basal levels of POMC, an anorexigenic factor and the precursor for alpha-MSH. Our results demonstrate that brain derived neurotrophic factor has an essential maintenance function in the regulation of anxiety-related behavior and in food intake through central mediators in both the basal and fasted state.

Topics: Animals; Anxiety; Body Weight; Brain; Brain-Derived Neurotrophic Factor; Fasting; Fluoxetine; Gene Deletion; Gene Expression; Hyperglycemia; Hyperinsulinism; Hyperkinesis; Hypothalamus; Integrases; Leptin; Mice; Neuropeptide Y; Obesity; Pro-Opiomelanocortin; RNA, Messenger; Selective Serotonin Reuptake Inhibitors; Serotonin; Transfection; Viral Proteins

Leptin and its principal mediators, NPY and alpha-MSH are postulated to play a pivotal role in energy balance. To determine the possibility of the disturbance in neuropeptides in human obesity and their consequent changes in response to negative energy balance, we evaluated plasma and cerebrospinal fluid (CSF) leptin, NPY, and alpha-MSH levels in obese women before and after weight loss in comparison with normal control women. Subjects included 16 obese women [mean body mass index (BMI), 35.6 kg/m(2)] before and after weight loss induced by a 2-wk very low caloric diet (800 kcal/d) and 14 normal weight women (mean BMI, 20.4 kg/m(2)). The CSF to plasma leptin ratio in normal weight subjects was 2.3-fold higher than that in obese subjects. After weight loss in obese subjects, plasma leptin levels decreased by 40% and CSF levels decreased by 51%. There was a positive linear correlation between CSF and plasma leptin levels at baseline in obese subjects (r = 0.74, P < 0.05) and a positive logarithmic correlation in normal weight subjects (r = 0.89, P < 0.05) and in obese subjects after weight loss (r = 0.64, P < 0.05). The BMI was negatively correlated with the CSF to plasma leptin ratio (r = -0.86, P < 0.05) in all subjects. Neither the baseline plasma levels nor the baseline CSF levels of NPY were different between normal weight subjects and obese subjects. After weight loss, the CSF NPY level decreased significantly compared with baseline values in obese subjects. The alpha-MSH levels in plasma and CSF did not differ significantly from controls in obese subjects at baseline or after weight loss. Baseline CSF leptin level correlated with neither the baseline CSF NPY level nor the baseline CSF alpha-MSH level. In conclusion, this study demonstrated that the efficiency of brain leptin delivery is reduced in human obesity and central nervous system leptin uptake involves a combination of a saturable and an unsaturable mechanism. CSF NPY and alpha-MSH did not differ from controls in human obesity, and the CSF NPY level decreased significantly whereas alpha-MSH did not differ after weight loss in obese subjects compared with baseline. There was no significant correlation between CSF leptin and CSF NPY or alpha-MSH. This could be the result of leptin resistance present in human obesity and/or the more complex mechanisms involved in modulating appetite and regulating energy balance in human obesity.

Topics: Adult; alpha-MSH; Energy Metabolism; Female; Humans; Leptin; Neuropeptide Y; Obesity; Receptor, Melanocortin, Type 4; Receptors, Corticotropin; Receptors, Leptin

Agouti-related protein (AGRP) is synthesized in the same neurones in the arcuate nucleus as neuropeptide Y (NPY), another potent orexigenic peptide. AGRP antagonizes the action of alpha-melanocyte stimulating hormone, a derivative of pro-opiomelanocortin (POMC) at the hypothalamic MC4 receptor to increase food intake. Although leptin has been shown to regulate Agrp/Npy and Pomc-expressing neurones, there are differences with respect to Agrp regulation in leptin receptor-deficient mice and rats. Unlike the obese leptin receptor-deficient db/db mouse, which exhibits upregulation of Agrp mRNA expression in the medial basal hypothalamus (MBH) compared to lean controls, the obese leptin receptor-deficient (faf; Koletsky) rat does not exhibit upregulation of Agrp expression. To determine whether this represents a general difference between leptin receptor-deficient mice and rats, neuropeptide gene expression was analysed in the MBH of lean and obese rats segregating for a different leptin receptor mutation, Leprfa (Zucker). Fasting in lean rats (+/fa) for 72 h significantly increased Agrp and Npy mRNA expression, and decreased Pomc mRNA expression as detected by a sensitive solution hybridization/S1 nuclease protection assay. Npy mRNA levels were significantly increased in fed obese fa/fa compared to lean rats, and further increased in the obese animals after fasting. In contrast, Agrp mRNA levels did not differ between fed lean and fed obese rats, and fasting did not significantly change Agrp levels in obese rats. To determine whether the change in Agrp expression that occurs with food deprivation in lean rats could be prevented by leptin replacement, Sprague-Dawley rats were fasted and infused via subcutaneous osmotic micropumps for 48 h with either saline or recombinant mouse leptin. Fasting significantly increased Agrp and Npy, and decreased Pomc mRNA levels. Leptin infusion almost completely reversed these changes such that there was no significant difference between the levels in the fasted rats and those that were fed ad libitum. Thus, in fasted lean rats, Agrp and Npy are upregulated in parallel when leptin levels fall and are downregulated by leptin infusion. By contrast, the absence of a functional leptin receptor results in the upregulation of Npy but not Agrp mRNA.

Topics: Agouti-Related Protein; Animals; Body Weight; Carrier Proteins; Fasting; Food Deprivation; Gene Expression; Hypothalamus, Middle; Intercellular Signaling Peptides and Proteins; Leptin; Male; Neuropeptide Y; Obesity; Pro-Opiomelanocortin; Proteins; Rats; Rats, Sprague-Dawley; Rats, Zucker; Receptors, Cell Surface; Receptors, Leptin; RNA, Messenger

Neuropeptide Y (NPY) is involved in the central regulation of appetite, sexual behavior, and reproductive function. We have previously shown that chronic infusion of NPY into the lateral ventricle of normal rats produced an obesity syndrome characterized by hyperphagia, hyperinsulinism and collapse of reproductive function. We further demonstrated that acute inhibition of LH secretion in castrated rats was preferentially mediated by the NPY receptor subtype 5 (Y(5)). In the present study, the effects of chronic, central infusion of NPY, or the mixed Y2-Y5 agonist PYY(3-36), were evaluated both in normal male C57BL/6J mice and Sprague-Dawley rats. After a 7-day infusion to male mice, both NPY and PYY(3-36) at 5 nmol per day, induced marked hyperphagia leading to significant increases in body and fat pad weights. Furthermore, both compounds markedly reduced several markers of the reproductive axis. In the rat study, PYY(3-36) was more active than NPY to inhibit the pituitary-testicular axis, confirming the importance of the Y5 subtype for such effects. In the mouse, chronic NPY infusion induced a sustained increase in corticosterone and insulin secretion. Plasma leptin levels were also markedly increased possibly explaining the observed reduction in gene expression for hypothalamic NPY. Gene expression for hypothalamic POMC was reduced in the NPY- or PYY(3-36)-infused mice, suggesting that NPY exacerbated food intake by both acting through its own receptor(s), and reducing the satiety signal driven by the POMC-derived alpha-MSH. The present study in the mouse suggests in analogy with available rat data, that constant exposure to elevated NPY in the hypothalamic area unabatedly enhances food intake leading to an obesity syndrome including increased adiposity, insulin resistance, hypercorticism, and hypogonadism, reminiscent of the phenotype of the ob/ob mouse, that displays elevated hypothalamic NPY secondary to lack of leptin negative feedback action.

Topics: Animals; Hyperphagia; Hypogonadism; Insulin Resistance; Lateral Ventricles; Leptin; Male; Mice; Mice, Inbred C57BL; Neuropeptide Y; Obesity; Peptide Fragments; Peptide YY; Rats; Rats, Sprague-Dawley; Syndrome

Altered fat distribution is a consequence of menopause, but the mechanisms responsible are unknown. Estrogen insufficiency in humans can be modeled using ovariectomized rats. We have shown that increased adiposity in these rats is due to reduced physical activity and transient hyperphagia, and can be reversed with 17beta-estradiol treatment. The aims of this study were to examine whether this altered energy balance is associated with circulating leptin insufficiency, central leptin insensitivity, decreased hypothalamic leptin receptor (Ob-Rb) expression, and/or increased hypothalamic neuropeptide Y (NPY).. Plasma leptin levels, adipose tissue ob gene expression, energy balance responses to i.c.v. leptin, hypothalamic Ob-Rb expression and NPY concentration in five separate hypothalamic regions were measured in adult female rats after either ovariectomy or sham operations.. Obesity was not associated with hypoleptinemia or decreased ob gene expression in ovariectomized rats; however, it was associated with insensitivity to central leptin administration. Food intake was less suppressed and spontaneous physical activity was less stimulated by leptin. This was not due to decreased hypothalamic Ob-Rb expression. NPY concentration in the paraventricular nucleus of the hypothalamus was elevated in the ovariectomized rats, consistent with leptin insensitivity; however this effect was transient and disappeared as body fat and leptin levels increased further and hyperphagia normalized.. Impaired central leptin sensitivity and overproduction of NPY may contribute to excess fat accumulation caused by estrogen deficiency.

Topics: Absorptiometry, Photon; Adipose Tissue; Animals; Body Composition; Body Weight; Carrier Proteins; Disease Models, Animal; Energy Intake; Estrogens; Female; Hypothalamus; Leptin; Neuropeptide Y; Obesity; Ovariectomy; Rats; Rats, Wistar; Receptors, Cell Surface; Receptors, Leptin; Reverse Transcriptase Polymerase Chain Reaction; RNA; RNA, Messenger

Hypothalamic neuropeptide Y (NPY) and corticotropin-releasing hormone (CRH) influence feeding and levels of plasma glucose, insulin, free fatty acids, and triglycerides. Treatment of genetically obese, ob/ob mice, with dopamine receptor D(1)/D(2) agonists normalizes hyperphagia, body weight gain, hyperglycemia, and hyperlipidemia. We therefore examined whether levels of NPY and CRH immunoreactivity in discrete hypothalamic nuclei are altered in ob/ob mice, and whether dopaminergic treatment reverses this alteration. Female ob/ob mice were treated daily at 1 h after light onset with the D(1)/D(2) agonists, SKF-38393 (20 mg/kg) and bromocriptine (15 mg/kg), respectively or vehicle for 2 weeks. Such treatment, while normalizing body weight gain and hyperglycemia, also significantly reduced elevated NPY immunoreactivity in the suprachiasmatic (by 39%), intergeniculate (by 43%), paraventricular (PVN; by 31%), and arcuate (by 41%) nuclei in obese mice to levels observed in lean mice. This treatment also caused a 45-50% decline in levels of CRH in the PVN and dorsomedial hypothalamus compared to obese controls to levels observed in lean mice. Taken together, these findings suggest that dopaminergic D(1)/D(2) receptor coactivation may improve hyperphagia, hyperglycemia, and obesity in the ob/ob mouse, in part, by normalizing elevated levels of both NPY and CRH.

Topics: Animals; Arcuate Nucleus of Hypothalamus; Blood Glucose; Corticotropin-Releasing Hormone; Dopamine D2 Receptor Antagonists; Dorsomedial Hypothalamic Nucleus; Eating; Female; Gene Expression; Hyperglycemia; Hypothalamus; Mice; Mice, Inbred C57BL; Mice, Obese; Neuropeptide Y; Obesity; Paraventricular Hypothalamic Nucleus; Receptors, Dopamine D1; RNA, Messenger; Suprachiasmatic Nucleus; Weight Gain

Gonadal failure induces bone loss while obesity prevents it. This raises the possibility that bone mass, body weight, and gonadal function are regulated by common pathways. To test this hypothesis, we studied leptin-deficient and leptin receptor-deficient mice that are obese and hypogonadic. Both mutant mice have an increased bone formation leading to high bone mass despite hypogonadism and hypercortisolism. This phenotype is dominant, independent of the presence of fat, and specific for the absence of leptin signaling. There is no leptin signaling in osteoblasts but intracerebroventricular infusion of leptin causes bone loss in leptin-deficient and wild-type mice. This study identifies leptin as a potent inhibitor of bone formation acting through the central nervous system and therefore describes the central nature of bone mass control and its disorders.

Topics: Animals; Bone Density; Bone Remodeling; Carrier Proteins; Cells, Cultured; Hypothalamus; Injections, Intraventricular; Leptin; Mice; Mice, Inbred C57BL; Mice, Obese; Mice, Transgenic; Neuropeptide Y; Obesity; Osteoblasts; Osteoclasts; Osteoporosis; Phenotype; Receptors, Cell Surface; Receptors, Leptin; Signal Transduction

Brain-derived neurotrophic factor (BDNF) was studied initially for its role in sensory neuron development. Ablation of this gene in mice leads to death shortly after birth, and abnormalities have been found in both the peripheral and central nervous systems. BDNF and its tyrosine kinase receptor, TrkB, are expressed in hypothalamic nuclei associated with satiety and locomotor activity. In heterozygous mice, BDNF gene expression is reduced and we find that all heterozygous mice exhibit abnormalities in eating behavior or locomotor activity. We also observe this phenotype in independently derived inbred and hybrid BDNF mutant strains. Infusion with BDNF or NT4/5 can transiently reverse the eating behavior and obesity. Thus, we identify a novel non-neurotrophic function for neurotrophins and indicate a role in behavior that is remarkably sensitive to alterations in BDNF activity.

Topics: Adipocytes; Animals; Appetite; Body Weight; Brain-Derived Neurotrophic Factor; Carrier Proteins; Feeding Behavior; Female; Heterozygote; Humans; Hypothalamus; Insulin; Leptin; Male; Mice; Mice, Inbred Strains; Mice, Knockout; Motor Activity; Nerve Tissue Proteins; Neuropeptide Y; Obesity; Receptor, trkB; Receptors, Cell Surface; Receptors, Leptin; RNA, Messenger

A special herbal tea has been used to treat clomiphene-resistant anovulatory disease and obesity effectively, especially in polycystic ovary syndrome (PCOS) cases with hyperinsulinemia. The effect of the herbal tea on obesity and anovulation was investigated in androgen-sterilized rats (ASR). The ASR model was established by subcutaneous injection of 1.25 mg testosterone propionate to Sprague-Dawley female rats at the age of 9 days. Rats were sacrificed around 112 days of age. ASR manifested with PCO, anovulation, high food intake, elevated body weight, and obesity. Immunocytochemistry demonstrated that estrogen receptors (ER) were predominantly distributed in the cytoplasm of neuropeptide Y (NPY)-containing neurons in the preoptic area (POA), and the coexpression was also found in the nuclei and fibers of NPY-synthesizing neurons in the arcuate nucleus (ARC). Compared with that in normal control rats, NPY expression was increased, the numbers of ER in hypothalamic ARC-median eminence (ME) decreased, gonadotropin-releasing hormone (GnRH) levels in ME was decreased, serum estrogen (E2) and leptin were elevated, and follicular stimulating hormone (FSH) and luteinizing hormone (LH) levels were reduced significantly in ASR. Significantly negative correlations between NPY and ER or GnRH, and between leptin and FSH or LH were observed. A positive correlation existed between serum leptin and body weight. These metabolic-endocrine changes in ASR were normalized after feeding the herbal tea. Both obesity and hypogonadotropin were expressed in ASR. The abnormal ovarian hormone milieu (elevated E2 levels) may have enhanced NPY expression and resulted in less GnRH and gonadotropin secretion. The herbal tea reduced body weight and induced ovulation in ASR.

Topics: Animals; Anovulation; Arcuate Nucleus of Hypothalamus; Beverages; Drugs, Chinese Herbal; Female; Gonadotropin-Releasing Hormone; Median Eminence; Neuropeptide Y; Obesity; Plant Extracts; Preoptic Area; Rats; Rats, Sprague-Dawley; Receptors, Estrogen; Sterilization, Reproductive; Testosterone

Topics: Adipocytes; alpha-MSH; Animals; Appetite; Body Weight; Carrier Proteins; Humans; Hypothalamic Hormones; Hypothalamus; Leptin; Melanins; Muscles; Neuropeptide Y; Neuropeptides; Obesity; Pituitary Hormones; Pro-Opiomelanocortin; Proteins; Receptors, Cell Surface; Receptors, Leptin; Repressor Proteins; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins; Transcription Factors

Neuropeptide Y (NPY) is a potent orexigenic peptide. In the normal adult rat, hypothalamic NPY mRNA expression is limited to the arcuate nucleus (ARH). The purpose of this study was to characterize the developmental expression of NPY mRNA in the hypothalamus of the rat. In contrast to the normal adult rat, NPY mRNA was observed in the ARH, the dorsomedial hypothalamic nucleus (DMH) and the perifornical region (PFR) during development. NPY mRNA expression in all three regions increased progressively from postnatal days 0-4 (P0-4) to reach maximum levels at P16 and subsequently decreased to near adult levels by P30. The unique expression of NPY mRNA in the PFR and DMH may be important in establishing the proper management of energy homeostasis and body weight in the adult animal.

Topics: Age Factors; Animals; Animals, Newborn; Feeding Behavior; Hypothalamus; Neurons; Neuropeptide Y; Obesity; Rats; RNA, Messenger

Effects of obesity on gene expression for opioid peptides and neuropeptide-Y (NPY) in the arcuate nucleus (ARC), and on opioid peptides and alpha-melanocyte stimulating hormone (alpha-MSH) in the paraventricular nucleus (PVN) were examined in obese Zucker rats (18 weeks old). Obese Zucker rats are insulin-resistant, diabetic and hyperleptinemic as indicated by high serum glucose, insulin and leptin levels. ARC proOpiomelanocortin (POMC) mRNA levels were significantly lower in the obese relative to lean Zucker rats and ARC proNeuropeptide Y (proNPY) mRNA levels were higher (P<0.05). There were no differences in proDynorphin and proEnkephalin mRNA levels in the ARC (0.05). Obese Zucker rats had lower alpha-MSH and dynorphin A(1-17) peptide levels in the paraventricular nucleus (PVN) (P<0.05), but did not have lower PVN beta-endorphin peptide levels (0.05). The decrease in POMC in the ARC and decrease in alpha-MSH in the PVN seen in the obese Zucker rat in the present study suggest that reduced activity of the melanocortin system in the ARC to PVN pathway may contribute to the related hyperphagia. Reduced activity of the melanocortin system in the ARC to PVN pathway may be due to a disturbance of leptin signaling coupling to POMC.

Topics: alpha-MSH; Animals; Arcuate Nucleus of Hypothalamus; beta-Endorphin; Blood Glucose; Dynorphins; Energy Metabolism; Enkephalins; Feeding Behavior; Gene Expression; Insulin; Leptin; Male; Melanocytes; Neuropeptide Y; Obesity; Paraventricular Hypothalamic Nucleus; Pro-Opiomelanocortin; Protein Precursors; Rats; Rats, Zucker; RNA, Messenger

Recently, we reported evidence for linkage between neuropeptide Y (NPY) and both obesity and several obesity-related quantitative measures in a sample of Mexican Americans from Starr County, Texas. The purpose of this study was to investigate putative variation within the coding and promoter regions of NPY.. Five young, obese individuals (body mass index [BMI] 33 to 45 kg/m2, age 14 to 30 years); five adult, lean individuals (BMI 20 to 26 kg/m2, age 39 to 65 years); and five sibling pairs sharing no alleles that were identical by descent at a marker locus proximal to NPY were selected for fluorescence-based sequencing of approximately 1100 base pairs (bp) immediately 5' from the start site and all four exons of NPY. We identified a total of eight variant sites, including a 2-bp insertion/deletion (I/D) within a putative negative regulatory region (-880I/D) and a 17-bp deletion at the exon 1/intron 1 junction (69I/D). The -880I/D and 69I/D variants were typed in a separate random sample of Mexican Americans (N = 914) from Starr County, Texas.. Analyses of variance resulted in a significant association between -880I/D and waist-to-hip ratio (p = 0.041) in the entire sample and between -880I/D and BMI (p = 0.031), abdominal circumference (p = 0.044), and waist-to-hip ratio (p = 0.041) in a non-obese subsample (BMI < 30 kg/m2, n = 594). The 69I/D variant was observed in only one pedigree and does not appear to segregate with obesity within this pedigree.. This study reports newly identified common human sequence variation within the regulatory and coding sequence of NPY. Several variants were observed, and of those tested, the -880I/D promoter region variant may influence body fat patterning in non-obese individuals but does not appear to play a major role in the etiology of common forms of obesity in this population.

Topics: Adolescent; Adult; Aged; Alleles; Base Sequence; Body Constitution; Body Mass Index; DNA; DNA Primers; Electrophoresis, Polyacrylamide Gel; Female; Gene Frequency; Genetic Variation; Humans; Male; Mexican Americans; Middle Aged; Molecular Sequence Data; Neuropeptide Y; Nuclear Family; Obesity; Pedigree; Polymerase Chain Reaction; Sequence Analysis, DNA; Texas

A multidisciplinary team may have discovered an important new weapon in the battle of the bulge. On page 2379 of this issue, the team reports that a molecule that is needed for fat synthesis in the body may play a key role in appetite signaling in the brain. Moreover, the investigators produced a synthetic inhibitor of this molecule that spurred a dramatic drop in appetite and weight in mice.

Topics: Animals; Appetite; Appetite Depressants; Brain; Enzyme Inhibitors; Fasting; Fatty Acid Synthases; Humans; Liver; Malonyl Coenzyme A; Mice; Neuropeptide Y; Obesity; RNA, Messenger; Weight Loss

Obesity occurs in 60% of women after menopause and is characterized by an excess of adipose tissue that depends on several orexigenic (neuropeptide Y (NPY) stimulates carbohydrate ingestion, galanin stimulates fat intake) and anorectic (leptin, cholecystokinin (CCK)) factors. Both leptin and insulin can reduce hypothalamic NPY production and secretion. Behavior related to the consumption of food is probably attributed to the NPY-galanin signalling route. We investigated basal levels of serum leptin, CCK, galanin and NPY in 16 non-obese premenopausal women, in 15 obese premenopausal women (body mass index (BMI) 34.6 +/- 1.3 SD) and in ten obese postmenopausal women (BMI 34.7 +/- 1.5 SD) to determine the relationship between obesity, menopause and these neuropeptides. Obese premenopausal women had three-fold elevations of serum leptin (32.1 +/- 3.2 ng/ml) in comparison to non-obese premenopausal women (10.3 +/- 1.5 ng/ml), but similar levels to those in obese postmenopausal women (35.3 +/- 4.1 ng/ml). In all 44 patients and in both sub-groups of premenopausal and postmenopausal women, serum leptin exhibited a strong positive correlation with BMI (r = 0.8692, p < 0.0001; r = 0.8803, p = 0.0001; r = 0.8184, p = 0.0001, respectively). Serum galanin values showed a statistically significant increment in the obese postmenopausal group (51.1 +/- 8.1 pg/ml) compared to both premenopausal groups: the non-obese (34.9 +/- 5.8 pg/ml) and the obese (36.0 +/- 5.5 pg/ml). Non-obese menstruating women demonstrated NPY levels (175.0 +/- 12.8 pg/ml) significantly higher than those of obese premenopausal women (126.0 +/- 12.1 pg/ml) and obese postmenopausal women (138.1 +/- 15.4 pg/ml). CCK values showed no differences between non-obese and obese pre- and postmenopausal groups. Basal insulin values were elevated in both obese groups compared to non-obese premenopausal women. Significantly increased leptin and galanin levels in postmenopausal obese women coupled with decreased NPY levels revealed some changes in the neuropeptides regulating eating behavior, which may be the reason for the onset of postmenopausal obesity.

Topics: Body Mass Index; Cholecystokinin; Female; Follicle Stimulating Hormone; Galanin; Humans; Insulin; Leptin; Luteinizing Hormone; Menopause; Neuropeptide Y; Obesity; Postmenopause; Premenopause

A high fat diet leads to progressive development of obesity and leptin resistance in C57 mice with a middle stage of peripheral, but not central, leptin resistance. This stage is characterized by increased fat accumulation despite relative hypophagia. At a later stage central leptin resistance ensues along with hyperphagia, rapid weight and fat gain. The aim of this study is to characterize the mRNA levels of leptin receptor (LR), neuropeptide Y (NPY) and pro-opiomelanocortin (POMC) in high fat (HFF) and low fat (LFF) fed groups of mice. The hypothalamic arcuate nucleus (Arc) was investigated, as was the choroid plexus (ChP) in the case of the leptin receptor. No differences between groups were seen in LR, NPY or POMC mRNA levels after 1 week of feeding. After 8 and 19 weeks, the HFF mice, compared to LFF controls, demonstrated a +45% (P<0. 003) and +84% (P<0.0001) increase in the ratio of visceral fat to body weight and +223% (P<0.0001) and +468% (P<0.0001) elevation in plasma leptin levels, respectively. At 8 weeks, LR mRNA expression showed a +98% (P<0.016) and +66% (P<0.0001) increase in ChP and Arc, respectively, while Arc NPY mRNA showed down-regulation by -45% (P<0. 006). Arc POMC mRNA showed no significant changes between groups at 8 weeks. However, after long-term (19 weeks) feeding, the HFF mice displayed significantly -26% (P<0.039) and -33% (P<0.0015) reduced LR mRNA in the ChP and Arc, respectively, with Arc POMC and NPY mRNAs down by -55% (P<0.004) and -32% (P<0.009), respectively. The present results suggest that in the middle stage of development of high fat-induced obesity, when central leptin sensitivity is maintained, the increased leptin receptor expression may play a role to defend against obesity which is overwhelmed as central leptin insensitivity develops. In this later stage the down-regulation of the POMC system may be important in the final breakdown of weight homeostasis.

Topics: Adipose Tissue; Animals; Brain; Carrier Proteins; Dietary Fats; Energy Intake; Epididymis; Kidney; Leptin; Male; Mice; Mice, Inbred C57BL; Neuropeptide Y; Obesity; Pro-Opiomelanocortin; Receptors, Cell Surface; Receptors, Leptin; RNA, Messenger

Obesity is an important factor predisposing to type 2 diabetes mellitus, especially for postmenopausal women. Experimental studies provided evidences that leptin, cholecystokinin (CCK), galanin (GAL), neuropeptide Y (NPY) and insulin are involved in feeding behaviour. The aim of the study was to evaluate their possible relationships in obese and diabetic women. Three groups of postmenopausal women (FSH > 30 mIU/ml) were evaluated: 8 diabetic (mean age 56.6 +/- 6.9 y, BMI 29.8 +/- 5.3 kg/m2), 10 obese non-diabetic (mean age 49.6 +/- 5.4 y, BMI 36.0 +/- 3.7 kg/m2) and 12 non-diabetic controls (mean age 52.7 +/- 3.5 y, BMI 27.3 1.9 kg/m2). For each patient BMI and WHR were measured and calculated. Blood samples were collected at 8:00 a.m. after an overnight fast. Plasma concentrations of FSH, leptin, CCK, GAL, NPY and insulin were determined using commercial RIA kits. Mean plasma NPY concentration was significantly higher in diabetic women than in controls (190.1 pg/ml +/- 85.4 vs 120.4 +/- 36.6). Compared to controls, mean plasma leptin level was significantly higher in obese non-diabetic women (32.9ng/ml +/- 9.2 vs 18.9 +/- 9.1). No significant differences were found between obese non-diabetic and diabetic women. In diabetic subjects positive correlations were found between: CCK and leptin (r= 0.8295; P= 0.011), CCK and insulin (r=0.7832; P=0.022), leptin and insulin (r=0.9302; P=0.001). In obese subjects a positive correlation between WHR and GAL (r= 0.6624; P= 0.037) and a negative between GAL and insulin (r= -0.6795; P= 0.031) were found. In controls positive correlations were found between WHR and CCK (r=0.6412; P=0.025), GAL and insulin (r=0.630; P=0.028) and negative between CCK and NPY (r = -0.6505; P= 0.022). Our results, ie higher mean plasma NPY levels in postmenopausal diabetic women and positive correlation of CCK with leptin and insulin, may suggest the role of these neuropeptides in metabolic disorders leading to type 2 diabetes mellitus.

Topics: Body Constitution; Body Mass Index; Cholecystokinin; Diabetes Mellitus; Diabetes Mellitus, Type 2; Female; Galanin; Humans; Insulin; Leptin; Middle Aged; Neuropeptide Y; Neuropeptides; Obesity

Exposure to high-fat diets for prolonged periods results in positive energy balance and obesity, but little is known about the initial physiological and neuroendocrine response of obesity-susceptible strains to high-fat feeding. To assess responses of C57BL/6J mice to high- and low-fat diets, we quantitated the hypothalamic expression of neuropeptides implicated in weight regulation and neuroendocrine function over a 2-wk period. Exposure to high-fat diet increased food consumption over a 2-day period during which leptin levels were increased when assessed by a frequent sampling protocol [area under the curve (AUC): 134.6 +/- 10.3 vs. 100 +/- 12.3, P = 0.03 during first day and 126.5 +/- 8.2 vs. 100 +/- 5.2, P = 0.02 during second day]. During this period, hypothalamic expression of neuropeptide Y (NPY) and agouti-related protein (AgRP) decreased by approximately 30 and 50%, respectively (P < 0.001). After 1 wk, both caloric intake and hypothalamic expression of NPY and AgRP returned toward baseline. After 2 wk, cumulative caloric intake was again higher in the high-fat group, and now proopiomelanocortin (POMC) was elevated by 76% (P = 0.01). This study demonstrates that high-fat feeding induces hyperphagia, hyperleptinemia, and transient suppression of orexigenic neuropeptides during the first 2 days of diet. The subsequent induction of POMC may be a second defense against obesity. Attempts to understand the hypothalamic response to high-fat feeding must examine the changes as they develop over time.

Topics: Agouti-Related Protein; Animals; Area Under Curve; Body Composition; Body Weight; Corticosterone; Dietary Fats; Eating; Energy Intake; Fatty Acids, Nonesterified; Hypothalamus; Insulin; Intercellular Signaling Peptides and Proteins; Leptin; Male; Mice; Mice, Inbred C57BL; Neuropeptide Y; Neuropeptides; Obesity; Pro-Opiomelanocortin; Protein Biosynthesis; Proteins; Repressor Proteins; RNA, Messenger; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins; Transcription Factors

The aim of the present study was to determine whether the anorexic and thermogenic effects of leptin were attenuated in overweight aged rats following intracerebroventricular (i.c.v.) injection of murine leptin. Male F344/BN rats of two ages (6 months: young (n=20) and 24 months: old (n=18)) were divided into three groups (control, pair-fed and leptin) and were treated with either vehicle (artificial cerebrospinal fluid) or leptin (15.6 microgram/day) for 3 days. There was an age-related increase in basal food intake (20+/-2%), serum leptin levels (363+/-106%) and leptin (OB) mRNA (72+/-16%) in perirenal white adipose tissue (PWAT). In contrast, basal expression of hypothalamic NPY mRNA and brown adipose tissue (BAT) uncoupling protein 1 (UCP1) mRNA was reduced significantly (-35+/-4% and -51+/-5%, respectively) with age. I.c.v. leptin treatment had a significantly greater effect in reducing food intake (-42+/-5% vs. -23+/-4%), serum leptin levels (-55+/-7% vs. 10+/-2%) and PWAT OB mRNA (-46+/-2% vs. 10+/-5%) in young than in old rats. Similarly, central leptin treatment also had a greater effect in suppressing hypothalamic NPY mRNA expression in young (-23+/-4%) than in old (-8+/-4%) rats compared with their age-matched pair-fed treated rats. The stimulatory effect of i.c.v. leptin treatment on BAT UCP1 mRNA expression was also significantly greater in young rats (45+/-8%) than in old rats (10+/-6%) compared with age-matched pair-fed rats. Our previous report indicated that these overweight aged rats were resistant to peripheral administered leptin. The present data extend those findings and demonstrate that the impaired anorexic and metabolic effects of leptin are centrally mediated. This leptin resistance may be due to either the elevated obesity and serum leptin with age or due to age itself or both. The development of leptin resistance with age may contribute to the hyperphagia, hyperleptinemia and impaired energy balance with age.

Topics: Adipose Tissue, Brown; Aging; Animals; Anorexia; Body Weight; Carrier Proteins; Eating; Gene Expression Regulation; Hypothalamus; Injections, Intraventricular; Ion Channels; Leptin; Male; Membrane Proteins; Membrane Transport Proteins; Mice; Mitochondrial Proteins; Neuropeptide Y; Obesity; Proteins; Rats; Rats, Inbred BN; Rats, Inbred F344; RNA, Messenger; Thermogenesis; Uncoupling Protein 1; Uncoupling Protein 2; Uncoupling Protein 3

The hypothalamus plays a major role in the control of energy balance via the coordination of several neuropeptides and their receptors. We used a unique polygenic animal model of obesity, Psammomys obesus, and performed differential display polymerase chain reaction on hypothalamic mRNA samples to identify novel genes involved in obesity. In this study, we describe a novel gene that encodes a small protein we have termed "beacon." Beacon mRNA gene expression in the hypothalamus was positively correlated with percentage of body fat. Intracerebroventricular infusion of beacon resulted in a dose-dependent increase in food intake and body weight and an increase in hypothalamic expression of neuropeptide Y (NPY). Simultaneous infusion of beacon and NPY significantly potentiated the orexigenic response and resulted in rapid body weight gain. These data suggest a role for beacon in the regulation of energy balance and body weight homeostasis that may be mediated, at least in part, through the NPY pathway.

Topics: Adipose Tissue; Amino Acid Sequence; Animals; Base Sequence; Body Composition; Brain; Eating; Energy Metabolism; Exons; Fluorescent Antibody Technique; Gene Expression; Gerbillinae; Hypothalamus; Introns; Molecular Sequence Data; Nerve Tissue Proteins; Neuropeptide Y; Obesity; Polymerase Chain Reaction; Proteins; RNA, Messenger; Ubiquitins; Weight Gain

In genetically obese leptin-deficient ob/ob mice, adrenalectomy reverses or attenuates the obese phenotype. Relative to lean controls, ob/ob mice also exhibit decreased hypothalamic proopiomelanocortin (POMC) mRNA and increased hypothalamic agouti-related peptide (AGRP) mRNA and neuropeptide Y (NPY) mRNA. It has been hypothesized that this profile of hypothalamic gene expression contributes to the obese phenotype caused by leptin deficiency. To assess if reversal of obese phenotype by adrenalectomy entails normalization of hypothalamic gene expression, male wild-type and ob/ob mice were adrenalectomized (with saline supplementation) or sham adrenalectomized at 2 months of age. Mice were sacrificed 2 weeks after adrenalectomy, during which time food intake and body weight were monitored daily. After sacrifice, hypothalamic gene expression was assessed by Northern blot analysis as well as in situ hybridization. In wild-type mice, adrenalectomy significantly decreased AGRP mRNA but did not significantly influence POMC or NPY mRNA. In ob/ob mice, adrenalectomy reduced the levels of plasma glucose, serum insulin and corticosterone, and food intake toward or below wild-type levels, and it restored hypothalamic POMC and AGRP mRNA but not NPY mRNA to wild-type levels. These studies suggest that adrenalectomy reverses or attenuates the obese phenotype in ob/ob mice, in part by restoring hypothalamic melanocortin tone toward wild-type levels. These studies also demonstrate that factors other than leptin may play a major role in regulating hypothalamic melanocortin function.

Topics: Adrenalectomy; Agouti-Related Protein; Animals; Blood Glucose; Blotting, Northern; Body Weight; Corticosterone; Eating; Gene Expression; Hypothalamus; In Situ Hybridization; Insulin; Intercellular Signaling Peptides and Proteins; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Neuropeptide Y; Obesity; Phenotype; Pro-Opiomelanocortin; Proteins

Chronic administration of sibutramine lowers body weight, presumably by altering brain monoamine metabolism. Here the effect of sibutramine on sympathoadrenal function (24-h urine norepinephrine and epinephrine levels) and arcuate nucleus (ARC) neuropeptide Y (NPY) and proopiomelanocortin (POMC) expression was assessed in diet-induced obese rats fed a low-fat diet. Chronic (10 wk) sibutramine [5 mg. kg(-1). day(-1) ip; rats fed ad libitum and injected with sibutramine (AS)] lowered body weight by 15% but only transiently (3-4 wk) reduced intake compared with vehicle-treated controls [rats fed chow ad libitum and injected with vehicle daily (AV)]. Other rats food restricted (RS) to 90% of the weight of AS rats and then given sibutramine restored their body weights to the level of AS rats when allowed libitum food intake. After reequilibration, RS rats were again energy restricted to reduce their weight to 90% of AS rats, and additional vehicle-treated rats (RV) were restricted to keep their body weights at the level of AS rats for 3 wk more. Terminally, total adipose depot weights and leptin levels paralleled body weights (AV > AS = RV > RS), although AS rats had heavier abdominal and lighter peripheral depots than RV rats of comparable body weights. Sibutramine treatment increased sympathetic activity, attenuated the increased ARC NPY, and decreased POMC mRNA levels induced by energy restriction in RV rats. Thus sibutramine lowered the defended body weight in association with compensatory changes in those central pathways involved in energy homeostasis.

Topics: Adipose Tissue; Animals; Appetite Depressants; Arcuate Nucleus of Hypothalamus; Body Weight; Cyclobutanes; Energy Intake; Epinephrine; Feeding Behavior; Gene Expression Regulation; Homeostasis; Leptin; Neuropeptide Y; Norepinephrine; Obesity; Organ Size; Pro-Opiomelanocortin; Rats; RNA, Messenger

Neuropeptide Y (NPY) is a powerful orexigenic factor, and alphaMSH is a melanocortin (MC) peptide that induces satiety by activating the MC4 receptor subtype. Genetic models with disruption of MC4 receptor signaling are associated with obesity. In the present study, a 7-day intracerebroventricular infusion to male rats of either the MC receptor antagonist SHU9119 or porcine NPY (10 nmol/day) was shown to strongly stimulate food and water intake and to markedly increase fat pad mass. Very high plasma leptin levels were found in NPY-treated rats (27.1 +/- 1.8 ng/ml compared with 9.9 +/- 0.9 ng/ml in SHU9119-treated animals and 2.1 +/- 0.2 ng/ml in controls). As expected, NPY infusion induced hypogonadism, characterized by an impressive decrease in seminal vesicle and prostate weights. No such effects were seen with the SHU9119 infusion. Similarly, whereas the somatotropic axis of NPY-treated rats was fully inhibited, this axis was normally activated in the obese SHU9119-treated rats. Chronic infusion of SHU9119 strikingly reduced hypothalamic gene expression for NPY (65.2 +/- 3.6% of controls), whereas gene expression for POMC was increased (170 +/- 19%). NPY infusion decreased hypothalamic gene expression for both POMC and NPY (70 +/- 9% and 75.4 +/- 9.5%, respectively). In summary, blockade of the MC4 receptor subtype by SHU9119 was able to generate an obesity syndrome with no apparent side-effects on the reproductive and somatotropic axes. In this situation, it is unlikely that hyperphagia was driven by increased NPY release, because hypothalamic NPY gene expression was markedly reduced, suggesting that hyperphagia mainly resulted from loss of the satiety signal driven by MC peptides. NPY infusion produced hypogonadism and hyposomatotropism in the face of markedly elevated plasma leptin levels and an important reduction in hypothalamic POMC synthesis. In this situation NPY probably acted both by exacerbating food intake through Y receptors and by reducing the satiety signal driven by MC peptides.

Topics: Adipose Tissue; alpha-MSH; Animals; Body Composition; Drinking; Eating; Gene Expression; Gonadotropins; Growth Hormone; Hypogonadism; Hypothalamus; Leptin; Male; Melanocyte-Stimulating Hormones; Neuropeptide Y; Obesity; Organ Size; Pituitary Gland; Pro-Opiomelanocortin; Rats; Rats, Sprague-Dawley; Receptor, Melanocortin, Type 4; Receptors, Corticotropin; Receptors, LHRH; Satiation; Signal Transduction

Neuropeptide Y (NPY) is a 36 amino acid peptide released in central and peripheral mammalian neurons, which appears to contribute to adiposity regulation by increasing food intake, thus promoting weight gain on animals. Nevertheless, little is known about NPY direct actions on white adipocytes. This trial, which was designed to test the possible effects of a new NPY antagonist, S.A.0204, on white adipose tissue, revealed that the administration of this novel molecule strongly ex vivo stimulates apoptosis and lipolysis in animals fed on a high-fat diet.

Topics: Adipocytes; Animals; Apoptosis; Body Temperature; Disease Models, Animal; Feeding Behavior; Female; Lipolysis; Neuropeptide Y; Obesity; Rats; Rats, Wistar

Electrolytic lesions placed in the ventromedial hypothalamus (VMH) of rats induce instant hyperphagia and excessive weight gain. Since neuropeptide Y (NPY) is a potent hypothalamic orexigenic signal, and leptin secreted by adipocytes regulates NPY output, we tested the hypothesis that altered NPYergic-leptin signaling may underlie hyperphagia in VMH-lesioned rats. VMH-lesioned rats exhibiting hyperphagia and excessive weight gain in a time-related fashion were sacrificed on days 2, 7, and 21 post-surgery. Quite unexpectedly, NPY concentrations in the hypothalamic paraventricular nucleus (PVN), a major site of NPY release for stimulation of feeding, and in other sites, such as the dorsomedial nucleus, lateral hypothalamic area and median eminence-arcuate nucleus decreased, with the earliest diminution occurring on day 2 in the PVN only. In vitro basal and K+-evoked NPY release from the PVN of VMH-lesioned rats was significantly lower than that of controls. Analysis of hypothalamic NPY gene expression showed that although the daily decrease in NPY mRNA from 0800 to 2200 h occurred as in control rats, NPY mRNA concentrations were markedly reduced at these times in the hypothalami of VMH-lesioned rats. Leptin synthesis in adipocytes as indicated by leptin mRNA levels was also profoundly altered in VMH-lesioned rats. The daily pattern of increase in adipocyte leptin mRNA at 2200 h from 0800 h seen in controls was abolished, higher levels of leptin gene expression at 2200 h were maintained at 0800 h. The pattern of increase in serum leptin and insulin levels diverged in VMH-lesioned rats. Serum insulin concentration increased to maximal on day 2 and remained at that level on day 21-post-lesion; serum leptin levels on the other hand, increased slowly in a time-related fashion during this period. These results demonstrate that hyperphagia and excessive weight gain in VMH-lesioned rats are associated with an overall decrease in hypothalamic NPY and augmented leptin signaling to the hypothalamus. The divergent time course of increases in serum leptin and insulin levels suggest independent mechanisms responsible for their augmented secretion, and neither these hormones nor VMH lesions altered the daily rhythm in NPY gene expression. These observations underscore the existence of an independent mechanism controlling the daily rhythm in hypothalamic NPY gene expression and suggest that leptin feedback action requires an intact VMH.

Topics: Adipocytes; Animals; Body Weight; Circadian Rhythm; Dorsomedial Hypothalamic Nucleus; Eating; Gene Expression; Hypothalamic Area, Lateral; In Vitro Techniques; Insulin; Leptin; Male; Neuropeptide Y; Obesity; Paraventricular Hypothalamic Nucleus; Proteins; Rats; Rats, Sprague-Dawley; RNA, Messenger; Signal Transduction; Time Factors; Ventromedial Hypothalamic Nucleus

Abnormalities of plasma high density lipoprotein (HDL) levels commonly reflect altered metabolism of the major HDL apolipoproteins, apoA-I and apoA-II, but the regulation of apolipoprotein metabolism is poorly understood. Two mouse models of obesity, ob/ob and db/db, have markedly increased plasma HDL cholesterol levels. The purpose of this study was to evaluate mechanisms responsible for increased HDL in ob/ob mice and to assess potential reversibility by leptin administration. ob/ob mice were found to have increased HDL cholesterol (2-fold), apoA-I (1.3-fold), and apoA-II (4-fold). ApoA-I mRNA was markedly decreased (to 25% of wild-type) and apoA-II mRNA was unchanged, suggesting a defect in HDL catabolism. HDL apoprotein turnover studies using nondegradable radiolabels confirmed a decrease in catabolism of apoA-I and apoA-II and a 4-fold decrease in hepatic uptake in ob/ob mice compared with wild-type, but similar renal uptake. Low dose leptin treatment markedly lowered HDL cholesterol and apoA-II levels in both ob/ob mice and in lean wild-type mice, and it restored apoA-I mRNA to normal levels in ob/ob mice. These changes occurred without significant alteration in body weight. Moreover, ob/ob neuropeptide Y-/- mice, despite marked attenuation of diabetes and obesity phenotypes, showed no change in HDL cholesterol levels relative to ob/ob mice. Thus, increased HDL levels in ob/ob mice reflect a marked hepatic catabolic defect for apoA-I and apoA-II. In the case of apoA-I, this is offset by decreased apoA-I mRNA, resulting in apoA-II-rich HDL particles. The studies reveal a specific HDL particle catabolic pathway that is down-regulated in ob/ob mice and suggest that HDL apolipoprotein turnover may be regulated by obesity and/or leptin signaling.

Topics: Animals; Apolipoprotein A-I; Apolipoprotein A-II; Female; Leptin; Lipoproteins, HDL; Liver; Mice; Mice, Inbred C57BL; Mice, Obese; Neuropeptide Y; Obesity; Proteins; RNA, Messenger

The neuropeptide Y (NPY) neurons in the hypothalamic arcuate nucleus regulate and are regulated by short-term changes in energy homeostasis. Both outbred and inbred strains of rats that develop diet-induced obesity (DIO) or are diet resistant (DR) when fed a diet relatively high in energy, fat, and sucrose content (HE diet) were used to study arcuate NPY mRNA expression during long-term changes in energy balance. Outbred, chow-fed obesity-prone rats had 59% higher NPY levels than obesity-resistant rats. After 14 wk on HE diet, DIO rats had 17% lower NPY levels than DR rats made comparably obese on a highly palatable diet. When switched to chow, obese DR rats spontaneously reduced their intake and their body weights fell to control levels in association with a 10% decrease in NPY levels. DIO rats lost weight only with energy restriction associated with a 21% increase in their NPY levels. When again fed ad libitum, the weight and NPY levels in the rats returned to those of unrestricted DIO rats. Chow-fed, inbred DIO rats weigh more and are fatter than age-matched inbred DR rats. As with outbred DIO rats fed the HE diet, inbred DIO rats had 20% lower NPY levels than DR rats. Thus preobese, outbred DIO rats have high levels of NPY message that are not susceptible to metabolic regulation. When obesity develops in both inbred and outbred rats, the levels of NPY mRNA fall but become responsive to alterations in energy availability.

Topics: Animals; Arcuate Nucleus of Hypothalamus; Diet; Dietary Fats; Dietary Sucrose; Disease Susceptibility; Energy Intake; Energy Metabolism; Homeostasis; Male; Neurons; Neuropeptide Y; Obesity; Rats; Rats, Sprague-Dawley; Weight Gain

Leptin inhibits feeding and decreases body weight. It may act partly by inhibiting hypothalamic neurons that express neuropeptide Y, a powerful inducer of feeding and obesity. These neuropeptide Y neurons express the Ob-Rb leptin receptor and are overactive in the fatty (fa/fa) Zucker rat. The fa mutation affects the extracellular domain of the leptin receptor, but its impact on leptin action and neuropeptide Y neuronal activity is not fully known. We compared the effects of three doses of leptin given intracerebroventricularly and three doses of leptin injected intraperitoneally on food intake and hypothalamic neuropeptide Y mRNA, in lean and fatty Zucker rats. In lean rats, 4-h food intake was reduced in a dose-related fashion (P<0.01) by all intracerebroventricular leptin doses and by intraperitoneal doses of 300 and 600 microg/kg. Neuropeptide Y mRNA levels were reduced by 28% and 21% after the highest intracerebroventricular and intraperitoneal doses respectively (P<0. 01 for both). In fatty rats, only the highest intracerebroventricular leptin dose reduced food intake (by 22%; P<0. 01). Neuropeptide Y mRNA levels were 100% higher in fatty rats than in lean animals, and were reduced by 18% (P<0.01) after the highest intracerebroventricular leptin dose. Intraperitoneal injection had no effect on food intake and neuropeptide Y mRNA. The fa/fa Zucker rat is therefore less sensitive to leptin given intracerebroventricularly and particularly intraperitoneally, suggesting that the fa mutation interferes both with leptin's direct effects on neurons and its transport into the central nervous system. Obesity in the fa/fa Zucker rat may be partly due to the inability of leptin to inhibit hypothalamic neuropeptide Y neurons.

Topics: Animals; Body Weight; Dose-Response Relationship, Drug; Eating; Hypothalamus; Injections, Intraperitoneal; Injections, Intraventricular; Leptin; Male; Neuropeptide Y; Obesity; Proteins; Rats; Rats, Zucker

The gene expression of prepro-orexin, the precursor of orexin-A and orexin-B which are hypothalamic pepetides that are associated with feeding behavior, were examined in control (C57B1/6J) and obese (ob/ob and db/db) mice using in situ hybridization histochemistry. Orexins are identical with hypocretins that have been identified by directional tag PCR subtractive hybridization method. In situ hybridization histochemistry revealed that the expression of the prepro-orexin gene was significantly decreased in ob/ob and db/db mice compared with control mice. The gene expression of neuropeptide Y (NPY), a potent feeding stimulant, is known to be increased in ob/ob and db/db mice. The expression of the NPY gene in the arcuate nucleus was increased remarkably in ob/ob and db/db mice compared to that of control mice. An immunohistochemical study showed that orexin-A and orexin-B immunoreactive neurons exhibited in the lateral and posterior hypothalamic areas and the perifornical nucleus were distributed similarly in control, ob/ob and db/db mice. These results suggest that the regulatory mechanism of orexins/hypocretins may be different from that of NPY in genetically obese mice.

Topics: Animals; Blood Glucose; Brain Chemistry; Carrier Proteins; DNA Probes; Gene Expression Regulation; Hypothalamic Area, Lateral; Immunohistochemistry; In Situ Hybridization; Intracellular Signaling Peptides and Proteins; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Neuropeptide Y; Neuropeptides; Neurotransmitter Agents; Obesity; Orexins; Protein Precursors; RNA, Messenger

We have studied the effect of leptin on food intake and neuroendocrine function in ovariectomized ewes. Groups (n = 5) received intracerebroventricular infusions of either vehicle or leptin (20 microg/h) for 3 days and were blood sampled over 6 h on days -1, 2, and for 3 h on day 3 relative to the onset of the infusion. The animals were then killed to measure hypothalamic neuropeptide Y expression by in situ hybridization. Plasma samples were assayed for metabolic parameters and pituitary hormones. Food intake was reduced by leptin, but did not change in controls. Leptin treatment elevated plasma lactate and nonesterified fatty acids, but did not affect glucose or insulin levels, indicating a state of negative energy balance that was met by the mobilization of body stores. Pulse analysis showed that the secretion of LH and GH was not affected by leptin treatment, nor were the mean plasma concentrations of FSH, PRL, or cortisol. Expression of messenger RNA for neuropeptide Y in the arcuate nucleus was reduced by the infusion of leptin, primarily due to reduced expression per cell rather than a reduction in the number of cells observed. Thus, the action of leptin to inhibit food intake is dissociated from neuroendocrine function. These results suggest that the metabolic effects of leptin are mediated via neuronal systems that possess leptin receptors rather than via endocrine effects.

Topics: Animals; Appetite; Feeding Behavior; Female; Humans; Hydrocortisone; In Situ Hybridization; Leptin; Neuropeptide Y; Neurosecretory Systems; Obesity; Ovariectomy; Ovary; Pituitary Hormones; Proteins; Sheep

Topics: Animals; Animals, Newborn; Feeding Behavior; Gene Expression; Hyperphagia; In Situ Hybridization; Neuropeptide Y; Obesity; Rats; Rats, Zucker

Recent advances in the molecular basis of body fat regulation have identified several genes in which genetic variation may influence obesity and related measures in human populations. Genes that have been shown to have a regulatory function in the control of body fat utilization, eating behavior, and/or metabolic rate in rodent models of obesity include leptin (LEP), leptin receptor (LEPR), neuropeptide Y (NPY), NPY Y1 receptor (NPYY1), glucagon-like peptide-1 (GLP-1), GLP-1 receptor (GLP1R), and uncoupling protein 1 (UCP1). We have typed microsatellite markers located within or near these seven candidate obesity genes in 302 non-diabetic individuals from 59 Mexican-American families from Starr County, Texas. Sib pair linkage analysis was used to examine linkage between these genes and obesity status (obese siblings only; n = 170 pairs) and several obesity-related quantitative variables (all siblings; n = 545 total sibling pairs). Significant linkage (P = 0.042) was found between obesity and NPY within the obese sibling pairs. No other candidate gene was linked to obesity status in this subsample. Consistent with the obese sib pair linkage results, NPY showed evidence of linkage to body weight (P = 0.020), abdominal circumference (P = 0.031), hip circumference (P = 0.012), diastolic blood pressure (P = 0.005), and a composite measure of body mass and size (P = 0.048) in the entire sibling sample. Other significant linkages observed were between LEP and waist/hip ratio (P = 0.010), total cholesterol (P = 0.030), and HDL cholesterol (P = 0.026) and between LEPR and fasting blood glucose (P = 0.018) and diastolic blood pressure (P = 0.003). These results support further investigation of NPY, LEP, and LEPR to identify genetic variation that may influence obesity status, glucose and lipid metabolism, and blood pressure in Mexican Americans.

Topics: Adult; Anthropometry; Carrier Proteins; Case-Control Studies; Chromosome Mapping; Female; Gene Frequency; Genetic Variation; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Ion Channels; Leptin; Male; Membrane Proteins; Mexican Americans; Microsatellite Repeats; Middle Aged; Mitochondrial Proteins; Neuropeptide Y; Obesity; Pedigree; Peptide Fragments; Protein Precursors; Proteins; Receptors, Cell Surface; Receptors, Glucagon; Receptors, Leptin; Receptors, Neuropeptide Y; Texas; Uncoupling Protein 1

The product of the ob gene, leptin, is thought to act in the hypothalamus to reduce food intake and body weight (b.w.) in rats and mice; however, the mechanisms of leptin action in the brain have not been fully elucidated. Corticotropin-releasing hormone (CRH) is a potent anorectic neuropeptide, and its type-2 receptor (CRHR-2) in the ventromedial hypothalamus (VMH) appears to play an important role in the expression of this anorectic effect. We explored here the impact of systemic leptin administration on CRH mRNA expression in the hypothalamic paraventricular nucleus (PVN) and CRHR-2 mRNA expression in the VMH in male rats, using in-situ hybridization histochemistry. The expression of CRH mRNA in the PVN and CRHR-2 mRNA in the VMH were increased at 2 h and 6 h, respectively, after a single intraperitoneal injection of leptin (1.0 mg/kg). Continuous subcutaneous infusion of leptin (1.2 mg/kg/day) via an osmotic minipump for 5 days increased the expression of CRHR-2 mRNA in the VMH, but not the expression of CRH mRNA in the PVN, compared with vehicle treatment. The rats that received the single or continuous administration of leptin showed reductions of food intake and b.w. compared with vehicle-treated rats. These results are consistent with our previous findings that the expression of CRHR-2 mRNA in the VMH is positively correlated with plasma leptin concentrations under various conditions, and highlight the importance of circulating leptin for the regulation of VMH CRHR-2 mRNA. The present results also raise the possibility that leptin reduces food intake and b.w. at least partially due to the enhancement of the anorectic effect of CRH via increased PVN CRH expression and/or VMH CRHR-2 expression.

Topics: Animals; Body Weight; Corticotropin-Releasing Hormone; Feeding Behavior; Humans; Hypothalamus, Middle; In Situ Hybridization; Leptin; Male; Neuropeptide Y; Obesity; Pro-Opiomelanocortin; Proteins; Rats; Rats, Wistar; Receptors, Corticotropin-Releasing Hormone; Receptors, Leptin; Recombinant Proteins; RNA, Messenger

It has been claimed that factors favoring the development or maintenance of animal or human obesity may include increases in glucocorticoid production or hyperresponsiveness of the hypothalamic-pituitary-adrenal axis. In normal rats, glucocorticoids have been shown to be necessary for chronic intracerebroventricular infusion of neuropeptide Y to produce obesity and related abnormalities. Conversely, glucocorticoids inhibited the body weight-lowering effect of leptin. Such dual action of glucocorticoids may occur within the central nervous system, since both neuropeptide Y and leptin act within the hypothalamus. The aim of this study was to determine the effects of glucocorticoids (dexamethasone) given intracerebroventricularly to normal rats on body weight homeostasis and hypothalamic levels of neuropeptide Y and corticotropin-releasing hormone. Continuous central glucocorticoid infusion for 3 days resulted in marked sustained increases in food intake and body weight relative to saline-infused controls. The infusion abolished endogenous corticosterone output and produced hyperinsulinemia, hypertriglyceridemia, and hyperleptinemia, three salient abnormalities of obesity syndromes. Central glucocorticoid infusion also produced a marked decrease in the expression of uncoupling protein (UCP)-1 and UCP-3 in brown adipose tissue and UCP-3 in muscle. Finally, chronic central glucocorticoid administration increased the hypothalamic levels of neuropeptide Y and decreased those of corticotropin-releasing hormone. When the same dose of glucocorticoids was administered peripherally, it resulted in decreases in food intake and body weight, in keeping with the decrease in hypothalamic neuropeptide Y levels. These results suggest that glucocorticoids induce an obesity syndrome in rodents by acting centrally and not peripherally.

Topics: Animals; Body Weight; Brain; Carrier Proteins; Corticosterone; Corticotropin-Releasing Hormone; Dexamethasone; Eating; Glucocorticoids; Homeostasis; Hyperinsulinism; Hypertriglyceridemia; Hypothalamus; Injections, Intraperitoneal; Ion Channels; Leptin; Membrane Proteins; Mitochondrial Proteins; Neuropeptide Y; Obesity; Proteins; Rats; Rats, Zucker; Uncoupling Protein 1

The antihypertensive agent moxonidine, an imidazoline Ii-receptor agonist, also induces hypophagia and lowers body weight in the obese spontaneously hypertensive rat, but the central mediation of this action and the neuronal pathways that moxonidine may interact with are not known. We studied whether moxonidine has anti-obesity effects in the genetically-obese and insulin-resistant fa/fa Zucker rat, and whether these are mediated through inhibition of the hypothalamic neuropeptide Y (NPY) neurones. Lean and obese Zucker rats were given moxonidine (3 mg kg(-1) day(-1)) or saline by gavage for 21 days. Moxonidine decreased food intake throughout by 20% in obese rats (P<0.001) and by 8% in lean rats (P<0.001), and reduced weight gain that final body weight was 15% lower in obese (P<0.001) and 7% lower in lean (P<0.01) rats than their untreated controls. Plasma insulin and leptin levels were decreased in moxonidine-treated obese rats (P<0.01 and P<0.05), but unchanged in treated lean rats. Uncoupling protein-1 gene expression in brown adipose tissue was stimulated by 40-50% (P< or =0.05) in both obese and lean animals given moxonidine. Obese animals given moxonidine showed a 37% reduction in hypothalamic NPY mRNA levels (P = 0.01), together with significantly increased NPY concentrations in the paraventricular nucleus (P<0.05), but no changes in the arcuate nucleus or other nuclei; this is consistent with reduced NPY synthesis in the arcuate nucleus and blocked release of NPY in the paraventricular nucleus. In lean animals, moxonidine did not affect NPY levels or NPY mRNA. The hypophagic, thermogenic and anti-obesity effects of moxonidine in obese Zucker rats may be partly due to inhibition of the NPY neurones, whose inappropriate overactivity may underlie obesity in this model.

Topics: Adipose Tissue; Animals; Anti-Obesity Agents; Antihypertensive Agents; Blood Glucose; Body Weight; Carrier Proteins; Eating; Feeding Behavior; Hormones; Hypothalamus; Imidazoles; Ion Channels; Leptin; Male; Membrane Proteins; Mitochondrial Proteins; Neurons; Neuropeptide Y; Obesity; Protein Biosynthesis; Rats; Rats, Zucker; RNA, Messenger; Uncoupling Protein 1

Lines of mice have been developed in our laboratory by divergent long-term selection for body fat content. This has resulted in a fivefold (23% vs 4%) higher fat percentage in the Fat line at 14 weeks of age, with little difference between the Fat and Lean lines in fat-free body weight. As part of an approach to characterize the physiological mechanisms underlying these different phenotypes, neuropeptide Y (NPY) mRNA levels in the hypothalamus and cerebral cortex of ad libitum-fed and fasted mice of the Fat and Lean selected lines were measured. Significant differences in NPY gene expression were confined to the hypothalamus. Under ad libitum-fed conditions, hypothalamic NPY mRNA levels did not differ significantly between the Fat and Lean lines. After an overnight fast of 18-20 h, hypothalamic NPY mRNA levels were increased significantly (P<0.05) by 31% in Lean animals relative to fed mice from the same line. However, fasting did not significantly stimulate NPY gene expression in the Fat line. Most plasma leptin measurements in the Lean line fell below the sensitivity threshold of the assay (0.1 ng/ml), but levels in the Fat line were at least 30 to 50 times higher under fasted and fed conditions respectively. After fasting, plasma leptin levels in the Fat line decreased significantly (P<0. 05) by 48%. Thus, unlike the situation in other rodent models, obesity in the Fat line is not associated with increased hypothalamic NPY mRNA levels in the ad libitum-fed state. The decreased sensitivity of hypothalamic NPY gene expression to fasting in the Fat line is consistent with an inhibitory effect of higher circulating leptin levels.

Topics: Adipose Tissue; Animals; Body Composition; Body Weight; Female; Gene Expression; Genetic Variation; Leptin; Male; Mice; Mice, Inbred CBA; Mice, Inbred Strains; Neuropeptide Y; Obesity; Proteins; RNA, Messenger; Selection, Genetic; Time Factors

Rats postnatally overnourished due to a reduced litter size become persistently overweight. A presumed pathophysiological mechanism consists of a change in the activity and responsiveness to neuropeptides of the neuronal system regulating feeding behavior. This study aimed to find differences in the action of neuropeptide Y, orexin-A and cholecystokinin on single unit activity of the ventromedial hypothalamic nucleus in brain slices of normal and postnatally overfed juvenile rats. NPY inhibited significantly more neurons (15 of 23) of obese than of normal rats (6 of 27; p < 0.01, chi2). Orexin-A and CCK-8S mainly activated the neurons without significant differences between the groups. In conclusion, the stronger inhibition by NPY of VMN neurons which signal satiety might contribute to increased feeding behavior in postnatally overfed rats.

Topics: Action Potentials; Age Factors; Animals; Carrier Proteins; Eating; Electrophysiology; Female; Intracellular Signaling Peptides and Proteins; Male; Neurons; Neuropeptide Y; Neuropeptides; Nootropic Agents; Obesity; Orexins; Organ Culture Techniques; Pregnancy; Rats; Rats, Wistar; Sincalide; Ventromedial Hypothalamic Nucleus

To determine how leptin concentrations and neuropeptide (NPY) are regulated in a model of dietary obesity in relation to relative growth (RG) and relative food consumption (RFC).. Sprague-Dawley rats were fed a moderately high-fat diet for 14 weeks over which time animals diverged into obesity-prone (OP) and obesity-resistant (OR) populations. RG rates and RFC were calculated weekly. Following the study, an adiposity index was calculated and arcuate nucleus (ARC) NPY expression was determined by in situ hybridization (ISH) or ribonuclease protection (RPA) assays.. Body weights were greater in OP rats after 2 weeks on the diet compared to OR rats and remained different throughout the study. RG and RFC were greater in OP rats compared to OR rats only during the first 2 weeks of the study. Leptin concentrations rose in both groups during the experiment, but the increase was greater in OP rats than in OR rats. Insulin changes paralleled those for leptin. ARC NPY mRNA expression was not different between OP and OR rats as measured by ISH and RPA.. Although NPY expression has been reported to be different initially in OP and OR rats, this difference dissipates following divergence of body weight. RFC and RG data suggest the initial NPY elevation may contribute to increased weight gain of OP rats during the first 2 weeks of the diet. Higher relative leptin concentrations in OP rats may be necessary to normalize differences in adiposity and apparent leptin and insulin resistance of OP rats.

Topics: Animals; Body Composition; Body Weight; Dietary Fats; Disease Models, Animal; Eating; Energy Intake; Gene Expression; Hypothalamus; In Situ Hybridization; Leptin; Male; Neuropeptide Y; Obesity; Rats; Rats, Sprague-Dawley; RNA, Messenger

Topics: Adolescent; Adult; Animals; Appetite Depressants; Behavior Therapy; Body Mass Index; Body Weight; Child; Diet, Reducing; Exercise; Female; Humans; Leptin; Male; Mice; Middle Aged; Neuropeptide Y; Obesity; Rats; Sex Factors; United States; Weight Loss

Topics: Adipocytes; Adult; Agouti Signaling Protein; Animals; Carrier Proteins; Child; Endorphins; Energy Intake; Energy Metabolism; Humans; Intercellular Signaling Peptides and Proteins; Leptin; Melanocyte-Stimulating Hormones; Neuropeptide Y; Obesity; Pro-Opiomelanocortin; Proteins; Receptor, Melanocortin, Type 4; Receptors, Cell Surface; Receptors, Cytoplasmic and Nuclear; Receptors, Leptin; Receptors, Peptide; Research; Transcription Factors; United States

Orexin-A and orexin-B (also called hypocretin-1 and hypocretin-2, respectively) are novel hypothalamic neuropeptides encoded by a single mRNA transcript; they stimulate food intake. We have determined the three-dimensional solution structure of human hypocretin-2/orexin-B using two-dimensional 1H-NMR data and dynamical simulated annealing calculations. On the basis of NOEs, 3JHNalpha coupling constants and hydrogen-deuterium exchange rates together with chemical shift indices, human hypocretin-2/orexin-B was deduced to consist of two alpha-helices connected with a short linker in both H2O and 30% trifluoroethanol solutions. The helical axis of helix I is oriented about 60-80 degrees relative to helix II. Hybrid distance geometry and simulated-annealing protocols were used to generate an ensemble of 30 structures with no constraint violations greater than 0.03 nm for distances and 3 degrees for angles. In addition, human hypocretin-2/orexin-B shares a similar secondary-structural motif with human neuropeptide Y. This result can form the basis for further study on ligand-receptor recognition of human orexin receptors.

Topics: Amino Acid Sequence; Animals; Circular Dichroism; Humans; Hypothalamus; Intracellular Signaling Peptides and Proteins; Magnetic Resonance Spectroscopy; Models, Molecular; Molecular Sequence Data; Neuropeptide Y; Neuropeptides; Neurotransmitter Agents; Obesity; Orexins; Protein Structure, Secondary; Sequence Homology, Amino Acid; Solutions

It has been reported that polycystic ovary syndrome (PCOS) is very frequently associated with obesity, insulin resistance and hyperinsulinemia. However, metabolic disorders may lead to suppression of reproductive hormone secretion during undernutrition and in obesity. Some neuropeptides, such as neuropeptide Y (NPY) and galanin, modulate the control of appetite and play an important role in the mechanism of luteinizing hormone-releasing hormone (LHRH) secretion. NPY and galanin regulate appetite via both central and peripheral mechanisms. The interaction between central and peripheral signals for the control of food intake is due to leptin. Leptin can modulate the activity of NPY and other peptides in the hypothalamus that are known to affect eating behavior. In order to evaluate the relationship between NPY, galanin and leptin, 28 women with PCOS, 32 obese women (non-PCOS) and 19 lean healthy women (control group) were investigated. Obese women with PCOS were divided into two groups: PCOS (A) overweight (body mass index, BMI 26-30 kg/m2), and PCOS (B) obese (BMI 31-40 kg/m2). Plasma NPY, galanin and leptin concentrations were measured by radioimmunoassay. Plasma leptin levels in obese women with PCOS (groups A and B) were significantly higher than those in the control group (p < 0.05, p < 0.05, respectively). A significant positive correlation between plasma leptin and BMI in women with PCOS was found (r = 0.427, p < 0.01). A positive correlation was demonstrated between leptin and testosterone in PCOS (r = 0.461, p < 0.01). Plasma galanin concentrations in PCOS were higher than in the control group but the differences were not significant. Plasma NPY levels were significantly elevated in both non-obese (normal) and obese women with PCOS (group A) (p < 0.01, p < 0.005, respectively). However, in obese non-PCOS women plasma NPY levels gradually increased with increase in BMI. No significant correlations were found between galanin, NPY and percentage change in response of LH to LHRH, as well as between NPY and insulin, and galanin and testosterone. Plasma insulin concentrations in women with PCOS (group B) were significantly higher than in the control group (p < 0.001). Increased plasma NPY levels are found in both obese and non-obese women with PCOS. The increase in NPY is independent of the increase in BMI. In obese women with PCOS, plasma leptin is increased compared with control lean women. Serum insulin concentration is increased in obese women with P

Topics: Adolescent; Adult; Body Mass Index; Estradiol; Female; Follicle Stimulating Hormone; Galanin; Humans; Immunoenzyme Techniques; Insulin; Leptin; Luteinizing Hormone; Neuropeptide Y; Obesity; Polycystic Ovary Syndrome; Prolactin; Radioimmunoassay; Testosterone

Mechanisms mediating genetic susceptibility to diet-induced obesity have not been completely elucidated. Elevated hypothalamic neuropeptide Y (NPY) and decreased hypothalamic proopiomelanocortin (POMC) are thought to promote the development and maintenance of obesity. To assess the potential role of hypothalamic neuropeptide gene expression in diet-induced obesity, the present study examined effects of a high-fat diet on hypothalamic NPY and POMC mRNA in three strains of mice that differ in susceptibility to develop diet-induced obesity. C57BL/6J, CBA, and A/J mice were fed either normal rodent chow or a high-fat diet for 14 weeks after which hypothalamic gene expression was measured. On the high-fat diet, C57BL/6J mice gained the most weight, whereas A/J mice gained the least weight. On the high-fat diet, NPY mRNA significantly decreased as body weight increased in CBA and A/J mice, but not in C57BL/6J mice. In addition, POMC mRNA significantly increased as body weight increased in A/J mice, but not in CBA and C57BL/6J mice. Since decreased NPY mRNA and increased POMC mRNA would presumably attenuate weight gain, these results suggest that a high-fat diet produces compensatory changes in hypothalamic gene expression in mice resistant to diet-induced obesity but not in mice susceptible to diet-induced obesity.

Topics: Animals; Blood Glucose; Body Weight; Dietary Fats; Hypothalamus; Insulin; Male; Mice; Mice, Inbred C57BL; Mice, Inbred CBA; Neuropeptide Y; Obesity; Pro-Opiomelanocortin; RNA, Messenger

Topics: Adipose Tissue; Arteriosclerosis; Cholesterol; Diet; Humans; Hypercholesterolemia; Neuropeptide Y; Obesity; Polymorphism, Genetic

Topics: Humans; Insulin; Neuropeptide Y; Obesity; RNA, Messenger

We evaluated neuropeptide Y (NPY) and galanin (GAL) immunoreactivity (IR) and mRNA in the paraventricular and arcuate nucleus, respectively, in rats that became overweight (Ov) or not (NOv) when fed a cafeteria diet. After 2 months of diet, NOv rats showed a significant increase in NPY IR, whereas Ov rats showed a significant increase in GAL mRNA levels. None of these changes was present in rats overfed for 6.5 months. These differential changes in hypothalamic GAL and NPY transmissions may contribute to the different susceptibility of the two rat subpopulations to the weight-promoting effects of the hypercaloric diet.

Topics: Animals; Arcuate Nucleus of Hypothalamus; Blood Glucose; Body Weight; Diet; Eating; Fatty Acids; Galanin; Hyperphagia; Immunohistochemistry; In Situ Hybridization; Insulin; Male; Neuropeptide Y; Obesity; Oligodeoxyribonucleotides; Paraventricular Hypothalamic Nucleus; Rats; Rats, Sprague-Dawley; RNA, Messenger

Chronic cold exposure stimulates sympathetically driven thermogenesis in brown adipose tissue (BAT), resulting in fat mobilization, weight loss, and compensatory hyperphagia. Hypothalamic neuropeptide Y (NPY) neurons are implicated in stimulating food intake in starvation, but may also suppress sympathetic outflow to BAT. This study investigated whether the NPY neurons drive hyperphagia in rats that have lost weight through cold exposure. Rats exposed to 4 degrees C for 21 days weighed 14% less than controls maintained at 22 degrees C (P < 0.001). Food intake increased after 3 days and remained 10% higher thereafter (P < 0.001). Increase BAT activity was confirmed by 64, 96, and 335% increases in uncoupling protein-1 mRNA at 2, 8, and 21 days. Plasma leptin decreased during prolonged cold exposure. Cold-exposed rats showed no significant changes in NPY concentrations in any hypothalamic regions or in hypothalamic NPY mRNA at any time. We conclude that the NPY neurons are not activated during cold exposure. This is in contrast with starvation-induced hyperphagia, but is biologically appropriate since enhanced NPY release would inhibit thermogenesis causing potentially lethal hypothermia. Other neuronal pathways must therefore mediate hyperphagia in chronic cold exposure.

Topics: Acclimatization; Animals; Body Temperature Regulation; Body Weight; Cold Temperature; Feeding Behavior; Hyperphagia; Hypothalamus; Leptin; Male; Neurons; Neuropeptide Y; Obesity; Proteins; Rats; Rats, Wistar; RNA, Messenger; Time Factors; Transcription, Genetic

Brown adipose tissue (BAT) has the capacity for uncoupled mitochondrial respiration and is proposed to be a key site for regulating energy expenditure in rodents. To better define the role of BAT in energy homeostasis, we previously created a line of transgenic mice with deficiency of BAT (UCP promoter-driven diphtheria toxin A transgenic mice [UCP-DTA]) mice. These mice develop obesity that initially is due to decreased energy expenditure and later accompanied by hyperphagia despite increased levels of circulating leptin. In addition, the obesity of these mice is accompanied by severe insulin-resistant diabetes and hyperlipidemia. To better define the basis for leptin resistance in this model, we treated UCP-DTA mice with leptin (300 microg i.p., b.i.d.) and compared their response with that of leptin-treated ob/ob and FVB control mice (30 microg i.p., b.i.d.). Leptin treatment of FVB and ob/ob mice decreased their body weight and food intake and improved their glucose homeostasis. In contrast, tenfold higher dosages of leptin had no effect on body weight, food intake, or circulating insulin or glucose concentrations of UCP-DTA mice. Hypothalamic neuropeptide Y (NPY) mRNA expression was lower in UCP-DTA mice than in littermate control FVB mice in the fed state, and increased progressively in response to food restriction as leptin levels fell. In parallel to the levels of hypothalamic NPY, corticosterone levels were initially suppressed and rose with food restriction. Thus food intake, body weight, and insulin and glucose homeostasis of UCP-DTA mice are all extraordinarily resistant to leptin, whereas hypothalamic NPY and the hypothalamopituitary adrenal (HPA) axis may remain under leptin control. Further elucidation of the mechanisms underlying leptin resistance in UCP-DTA mice may provide valuable insights into the basis for leptin resistance in human obesity.

Topics: Adipose Tissue, Brown; Animals; Blood Glucose; Carrier Proteins; Corticosterone; Diphtheria Toxin; Drug Resistance; Energy Metabolism; Female; Hypothalamus; Insulin; Ion Channels; Leptin; Male; Membrane Proteins; Mice; Mice, Transgenic; Mitochondrial Proteins; Neuropeptide Y; Obesity; Promoter Regions, Genetic; Proteins; RNA, Messenger; Uncoupling Protein 1

Reduction in the activity of the alpha-melanocyte-stimulating hormone (alpha-MSH) system causes obesity, and infusions of alpha-MSH can produce satiety, raising the possibility that alpha-MSH may mediate physiological satiety signals. Since alpha-MSH is coded for by the pro-opiomelanocortin (POMC) gene, we examined if POMC gene expression would be inhibited by fasting in normal mice or in models of obesity characterized by leptin insufficiency (ob/ob) or leptin insensitivity (db/db). In wild-type mice, hypothalamic POMC mRNA was decreased > 60% after a 2-day fast and was positively correlated with leptin mRNA. Similarly, compared with controls, POMC mRNA was decreased by at least 60% in both db/db and ob/ob mice. POMC mRNA was negatively correlated with both neuropeptide Y (NPY) and melanin-concentrating hormone (MCH) mRNA. Finally, treatment of both male and female ob/ob mice with leptin stimulated hypothalamic POMC mRNA by about threefold. These results suggest that impairment in production, processing, or responsiveness to alpha-MSH may be a common feature of obesity and that hypothalamic POMC neurons, stimulated by leptin, may constitute a link between leptin and the melanocortin system.

Topics: Animals; Blotting, Northern; Drug Resistance; Fasting; Female; Gene Expression; Hypothalamic Hormones; Hypothalamus; Leptin; Male; Melanins; Mice; Mice, Inbred C57BL; Mice, Inbred CBA; Mice, Obese; Neuropeptide Y; Obesity; Pituitary Hormones; Proteins; RNA, Messenger

The effects of leptin on the levels of CRF messenger RNA (mRNA) in the paraventricular hypothalamic nucleus (PVN), on the activation of the PVN CRF cells, and on the plasma levels of corticosterone were investigated in lean (+/?) and obese (ob/ob) C57BL/6J male mice. Murine leptin was s.c. infused using osmotic minipumps. The treatment period extended to 7 days, and the daily dose of leptin delivered was 100 microg/kg. The mice were killed either in a fed state or following 24 h of total food deprivation. The starvation paradigm was employed to enhance the activity of the hypothalamic-pituitary-adrenal axis in obese mice. In situ hybridization histochemistry was performed to determine the PVN levels of CRF mRNA and the arcuate nucleus levels of neuropeptide Y mRNA. The activity of the PVN CRF cells was estimated from the number of PVN cells colocalizing CRF mRNA and the protein Fos. Leptin led to a reduction in body weight gain and fat deposition. These effects were seen in both +/? and ob/ob mice and were observed to be particularly striking in obese mutants, in which leptin also caused an important reduction in food intake. Leptin also was found to affect plasma levels of corticosterone. It lowered the high corticosterone levels of obese mutants, an effect that appeared more evident in food-deprived than in fed mice. Finally, leptin prevented the induction of CRF synthesis in the PVN and the activation of the PVN CRF neurons observed in food-deprived ob/ob mice and hindered the elevation of arcuate nucleus neuropeptide Y synthesis in ob/ob mice. Together these results suggest a role for leptin in the excessive response of the hypophysiotropic CRF system of the ob/ob mouse.

Topics: Adipose Tissue; Animals; Arcuate Nucleus of Hypothalamus; Body Weight; Corticosterone; Corticotropin-Releasing Hormone; Eating; Gene Expression; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Neurons; Neuropeptide Y; Obesity; Organ Size; Paraventricular Hypothalamic Nucleus; Proteins; RNA, Messenger

The obesity syndrome in Zucker rats is associated with an elevated neuropeptide Y (NPY) content in the hypothalamus. It is recognized that the axons of NPY-ergic neurons arriving from the arcuate nucleus and the midbrain are the major source of NPY in this area. In magnocellular hypothalamic neurosecretory neurons (MCN) of normal rats NPY is expressed only in response to hyperosmotic stimulation. This study used immunohistochemistry with colchicine treatment aimed at MCN to compare NPY localization in obese (fa/fa) and in lean (Fa/Fa) Zucker rats. It was found that the obese (fa/fa), in contrast to the lean (Fa/Fa) Zucker rat, displays NPY immunoreactivity in numerous MCN of the paraventricular, supraoptic as well as accessory neurosecretory nuclei. This finding suggests local synthesis of NPY in the MCN of obese (fa/fa) rats and involvement of hydro-osmotic disorders in the Zucker syndrome of obesity.

Topics: Animals; Colchicine; Hypothalamus; Immunohistochemistry; Male; Neurons; Neuropeptide Y; Neurosecretory Systems; Obesity; Paraventricular Hypothalamic Nucleus; Rats; Rats, Zucker; Supraoptic Nucleus; Tissue Distribution

The mammalian hypothalamus strongly influences ingestive behaviour through several different signalling molecules and receptor systems. Here we show that CART (cocaine- and amphetamine-regulated transcript), a brain-located peptide, is a satiety factor and is closely associated with the actions of two important regulators of food intake, leptin and neuropeptide Y. Food-deprived animals show a pronounced decrease in expression of CART messenger RNA in the arcuate nucleus. In animal models of obesity with disrupted leptin signalling, CART mRNA is almost absent from the arcuate nucleus. Peripheral administration of leptin to obese mice stimulates CART mRNA expression. When injected intracerebroventricularly into rats, recombinant CART peptide inhibits both normal and starvation-induced feeding, and completely blocks the feeding response induced by neuropeptide Y. An antiserum against CART increases feeding in normal rats, indicating that CART may be an endogenous inhibitor of food intake in normal animals.

Topics: Animals; Anorexia; Arcuate Nucleus of Hypothalamus; Cloning, Molecular; Escherichia coli; Fasting; Feeding Behavior; Gene Expression Regulation; Hypothalamus; Immunoenzyme Techniques; Leptin; Mice; Nerve Tissue Proteins; Neuropeptide Y; Obesity; Proteins; Rats; Rats, Wistar; Rats, Zucker; Recombinant Fusion Proteins; RNA, Messenger; Signal Transduction

Neuropeptide Y (NPY) is one of the most potent orexigenic substances known. 1229U91 was found to be a potent and selective NPY antagonist. To elucidate a physiological role of NPY in hyperphagia in obese animals, we studied the effect of 1229U91 on spontaneous food intake in obese and lean Zucker rats. The food intake of Zucker rats was suppressed by intracerebroventricular administration of 1229U91 more potently in obese than in lean animals without abnormal behavior (31.7 and 67.3% inhibition at doses of 10 and 30 micrograms, respectively, in Zucker fatty rats and 22.2% inhibition at 30 micrograms in lean rats). This compound markedly suppressed NPY-induced food intake at 30 micrograms but did not affect galanin-induced food intake, suggesting that the feeding suppression seen in Zucker fatty and lean rats is pharmacologically and behaviorally specific. These results suggest that NPY is involved in feeding behavior in Zucker fatty rats and that NPY contributes to feeding to a greater degree in Zucker fatty than in lean rats. The hyperphagia in Zucker fatty rats may be due to the abnormal overactivation of the NPYergic system.

Topics: Animals; Eating; Neuropeptide Y; Obesity; Peptides, Cyclic; Rats; Rats, Zucker

Neuropeptide Y (NPY), a 36-amino-acid neuromodulator abundantly expressed in the brain, has been implicated in the regulation of food intake and body weight. Pharmacological data suggest that NPY's stimulatory effect on appetite is transduced by the G-protein-coupled NPY Y5 receptor (Y5R). We have inactivated the Y5R gene in mice and report that younger Y5R-null mice feed and grow normally; however, they develop mild late-onset obesity characterized by increased body weight, food intake and adiposity. Fasting-induced refeeding is unchanged in younger Y5R-null mice and they exhibit normal sensitivity to leptin. Their response to intracerebroventricular (i.c.v.) administration of NPY and related peptides is either reduced or absent. NPY deficiency attenuates the obesity syndrome of mice deficient for leptin (ob/ob), but these effects are not mediated by NPY signaling through the Y5R because Y5R-null ob/ob mice are equally obese. These results demonstrate that the Y5R contributes to feeding induced by centrally administered NPY and its analogs, but is not a critical physiological feeding receptor in mice.

Topics: Animals; Body Weight; Dose-Response Relationship, Drug; Feeding Behavior; Female; Genotype; Humans; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Inbred Strains; Mice, Mutant Strains; Molecular Sequence Data; Mutagenesis, Site-Directed; Mutation; Neuropeptide Y; Obesity; Pancreatic Polypeptide; Peptide YY; Peptides, Cyclic; Phenotype; Proteins; Receptors, Neuropeptide Y; RNA, Messenger; Time Factors

This study examined whether leptin can exert inhibitory actions on brain NPY overflow in Sprague-Dawley and in lean and obese Zucker rats, and tested the site-specificity of the effect. Slices of rat hypothalamus, cerebral cortex and medulla oblongata were perfused with modified Krebs buffer containing either leptin or KCl. Depolarization of tissues with 40 mM KCl elicited a significant doubling of NPY overflow in all brain regions tested. At 1 microM, leptin significantly reduced NPY overflow only in the rat hypothalamus, while at 3 microM, leptin reduced NPY overflow from all regions. However, no effect of 1 microM leptin was observed in the hypothalamus of obese Zucker rats: this insensitivity to leptin is in keeping with their genetic defect. In conclusion, the inhibitory effect of leptin on hypothalamic NPY overflow provides further evidence for important modulatory actions between these two feeding mediators. Moreover, the effect of leptin observed in the cerebral cortex and medulla oblongata supports a role of leptin in brain regions other than the hypothalamus.

Topics: Adipose Tissue; Animals; Cerebral Cortex; Hypothalamus; In Vitro Techniques; Kinetics; Leptin; Male; Medulla Oblongata; Neuropeptide Y; Obesity; Organ Specificity; Potassium Chloride; Proteins; Rats; Rats, Sprague-Dawley; Rats, Zucker; Thinness

The obese gene (OB) product, leptin, has been shown to exert control on metabolic processes such as food intake and body weight homeostasis, possibly through a neuropeptide Y (NPY) neurotransmission. More recently, leptin has been shown to control several neuroendocrine axes, modulating pituitary hormone secretions in function of metabolic conditions. Since in the rat growth hormone (GH) secretion is dependent upon prevailing metabolic conditions, and NPY has been shown to be implicated in the feedback mechanisms of this hormone, we reasoned that leptin could also exert control over GH secretion and we examined this hypothesis in male rats submitted to a 3-day fast. Circulating leptin concentrations measured by RIA abruptly fell to low values after 24 h of fasting and remained low thereafter. Upon refeeding, leptin secretion regularly increased. As shown by others, pulsatile GH secretion had disappeared after 3 days of fasting. Centrally administered leptin (10 microg/day, i.c.v. infusion initiated at the beginning of the fasting period) totally prevented the disappearance of pulsatile GH secretion. No leak of centrally administered leptin to the general circulation was observed. Infusing the same amount of leptin intracerebroventricularly to rats receiving ad libitum feeding produced a severe reduction in food intake but maintained a normal GH secretory pattern. In contrast, pair-fed rats, submitted to the same food restriction, exhibited a marked reduction in GH secretion. Hypothalamic NPY gene expression, estimated by Northern blot analysis, was significantly increased in fasting rats, and decreased in leptin-treated, fasting rats. In rats receiving ad libitum feeding, leptin treatment reduced NPY gene expression, consistent with the observed reduction in food intake, whereas pair-fed animals logically exhibited increased NPY gene expression. In both situations with reduced feeding, normal GH secretion was seen in leptin-treated animals exhibiting low NPY gene expression, whereas decreased or abolished GH secretion was seen in animals not receiving leptin and exhibiting increased NPY mRNA levels. Interestingly, despite maintenance of normal GH secretion in leptin-treated, fasting rats, plasma IGF-I levels were low, as in vehicle-treated rats. Indeed, hepatic gene expression for both GH receptor and IGF-I was markedly reduced by fasting, and no correction was seen with leptin treatment. In summary, the regulation of GH secretion, at least the changes li

Topics: Animals; Cerebral Ventricles; Fasting; Growth Hormone; Infusions, Parenteral; Insulin-Like Growth Factor I; Leptin; Liver; Male; Neuropeptide Y; Obesity; Proteins; Rats; Rats, Sprague-Dawley; Secretory Rate

The goal of this study was to ascertain whether neuropeptide Y (NPY) is required in mice for the development of obesity induced by a high-fat diet (HFD), chemical lesions of the hypothalamus caused by monosodium glutamate (MSG) or gold thioglucose (GTG), impaired brown adipose tissue (BAT) due to a diphtheria toxin transgene driven by the uncoupling protein 1 promoter (UCP-DTA) or the lethal yellow agouti mutation (Ay).. The obesity syndrome of the leptin-deficient (ob/ob) mouse can be partially reversed by the genetic removal of NPY. In the murine models of obesity examined in this study, the animals become obese despite increased serum leptin levels, indicating that they are resistant to the weight-limiting actions of leptin. The role of NPY in these obesity models with elevated leptin levels is unknown.. Mice lacking NPY due to genetic disruption of the gene and wildtype littermates were made obese by allowing them access to a highly palatable HFD, by treatment with MSG, or GTG, or by inheriting the dominant UCP-DTA or Ay alleles. Food consumption, body weight and dissectable fat pad weights were measured and compared to values obtained from non-obese littermates.. In each model of obesity tested, NPY-deficient mice achieved the same food intake, body weight and fat content as wildtype littermates.. NPY is not necessary for the progressive development of obesity exhibited by multiple murine models with leptin resistance.

Topics: Adipose Tissue, Brown; Agouti Signaling Protein; Animals; Aurothioglucose; Body Composition; Body Weight; Carrier Proteins; Diet; Diphtheria Toxin; Eating; Female; Hypothalamus; Intercellular Signaling Peptides and Proteins; Ion Channels; Leptin; Male; Membrane Proteins; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mitochondrial Proteins; Mutation; Neuropeptide Y; Obesity; Proteins; Sodium Glutamate; Uncoupling Protein 1

Obese Zucker rats are characterized by a reduced hypothalamic NPY receptor density. We tested the effects of intracerebroventricular injections of human NPY (hNPY) and [D-Trp32]NPY, a weak but selective NPY Y5 receptor agonist, on food intake in lean and obese Zucker rats. The effect of a maximal dose of hNPY (10 microg) on feeding was more pronounced in lean than in obese rats. [D-Trp32]NPY (10 microg) stimulated feeding in lean but not in obese Zucker rats. It did not affect the feeding response to hNPY, excluding the activation of an inhibitory receptor. These results are in favor of a down-regulation of the NPY 'feeding' receptor in the obese rat, which is suggested to be the Y5 subtype.

Topics: Animals; Down-Regulation; Eating; Humans; Injections, Intraventricular; Male; Neuropeptide Y; Obesity; Rats; Rats, Zucker; Receptors, Neuropeptide Y

The tubby mouse is characterized by an autosomal recessive mutation which results in the development of maturity-onset obesity and sensorineural hearing loss and retinal degeneration. Although the tubby mutation which leads to a splicing defect of the tub gene has been identified recently, the mechanism by which it causes the obesity syndrome has not been established. In this study, the potential dysfunction of several hypothalamic neuroendocrine pathways involved in the central regulation of energy metabolism was investigated in tubby mice. In comparison with the wild-type controls, a significant reduction (20%) of pro-opiomelanocortin (POMC) mRNA expression was observed in the arcuate nucleus (ARC) of the mature, obese but not in the juvenile, non-obese tubby mice. Similarly, an age and body mass-dependent induction (about 30-fold) of neuropeptide Y (NPY) mRNA was observed in the dorsomedial (DMH) and ventromedial (VMH) hypothalamic nuclei of the tubby mice. However, NPY mRNA in the ARC was decreased by approximately 30 to 40% in both juvenile and mature tubby mice. The hypothalamic expression patterns of corticotropin releasing hormone (CRH) and the long form leptin receptor (OB-Rb) were not significantly altered in the mutant mice. These results suggest that the altered hypothalamic POMC and/or NPY functions may be important contributing factors for the development of obesity in this animal model.

Topics: Adaptor Proteins, Signal Transducing; Animals; Female; Gene Expression; Hypothalamus; In Situ Hybridization; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Neuropeptide Y; Obesity; Pro-Opiomelanocortin; Proteins; RNA, Messenger

Topics: Adipose Tissue; Animals; Carrier Proteins; Diabetes Mellitus; Diabetes Mellitus, Type 2; Humans; Insulin; Insulin Resistance; Leptin; Mice; Mice, Obese; Neuropeptide Y; Obesity; Proteins; Receptor, Insulin; Receptors, Cell Surface; Receptors, Leptin

Neuropeptide Y (NPY) is known to stimulate eating behavior and to be related to behavioral patterns of carbohydrate ingestion. The present report investigates this relationship further to: (1) characterize the specific NPY projection activated in different dietary paradigms; (2) understand associated changes in circulating hormones that may mediate dietary effects on NPY neurons; and (3) determine whether endogenous NPY in conditions with macronutrient diets can be linked to body fat. Male albino Sprague-Dawley rats were tested in two feeding paradigms, one in which the rats were given a choice of the macronutrients, carbohydrate, fat or protein, or the other involving a single diet varying in carbohydrate of fat content. These studies consistently demonstrated a close association between the ingestion of carbohydrate and NPY levels, specifically in the arcuate nucleus (ARC) and medial portion of the paraventricular nucleus (PVN) of the hypothalamus. In addition to revealing increased NPY activity in animals that naturally select high carbohydrate when given a choice of macronutrients, a single diet with 65% carbohydrate (10% fat), compared to a control diet with 45% carbohydrate (30% fat), significantly potentiates NPY gene expression and NPY-immunoreactivity, as determined by in situ hybridization and immunohistochemistry. A further lowering of carbohydrate to 15% has little effect on NPY. Studies of medial hypothalamic fragments in vitro also reveal enhanced NPY release from hypothalamic tissue taken from rats maintained on high-carbohydrate diet. Together with NPY, circulating corticosterone (CORT) levels are also highest in a high-carbohydrate condition and positively correlated with NPY in the ARC. An association between NPY and adiposity in these dietary conditions is indicated by significantly higher levels of NPY in the medial PVN in rats with high body fat, whether consuming a high-carbohydrate of high-fat diet. This evidence, linking NPY to carbohydrate intake and circulating CORT, suggests a role for this peptide in glucose homeostasis that is normally exhibited under conditions when carbohydrate stores are low. Disturbances in this homeostatic process, associated with hyperinsulinemia and higher levels of NPY, become evident with only a moderate rise in body fat on a high-carbohydrate as well as high-fat diet.

Topics: Adipose Tissue; Animals; Corticosterone; Diet; Dietary Carbohydrates; Dietary Fats; Hypothalamus; Male; Neuropeptide Y; Obesity; Paraventricular Hypothalamic Nucleus; Rats; Rats, Sprague-Dawley; RNA, Messenger; Tissue Distribution

Twin studies, adoption studies, and studies of familial aggregation indicate that obesity has a genetic component. Whereas, the genetic factors predisposing to obesity have been elucidated for several rare syndromes, the factors responsible for obesity in the general population have remained elusive. Genetic studies of complex traits are often accelerated by the use of candidate genes. To facilitate genetic studies of human obesity, seven multiplex panels of candidate genes for obesity that are suitable for fluorescent genotyping have been assembled. The multiplex panels are composed of 66 microsatellite markers linked tightly to 16 human gene products that are of potential importance in the control of body weight or linked to syndromic forms of obesity. As part of these efforts 12 previously cloned genes have been placed on the human physical map. In addition the chromosomal location of three of these genes, ART, NYP Y6R, and PPARgamma, are reported for the first time. These resources will be of use in studies to identify the genetic factors responsible for human obesity. [Figures are available at http://www.genome.org]

Topics: Agouti-Related Protein; Automation; Chromosomes, Artificial, Yeast; Contig Mapping; Genotype; Humans; Intercellular Signaling Peptides and Proteins; Microsatellite Repeats; Neuropeptide Y; Obesity; Physical Chromosome Mapping; Proteins; Receptors, Cytoplasmic and Nuclear; Receptors, Neuropeptide Y; Sequence Tagged Sites; Transcription Factors

This study aimed to elucidate possible age-related changes in islet blood perfusion in lean and obese C57BL/6 mice. Obese mice aged 1 mo were hyperglycemic and hyperinsulinemic and had an increased islet blood flow compared with age-matched lean mice. This augmented blood flow could be abolished by pretreatment with leptin. The islet blood perfusion was, in contrast to this, markedly decreased in obese 6- to 7-mo-old animals compared with age-matched lean mice. Reversal of hyperglycemia, but not hyperinsulinemia, in these obese mice with phlorizin normalized the islet blood flow. Spontaneous reversal of hyperglycemia, but not hyperinsulinemia, was seen in the 12-mo-old obese mice. Islet blood perfusion in obese mice at this age did not differ compared with lean mice. It is suggested that the initial increase in islet blood flow in obese mice is due to the leptin deficiency. The subsequent decrease in islet blood perfusion is probably caused by the chronic hyperglycemia. The described islet blood flow changes may be of importance for impairment of islet function in obese-hyperglycemic mice.

Topics: Aging; Animals; Arginine; Blood Glucose; Body Weight; Hyperglycemia; Hyperinsulinism; Insulin; Insulin Secretion; Islets of Langerhans; Leptin; Mice; Mice, Inbred C57BL; Mice, Obese; Neuropeptide Y; Obesity; Organ Size; Pancreas; Perfusion; Phlorhizin; Proteins; Receptors, Leptin; Receptors, Neuropeptide Y; Regional Blood Flow

Genetic obesity is associated with increased neuropeptide Y (NPY) messenger RNA (mRNA) and decreased POMC mRNA in the hypothalamus of ob/ob and db/db mice, or impaired sensitivity to alphaMSH (derived from POMC) in the yellow agouti mouse. Acquired obesity can be produced by chemically lesioning the hypothalamus with either monosodium glutamate (MSG) in neonates or gold thioglucose (GTG) in adult mice. The present study examined whether elevated NPY mRNA and/or decreased POMC mRNA in the hypothalamus are associated with obesity due to hypothalamic lesions. GTG injection into adult mice produced a profound obese phenotype, including hyperphagia, increased body weight, and increased leptin mRNA and peptide, in association with reduced hypothalamic NPY mRNA and POMC mRNA. MSG treatment produced virtual elimination of NPY mRNA in the arcuate nucleus and a reduction of hypothalamic POMC mRNA, and led to elevated leptin. MSG pretreatment did not attenuate GTG-induced hyperphagia and obese phenotype. These results do not support a role for NPY-synthesizing neurons in the arcuate nucleus in mediating hypothalamic acquired obesity, but are consistent with the hypothesis that decreased activity of hypothalamic neurons synthesizing POMC play a role in mediating hypothalamic obesity.

Topics: Animals; Aurothioglucose; Blotting, Northern; Body Weight; Hyperphagia; Hypothalamus; In Situ Hybridization; Leptin; Mice; Mice, Inbred C57BL; Neuropeptide Y; Obesity; Pro-Opiomelanocortin; Protein Biosynthesis; RNA, Messenger; Sodium Glutamate; Weight Gain

Brown adipose tissue-deficient [uncoupling protein (UCP)-promoter-driven diphtheria toxin A (DTA)] mice develop obesity as a result of both decreased energy expenditure and hyperphagia. The hyperphagia occurs despite high serum leptin levels. Hence, this is a model of leptin-resistant obesity in which the mechanism driving hyperphagia is unknown. Leptin is a regulator of a number of hypothalamic neuropeptides involved in energy homeostasis. In ob/ob mice, leptin deficiency results in increased expression of neuropeptide Y (NPY), agouti-related protein (AGRP), and melanin-concentrating hormone (MCH), and decreased expression of POMC. We have previously shown that NPY is reduced in the UCP-DTA mouse, suggesting a normal NPY response to leptin. To define other potential sites of leptin resistance, we used in situ hybridization to evaluate the expression of messenger RNAs (mRNAs) encoding a number of peptides, including NPY, AGRP, MCH, and POMC. We confirmed that the decrease in NPY expression previously detected by Northern blots reflects a decrease in NPY expression in the arcuate nucleus. AGRP mRNA was also decreased, whereas POMC mRNA levels in the arcuate nucleus were the same as control. MCH mRNA levels in the lateral hypothalamic area were also decreased. In contrast, there was induction of NPY expression in the dorsomedial hypothalamic nucleus in the UCP-DTA animals but not in the controls. The results indicate that these neuropeptides generally respond to leptin and that the hyperphagia seen in the UCP-DTA mice is likely the result of dysregulated expression of other, as yet unexamined, hypothalamic peptides, or lies at sites distal to the hypothalamus.

Topics: Adipose Tissue, Brown; Animals; Appetite; Autoradiography; Diphtheria Toxin; Hypothalamus; In Situ Hybridization; Leptin; Male; Mice; Neuropeptide Y; Neuropeptides; Obesity; Pro-Opiomelanocortin; Proteins; RNA, Antisense

Recent evidence suggests that leptin reduces food intake (FI) by acting at the hypothalamic level. Leptin decreases hypothalamic neuropeptide Y (NPY), melanin-concentrating hormone (MCH) and galanin (GAL) gene expression in rats. The purpose of the present study was to test the hypothesis that leptin decreases FI by additionally modulating the action of NPY, MCH or GAL in the hypothalamus. Intracerebroventricular (i.c.v.) administration of NPY, MCH or GAL induced FI in satiated rats. A prior i.c.v. injection of leptin (4 microg) completely prevented the increase of FI either by MCH, GAL or NPY. These results suggest that modulation of post-synaptic actions of MCH, GAL and NPY is one of the mechanisms of leptin signaling in the hypothalamus.

Topics: Animals; Appetite Stimulants; Eating; Galanin; Hypothalamic Hormones; Injections, Intraventricular; Leptin; Male; Melanins; Neuropeptide Y; Obesity; Pituitary Hormones; Proteins; Rats; Rats, Sprague-Dawley

Obese Zucker rats are hyperphagic, overweight, and infertile. It has been postulated that neuropeptide Y (NPY) overproduction may contribute to obesity and infertility in these animals. To test this hypothesis, ovariectomized, adult obese Zucker rats were implanted with cannulae in the third ventricle and subsequently injected with NPY antisera or normal rabbit sera (NRS) 6, 4 and 2 h before experimental observation. Steroid-treated females injected with NPY antisera were significantly more receptive and were more likely to show proceptive behaviors than after treatment with NRS (e.g., lordosis quotient: NPY antisera, 65.5+/-6.9%; NRS, 30.9+/-11.6%, P < 0.02; 91% displaying proceptivity after NPY antisera injection vs. 36% after NRS, P < 0.03). Injection of NPY antisera also curbed food intake and weight gain (24 h food intake: NPY antisera, 10.5+/-2.1 g; NRS, 20.5+/-1.7 g, P < 0.01; 24 h weight gain: NPY antisera, -5.4+/-2.2 g; NRS, 5.8+/-0.7 g, P < 0.01). Locomotor activity was similar after NRS and NPY antisera treatment (P > 0.5) suggesting that general malaise was not responsible for the effects of NPY antisera on food intake or body weight. These data suggest that endogenous neuropeptide Y contributes to excessive feeding and weight gain, and suppressed reproductive behaviors in obese Zucker female rats.

Topics: Animals; Antibodies; Feeding Behavior; Female; Infertility, Female; Injections, Intraventricular; Male; Neuropeptide Y; Obesity; Ovariectomy; Rabbits; Rats; Rats, Zucker; Sexual Behavior, Animal; Weight Gain

To test the hypothesis that NPY-induced overfeeding activates compensatory responses that inhibit hypothalamic NPY gene expression, we investigated the effect of chronically administered neuropeptide Y (NPY) on plasma hormones involved in energy balance and on the level of mRNA for hypothalamic neuropeptides. After cannulation of the third cerebral ventricle, male Long-Evans rats received a 4.5-day intracerebroventricular (i.c.v.) infusion of either human NPY (12 microg per day), or synthetic cerebrospinal fluid (CSF). NPY-treated animals were either allowed ad libitum access to food or were pairfed to the intake of CSF-treated controls. In rats fed ad libitum, i.c.v. NPY induced significant increases in food intake (75%), body weight (9%), plasma insulin (150%) and plasma leptin levels (300%) as compared to the i.c.v. CSF group. Levels of plasma leptin, but not insulin, remained elevated in NPY-treated rats that were pairfed to the intake of the CSF group. NPY mRNA levels in the midregion of the arcuate nucleus (ARC) were reduced by 50% in NPY-treated rats that were allowed to overeat, but not in the pairfed group, as determined by in situ hybridization. In contrast, mRNA for corticotropin-releasing hormone (CRH) in the paraventricular nucleus (PVN) and proopiomelanocortin (POMC) in the rostral ARC were not significantly different among groups. These findings indicate that NPY-induced overfeeding suppresses ARC NPY mRNA expression, and that this effect unlikely to be mediated by a direct action of NPY, since it was abolished by limiting food intake in NPY-treated animals to that observed in controls. NPY-induced overfeeding was also associated with elevated plasma levels of leptin and insulin. The effect of these hormones to inhibit NPY gene expression may therefore have contributed to the decrease of NPY mRNA.

Topics: Animals; Arcuate Nucleus of Hypothalamus; Eating; Gene Expression; Humans; Hyperphagia; Hypothalamus; In Situ Hybridization; Injections, Intraventricular; Insulin; Leptin; Male; Neuropeptide Y; Obesity; Paraventricular Hypothalamic Nucleus; Proteins; Rats; RNA, Messenger; Weight Gain

OB protein (or leptin) administration causes a long-lasting reduction in food intake and body weight in obese ob/ob mice. Neuropeptide Y, a stimulator of feeding, has been proposed to be a major mediator of the biological actions of OB protein. To test this hypothesis, the interaction of brain administration of exogenous OB protein and NPY on the feeding behavior of ob/ob mice was examined. Human OB protein, in a dose-dependent manner, partially or completely blocked feeding induced by exogenous NPY. These results demonstrate that OB protein can functionally antagonize and dominate the actions of exogenous NPY on feeding.

Topics: Animals; Brain; Corticotropin-Releasing Hormone; Drug Interactions; Eating; Female; Humans; Injections, Intraventricular; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Neuropeptide Y; Obesity; Pro-Opiomelanocortin; Proteins; Recombinant Proteins

Neuropeptide Y (NPY) exerts effects on food intake at the level of the paraventricular nucleus (PVN), which receives a dense projection from the arcuate nucleus. Monosodium glutamate (MSG) has been shown to induce hyperadiposity despite hypophagia associated with chemical ablation of the arcuate nucleus. We investigated the mechanism for the excess fat accumulation by studying the time course of changes in brain NPY content, food intake, leptin levels and BAT GLUT4 content after neonatal MSG treatment. Male rat pups were injected with MSG or saline vehicle on days 2, 4, and 6 and examined at 30 and 90 days. Plasma leptin, body mass, length, adipose tissue mass and brown fat GLUT4 were measured and brains dissected for measurement of NPY content. By 30 days, NPY concentrations were reduced in the arcuate nucleus and anterior hypothalamus, and animals tended to be hypophagic. Peripheral adipose tissue levels were less than controls, in line with their low leptin concentrations. At 90 days, MSG treatment was associated with marked reductions in NPY concentrations in several hypothalamic areas, including the PVN and arcuate nucleus, along with increased adiposity and plasma leptin. Animals also displayed marked hypophagia. Levels of GLUT4 transporter were reduced in brown adipose tissue at both ages. The early decrease in brown fat GLUT4 suggests an impairment of the hypothalamic sympathetic input to brown fat which disrupts thermogenesis, contributing to the development of adiposity in the presence of hypophagia.

Topics: Adipose Tissue, Brown; Animals; Animals, Newborn; Body Temperature Regulation; Brain; Eating; Glucose Transporter Type 4; Hypothalamus; Male; Monosaccharide Transport Proteins; Muscle Proteins; Neuropeptide Y; Obesity; Rats; Rats, Sprague-Dawley; Sodium Glutamate; Time Factors

Female Zucker lean and obese rats were treated for 14 days with 3.5 micromol/kg oleoyl-estrone (OE) in liposomes (Merlin-2). After 0, 3, 6, 10, and 14 days of treatment, the rats were killed and hypothalamic nuclei (lateral preoptic, median preoptic, paraventricular, ventromedial and arcuate) were used for neuropeptide Y (NPY) radioimmunoassay. In 14 days, OE decreased food intake by 26% in lean and 38% in obese rats and energy expenditure by 6% in lean and 47% in obese rats; the body weight gap between controls and treated rats becoming -17.8% of initial b.wt. in the lean and -13.6% in the obese rats. Obese rats showed higher NPY levels in all the nuclei than the lean rats. Despite a negative energy balance and decreased food intake, there were practically no changes in NPY with OE treatment. The results indicate that oleoyl-estrone does not act through NPY in its control of either food intake or thermogenesis in lean and genetically obese rats.

Topics: Animals; Anti-Obesity Agents; Body Weight; Eating; Energy Metabolism; Estrone; Female; Hypothalamus; Neuropeptide Y; Obesity; Oleic Acids; Rats; Rats, Zucker

Leptin is proposed to control food intake at least in part by regulating hypothalamic neuropeptide Y (NPY), a stimulator of food intake, and corticotropin-releasing hormone (CRH), an inhibitor of food intake. Ob/ob mice are leptin-deficient and would thus be expected to exhibit alterations in hypothalamic NPY and CRH. We therefore measured concentrations of NPY and CRH in discrete regions of the hypothalamus (i.e., ARC, arcuate nucleus; PVN, paraventricular nucleus; VMH, ventromedial nucleus; DMH, dorsomedial nucleus; and SCN, suprachiasmatic nucleus) of 6.5-7-wk-old ob/ob and lean mice with free access to stock diet, 24 h after food deprivation, and 1 h after refeeding. Fed ob/ob mice had 55-75% higher concentrations of NPY in the ARC, VMH and SCN than lean mice. Food deprivation increased NPY concentrations approximately 70% in the ARC, PVN and VMH of lean mice, and refeeding lowered NPY concentrations approximately 70% in the PVN of these mice. NPY in these hypothalamic regions of ob/ob mice was unresponsive to food deprivation or refeeding. The most pronounced change in CRH concentrations within the regions examined (i.e., ARC, PVN and VMH) occurred in the ARC of lean mice where refeeding lowered CRH concentrations by 75% without influencing ARC CRH concentrations in ob/ob mice. The hypothalamic concentrations of two neuropeptides involved in body weight regulation (i.e., NPY and CRH) in leptin-deficient ob/ob mice respond abnormally to abrupt changes in nutritional status.

Topics: Animals; Blood Glucose; Corticotropin-Releasing Hormone; Food; Food Deprivation; Hypothalamus; Insulin; Male; Mice; Mice, Obese; Neuropeptide Y; Obesity; Species Specificity

Increased levels of hypothalamic neuropeptide-Y (NPY) are thought to contribute to the manifestation of the obese phenotype. The aim of this study was to characterize the interactions between leptin, insulin and NPY in the pathogenesis of polygenic obesity.. A polygenic obese animal model, the New Zealand obese mouse (NZO) and its age-matched control, was used to assess the hypothalamic mRNA expression of NPY, the insulin receptor (IR) and the leptin receptor (Ob-Rb), by semiquantitative polymerase chain reaction. Experiments were performed early (at eight weeks old) and late (at 40 weeks old) in the life of these animals.. Serum glucose was significantly elevated in obese mice. Serum insulin levels were not different between obese and lean mice, whereas serum leptin levels were significantly elevated in obese mice and increased continuously during life [reaching extremely high values at 40 weeks (41.5+/-4.1 vs 3.4+/-0.25 ng/ml for obese and lean, respectively). The hypothalamic expression of NPY mRNA was significantly higher in NZO mice compared to controls at both eight weeks (2.3-fold) and 40 weeks (1.9-fold), respectively, whereas expression of IR and Ob-Rb remained unaffected.. Increased hypothalamic expression of NPY due to leptin resistance, may be involved in the development of polygenic obesity. Unchanged Ob-Rb expression suggests that either a defective hypothalamic uptake or defects in Ob-Rb signalling underly this process.

Topics: Aging; Animals; Blood Glucose; Carrier Proteins; Gene Expression; Hypothalamus; Insulin; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Neuropeptide Y; Obesity; Proteins; Receptor, Insulin; Receptors, Cell Surface; Receptors, Leptin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

High serum total and low-density lipoprotein (LDL) cholesterol levels constitute the main risk factor for atherosclerotic vascular diseases. Both genetic and environmental factors are involved in the regulation of serum cholesterol levels. Neuropeptide Y (NPY), which is widely expressed in both the central and peripheral nervous systems, is known to regulate food intake and energy balance but its role in cholesterol metabolism has remained almost untouched in former literature. A newly discovered association between a leucine(7)-to-proline(7) polymorphism (Pro(7)) in the signal peptide of NPY and a high cholesterol level may provide new ideas for the genetic regulation of cholesterol metabolism. The presence of the Pro(7) in NPY results in serum total cholesterol levels 0.6-1.4 mmol/L higher compared with subjects without this gene variant. The Pro(7) in NPY was detected in 14% of Finns but only in 6% of Dutchmen, and its impact on serum cholesterol concentration seems to be stronger in obese than in normal-weight subjects. At least among Finns, the Pro(7) in NPY is one of the strongest genetic factors identified thus far affecting serum cholesterol levels.

Topics: Arteriosclerosis; Cholesterol; Female; Humans; Male; Neuropeptide Y; Neurosecretory Systems; Obesity; Risk Factors

Topics: Adipose Tissue; Animals; Body Weight; Hypothalamus; Leptin; Melanocyte-Stimulating Hormones; Mice; Neuropeptide Y; Obesity; Proteins; Receptor, Melanocortin, Type 4; Receptors, Peptide

Dominant alleles at the agouti locus (A) cause an obesity syndrome in the mouse, as a consequence of ectopic expression of the agouti peptide. This peptide, normally only found in the skin, is a high-affinity antagonist of the melanocyte-stimulating hormone receptor (MC1-R), thus explaining the inhibitory effect of agouti on eumelanin pigment synthesis. The agouti peptide is also an antagonist of the hypothalamic melanocortin-4 receptor (MC4-R). To test the hypothesis that agouti causes obesity by antagonism of hypothalamic melanocortin receptors, we identified cyclic melanocortin analogues that are potent agonists or antagonists of the neural MC3 (refs 11, 12) and MC4 receptors. Intracerebroventricular administration of the agonist, MTII, inhibited feeding in four models of hyperphagia: fasted C57BL/6J, ob/ob, and A(Y) mice, and mice injected with neuropeptide Y. Co-administration of the specific melanocortin antagonist and agouti-mimetic SHU9119 completely blocked this inhibition. Furthermore, administration of SHU9119 significantly enhanced nocturnal feeding, or feeding stimulated by a prior fast. Our data show that melanocortinergic neurons exert a tonic inhibition of feeding behaviour. Chronic disruption of this inhibitory signal is a likely explanation of the agouti obesity syndrome.

Topics: Agouti Signaling Protein; alpha-MSH; Animals; Eating; Feeding Behavior; Female; Intercellular Signaling Peptides and Proteins; Male; Melanocyte-Stimulating Hormones; Mice; Mice, Inbred C57BL; Mice, Obese; Neurons; Neuropeptide Y; Obesity; Proteins; Receptor, Melanocortin, Type 3; Receptor, Melanocortin, Type 4; Receptors, Corticotropin; Receptors, Peptide

Neuropeptide Y (NPY) in the hypothalamus plays an important role in the regulation of food intake and body weight and seems to be implicated in the etiology of obesity. When intracerebroventricularly (ICV) infused for 6 days in normal rats, NPY resulted in hyperphagia, increased body weight gain, hyperinsulinemia, hypercorticosteronemia, and hypertriglyceridemia compared with vehicle-infused control rats. NPY infusion also resulted in an insulin-resistant state in muscles and in a state of insulin hyperresponsiveness in white adipose tissue, as assessed by the measurement of the in vivo glucose utilization index of these tissues during euglycemic-hyperinsulinemic clamps. All of these hormono-metabolic effects produced by chronic central NPY infusion were completely prevented when rats were adrenalectomized before NPY administration. Adrenalectomy per se had no effect on any of the parameters mentioned above. The levels of mRNA for the obese gene were increased in white adipose tissue after 6 days of ICV NPY infusion in normal rats, and white adipose tissue weight was also increased. These effects of ICV NPY infusion were markedly decreased by prior adrenalectomy, although NPY infusion was able to somewhat enhance the low white adipose tissue obese mRNA levels and tissue weight of adrenalectomized rats. In conclusion, intact adrenal glands, and probably circulating corticosterone in particular, are necessary for the establishment of most of the hormonal and metabolic effects induced by chronic ICV infusion of NPY in normal rats.

Topics: Adipose Tissue; Adrenalectomy; Animals; Corticosterone; Drug Administration Schedule; Female; Gene Expression; Glucose; Injections, Intraventricular; Insulin; Leptin; Muscles; Neuropeptide Y; Obesity; Proteins; Rats; Rats, Sprague-Dawley; RNA, Messenger; Triglycerides

Leptin acts on the brain to inhibit feeding, increase thermogenesis, and decrease body weight. Neuropeptide Y (NPY)-ergic neurons of the hypothalamic arcuate nucleus (ARC) that project to the paraventricular nuclei (PVN) and dorsomedial nuclei (DMH) are postulated to control energy balance by stimulating feeding and inhibiting thermogenesis, especially under conditions of energy deficit. We investigated whether leptin's short-term effects on energy balance are mediated by inhibition of the NPY neurons. Recombinant murine leptin (11 microg) injected into the lateral ventricle of fasted adult Wistar rats inhibited food intake by 20-25% between 2 and 6 h after administration, compared with saline-treated controls (P < 0.05). Uncoupling protein mRNA levels in brown adipose tissue (BAT) rose by 70% (P < 0.01). Leptin treatment significantly reduced NPY concentrations by 20-50% (P < 0.05) in the ARC, PVN, and DMH and significantly decreased hypothalamic NPY mRNA levels (0.61 +/- 0.02 vs. 0.78 +/- 0.03 arbitrary units; P < 0.01). A second study examined changes in leptin during 5 days' intracerebroventricular NPY administration (10 microg/day), which induced sustained hyperphagia and excessive weight gain. In NPY-treated rats, leptin mRNA levels in epididymal fat were comparable to those in saline-treated controls (0.94 +/- 0.17 vs. 1.0 +/- 0.28 arbitrary units; P > 0.1), but plasma leptin levels were significantly higher (4.88 +/- 0.66 vs. 2.85 +/- 0.20 ng/ml; P < 0.01). Leptin therefore acts centrally to decrease NPY synthesis and NPY levels in the ARC-PVN projection; reduced NPY release in the PVN may mediate leptin's hypophagic and thermogenic actions. Conversely, NPY-induced obesity results in raised circulating leptin concentrations. Leptin and the NPY-ergic ARC-PVN neurons may interact in a homeostatic loop to regulate body fat mass and energy balance.

Topics: Adipose Tissue, Brown; Animals; Carrier Proteins; Cerebral Ventricles; Feeding Behavior; Hyperphagia; Hypothalamus; Infusions, Parenteral; Ion Channels; Leptin; Male; Membrane Proteins; Mitochondria; Mitochondrial Proteins; Neurons; Neuropeptide Y; Obesity; Oligonucleotide Probes; Protein Biosynthesis; Proteins; Rats; Rats, Wistar; Recombinant Proteins; RNA, Messenger; Transcription, Genetic; Uncoupling Protein 1; Weight Gain

Topics: Agouti Signaling Protein; alpha-MSH; Animals; Body Weight; Carrier Proteins; Hormones; Humans; Hypothalamus; Intercellular Signaling Peptides and Proteins; Leptin; Mice; Mice, Obese; Neuropeptide Y; Obesity; Proteins; Receptors, Cell Surface; Receptors, Corticotropin; Receptors, Leptin; Receptors, Melanocortin; Starvation

The pathogenetic mechanisms behind insulin resistance in polycystic ovary syndrome (PCOS) are far from fully elucidated. Aberrant counterregulatory responses to hypoglycaemia have been reported in patients with insulin resistance, and recent reports suggest that plasma glucose may be regulated at lower levels in women with PCOS. In this study we investigated the complete hormonal counterregulatory response to hypoglycaemia in women with PCOS.. Prospective cross-sectional study.. Eight obese (BMI > or = 25) and 10 non-obese (BMI < 25) women with PCOS, diagnosed by means of ultrasonography and clinical signs of chronic anovulation. Eight obese and 9 non-obese controls.. Hypoglycaemia was induced by an intravenous bolus of soluble insulin (0.15 IU/kg body weight). The counterregulatory responses of cortisol, GH, catecholamines, glucagon, chromogranin A (CGA), and neuropeptide Y (NPY) were studied together with symptoms of hypoglycaemia.. The obese women with PCOS had a more pronounced truncal-abdominal body fat distribution (waist hip ratio, WHR) and were hyperinsulinaemic, compared with the obese controls. All the women exhibited blood glucose levels (< 2 mmol/l) well below the threshold for the hormonal counterregulatory response and for the appearance of clinical symptoms. The non-obese women with PCOS showed a greater increase in serum concentrations of GH than the lean controls. The obese women with PCOS exhibited blunted responses of noradrenaline and NPY, but similar increases of adrenaline and CGA, compared with the obese controls. They also showed a lower symptom score during hypoglycaemia. The response of noradrenaline to hypoglycaemia correlated inversely with fasting insulin levels in the women with PCOS. Among all the obese women (PCOS and controls pooled) basal levels of noradrenaline correlated inversely with the WHR.. All the women with PCOS, independent of BMI, body fat distribution and insulin levels, showed preserved counterregulatory responses to hypoglycaemia. The reduced plasma levels of noradrenaline and the lower perception of hypoglycaemic symptoms in the obese women with PCOS could both reflect a lower activation of the sympathetic nervous system. This aberration seems related to truncal-abdominal obesity and hyperinsulinaemia. The finding of an increased response of GH in the lean women with PCOS could support previous suggestions of an altered activity of the GH/IGF-I system in these women.

Topics: Adult; Body Mass Index; C-Peptide; Chromogranin A; Chromogranins; Cross-Sectional Studies; Female; Growth Hormone; Humans; Hypoglycemia; Insulin; Neuropeptide Y; Norepinephrine; Obesity; Polycystic Ovary Syndrome; Prospective Studies

Dominant mutations at the agouti locus induce several phenotypic changes in the mouse including yellow pigmentation (phaeomelanization) of the coat and adult-onset obesity. Nonpigmentary phenotypic changes associated with the agouti locus are due to ectopic expression of the agouti-signaling protein (ASP), and the pheomelanizing effects on coat color are due to ASP antagonism of alpha-MSH binding to the melanocyte MC1 receptor. Recently it has been demonstrated that pharmacological antagonism of hypothalamic melanocortin receptors or genetic deletion of the melanocortin 4 receptor (MC4-R) recapitulates aspects of the agouti obesity syndrome, thus establishing that chronic disruption of central melanocortinergic signaling is the cause of agouti-induced obesity. To learn more about potential downstream effectors involved in these melanocortinergic obesity syndromes, we have examined expression of the orexigenic peptides galanin and neuropeptide Y (NPY), as well as the anorexigenic POMC in lethal yellow (A(y)), MC4-R knockout (MC4-RKO), and leptin-deficient (ob/ob) mice. No significant changes in galanin or POMC gene expression were seen in any of the obese models. In situ hybridizations using an antisense NPY probe demonstrated that in obese A(y) mice, arcuate nucleus NPY mRNA levels were equivalent to that of their C57BL/6J littermates. However, NPY was expressed at high levels in a new site, the dorsal medial hypothalamic nucleus (DMH). Expression of NPY in the DMH was also seen in obese MC4-RKO homozygous (-/-) mice, but not in lean heterozygous (+/-) or wild type (+/+) control mice. This identifies the DMH as a brain region that is functionally altered by the disruption of melanocortinergic signaling and suggests that this nucleus, possibly via elevated NPY expression, may have an etiological role in the melanocortinergic obesity syndrome.

Topics: Agouti Signaling Protein; Animals; Galanin; Gene Expression Regulation; Hypothalamus; Intercellular Signaling Peptides and Proteins; Mice; Mice, Inbred C57BL; Mice, Obese; Mutation; Neuropeptide Y; Obesity; Pro-Opiomelanocortin; Proteins

Topics: Adipose Tissue; Animals; Body Composition; Body Weight; Eating; Energy Intake; Energy Metabolism; Leptin; Mice; Mice, Obese; Neuropeptide Y; Obesity; Oxygen Consumption; Proteins

Neuropeptide Y (NPY) neurons in the hypothalamic arcuate nucleus (ARC) produce metabolic and physiological effects that promote the development and maintenance of obesity. In turn, NPY metabolism in these neurons is inhibited by dopamine release. In this study, ARC prepro-NPY mRNA and ARC/median eminence (ME) dopamine turnover were assessed in chow-fed male Sprague-Dawley rats prone to develop diet-induced obesity (DIO) or to be diet resistant (DR) when fed a high-energy (HE) diet. By in situ hybridization, DIO-prone rats had 39% more ARC NPY mRNA expression than DR-prone rats under chow-fed conditions. DIO-prone rat ARC/ME dopamine levels were 14% higher, but dopamine half-life was 176% longer and turnover was 59% less than DR-prone rats. Neither a 48-h fast nor 50% energy intake restriction for 5 days affected the already increased ARC NPY mRNA levels in DIO-prone rats. Both manipulations increased NPY expression to the level of DIO-prone rats in DR-prone rats by 23 and 35%, respectively. Finally, when fed HE diet for 2 wk, neither DIO- nor DR-prone rats altered their ARC NPY expression despite the development of obesity and hyperinsulinemia in DIO rats. Thus DIO-prone rats overexpress and fail to regulate ARC NPY mRNA to energy restriction or hyperinsulinemia. This dysregulation is possibly secondary to reduced inhibition because of defective ARC/ME dopamine turnover. Both may be important predisposing factors in the development of DIO.

Topics: Animals; Arcuate Nucleus of Hypothalamus; Dopamine; Energy Intake; Gene Expression; Male; Neuropeptide Y; Norepinephrine; Obesity; Protein Precursors; Rats; Rats, Sprague-Dawley; RNA, Messenger

Topics: Animals; Anticonvulsants; Brain; Drug Design; Epilepsy; Humans; Neuropeptide Y; Obesity; Proto-Oncogene Proteins c-fos; Receptors, Neuropeptide Y

Topics: Animals; Hypothalamus; Leptin; Mice; Mice, Mutant Strains; Neuropeptide Y; Obesity; Proteins

The effect of food deprivation on hypothalamic neuropeptide Y (NPY) and corticotropin-releasing factor (CRF) gene expression in the Djungarian hamster was quantified by in situ hybridization. Hamsters housed in short days (SD) for 18 wk decreased body weight by 40% and exhibited 200% increases in both NPY and CRF mRNA when deprived of food for 24 h. Prior gonadectomy in long days (LD) affected neither basal gene expression nor the induction of gene expression by food deprivation. Gene expression in juvenile LD hamsters similar in body weight to SD animals was relatively insensitive to food deprivation of either 24- or 48-h duration or to subsequent refeeding. In juvenile hamsters, food deprivation for 24 but not 48 h decreased ob (obese) gene expression in inguinal but not epididymal white adipose tissue; ob mRNA levels were restored by refeeding. All food-deprived hamsters had reduced plasma insulin concentrations, but plasma cortisol was only elevated in SD food-deprived animals. NPY gene expression was also increased after daily dexamethasone injections in adult LD hamsters. These results suggest that the neuroendocrine consequences of food deprivation in SD Djungarian hamsters are determined by some factor other than absolute body mass such as the size of adipose tissue reserves.

Topics: Animal Feed; Animals; Corticotropin-Releasing Hormone; Cricetinae; Dexamethasone; Food Deprivation; Gene Expression; Glucocorticoids; Hypothalamus; Male; Neuropeptide Y; Obesity; Phodopus; Photoperiod; RNA, Messenger; Weight Loss

Topics: Animals; Body Weight; Carrier Proteins; Gene Expression Regulation; Humans; Leptin; Mice; Neuropeptide Y; Obesity; Parabiosis; Proteins; Receptors, Cell Surface; Receptors, Leptin

Topics: Adipose Tissue; Animals; Body Weight; Central Nervous System; Gene Expression Regulation; Humans; Leptin; Mice; Neuropeptide Y; Obesity; Proteins

Topics: Adipose Tissue; Animals; Drug Resistance; Female; Humans; Leptin; Lipectomy; Male; Mice; Neuropeptide Y; Obesity; Proteins

The paraventricular nucleus (PVN) of the hypothalamus is an important site for the regulation of feeding behavior. Neuropeptide Y (NPY) injected into this nucleus strongly stimulates food intake. In the current study we measured NPY release in the PVN of unrestrained rats through the push-pull technique. The rats were placed in their habitual environment and conditions of life. NPY release was augmented by > 40% (P < 0.01) in Long-Evans rats deprived of food for 12 h. It returned to the baseline as measured in ad libitum-fed rats 90 min after food access. Its stimulation by 55 mM KCl in refed animals indicated that the whole stock of NPY was not used during a short fast. During the light-dark transition, when feeding behavior is initiated. NPY release in lean Zucker rats showed a peak 20 min after lights off and then declined. It corresponded well with the first feeding episodes. In the obese Zucker rats, this peak was absent. NPY release was totally anarchic but at a high level. The feeding behavior of the obese rats was not as time delimited as in the lean rats. This study performed in very physiological conditions therefore indicates that NPY release could drive feeding behavior in the normal life. Its dysregulation in obese rats could participate in overeating and absence of feeding rhythm measured in these rats and speed up the development of their obesity.

Topics: Animals; Circadian Rhythm; Eating; Fasting; Habituation, Psychophysiologic; Male; Neuropeptide Y; Obesity; Paraventricular Hypothalamic Nucleus; Potassium Chloride; Rats; Rats, Zucker

The study objective was to determine circulating levels of the appetite-controlling neuropeptides, neuropeptide Y (NPY), galanin, and leptin, in subjects with eating disorders. The study group consisted of 48 obese women aged 19 to 45 years, 15 women with anorexia nervosa aged 18 to 23 years, and 19 lean healthy women aged 18 to 42 years (control group). The obese women were divided into four groups: (A) body mass index (BMI) = 25 to 30 kg/m2, n = 9 (overweight); (B) BMI = 31 to 40 kg/m2, n = 23 (moderate obesity); (C) BMI greater than 40 kg/m2, n = 9 (severe obesity); and (D) BMI = 31 to 40 kg/m2, n = 7 (moderate obesity + non-insulin-dependent diabetes mellitus [NIDDM]). Plasma NPY, galanin, and leptin concentrations were measured in peripheral blood samples with radioimmunoassay methods. Plasma NPY levels in obese women (groups A, B, C, and D) were significantly higher as compared with the control group (P < .01, P < .001, P < .001, and P < .001, respectively). The highest plasma NPY concentrations were observed in obese women with NIDDM. Plasma galanin levels were significantly higher in groups B, C, and D (P < .001, P < .001, and P < .001, respectively). Plasma leptin concentrations were significantly higher in groups C and D as compared with the control group (P < .001 and P < .001, respectively). Plasma NPY and galanin concentrations in women with anorexia nervosa did not differ from the levels in the control group. However, plasma leptin concentrations were significantly lower in anorectic women than in the control group (P < .01). Our results indicate that inappropriate plasma concentrations of NPY, galanin, and leptin in obese women may be a consequence of their weight status, or could be one of many factors involved in the pathogenesis of obesity.

Topics: Adolescent; Adult; Anorexia Nervosa; Body Mass Index; Body Weight; Diabetes Mellitus, Type 2; Female; Galanin; Humans; Leptin; Neuropeptide Y; Obesity; Proteins; Radioimmunoassay

Disruption of neural signaling by microinjection of a neurotoxin, colchicine (COL), in the ventromedial hypothalamus (VMH) of rats results in rapid and transient hyperphagia and body weight gain. Since neuropeptide Y (NPY) is a potent hypothalamic orexigenic signal and continuous NPY receptor activation by intracerebroventricular (icv) NPY infusion results in hyperphagia and obesity, we tested the hypothesis that altered NPYergic signaling may underlie the transient hyperphagia in COL-injected rats. Immediately following COL (4 microg) microinjections in the ventromedial nucleus (VMN) rats displayed hyperphagia both during the lights-on and lights-off periods. Concomitant with hyperphagia, preproNPY mRNA levels in the arcuate nucleus and NPY levels in the paraventricular nucleus decreased in a time-dependent manner. However, food intake in response to intracerebroventricular injections of NPY (29, 117 and 470 pmole) was significantly higher in COL-injected rats and the latency to initiation of feeding was markedly reduced as compared to controls. The smallest dose of NPY which was virtually ineffective in control rats, evoked near maximal intake in COL-injected rats. This enhanced response lasted for only 4 days paralleling the transient hyperphagia. The NPY Y1 receptor antagonist 1229U91 (5 or 30 microg/rat, icv) significantly suppressed feeding in COL-treated rats thereby indicating that hyperphagia in these rats was dependent upon endogenous NPY. Overall, these studies demonstrate that not only high levels, but low levels of NPY may also result in hyperphagia and increased body weight and this hyperphagia may be attributed to the rapid development of NPY Y1 receptor hypersensitivity.

Topics: Animals; Appetite Stimulants; Behavior, Animal; Binding, Competitive; Colchicine; Darkness; Dose-Response Relationship, Drug; Eating; Hyperphagia; Hypothalamus; Injections, Intraventricular; Light; Male; Neuropeptide Y; Obesity; Peptides, Cyclic; Rats; Rats, Sprague-Dawley; Receptors, Neuropeptide Y; RNA, Messenger; Signal Transduction; Ventromedial Hypothalamic Nucleus; Weight Gain

NPY has been reported to co-exist within catecholaminergic neurons of the central and peripheral nervous systems. The functional significance in noradrenergic neurons has been related to the vasomotor effects of NPY which complement and interact with NE which is known to have central and peripheral effects on resting metabolic rate (RMR), food intake and body weight of rats. We have studied the effect of chronic peripheral administration of NPY on the metabolic action of NE in obese adult male rats. A group of 20 adult male obese (fa/fa) Zucker rats were acclimated to environmental temperature of either 28 degrees C or 17 degrees C. Each group was divided into 5 subgroups: (I) untreated controls; (II) Carrier-treated Controls; (III) NPY treated; (IV) NE treated and (V) NPY + NE treated. In subgroups II-V, Alzet (2002) osmotic minipumps were implanted under the skin in the interscapular region. Pumps were filled with carrier alone (subgroups II) plus NPY (subgroups III), or NE (subgroups IV), or both (subgroups V). Delivery rates were calculated to be 0.5 microgram/h NPY; 20 micrograms/h NE, extending over a period of 14 days. Starting from day 2, cumulative food intake and cumulative changes in total body weight were measured every two days. RMR of the animals was measured on days 2, 8, and 14 (indirectly as minimal oxygen consumption). On day 15 animals were sacrificed and specimens of the interscapular BAT were fixed for microscopic examination and measurement of the cross-sectional area of the triglyceride droplets as index for tissue activity. In warm environmental conditions the combined treatment with NE and NPY was the only treatment that caused significant reduction of total body weight by inhibiting food intake and enhancing RMR. The involvement of BAT in this function was observed. In the cold environment the NE and NPY together showed similar but less enhancing effect on body weight; this was mainly due to the significant depression of food intake and slight metabolic response. BAT of this group showed significant response to the combined treatment and slight response to the separate treatments with either NE or NPY.

Topics: Adipose Tissue, Brown; Animals; Basal Metabolism; Eating; Infusion Pumps, Implantable; Male; Neuropeptide Y; Norepinephrine; Obesity; Oxygen Consumption; Rats; Rats, Zucker; Temperature; Weight Loss

The effects of altered gravity on body mass, food intake, energy expenditure, and body composition are examined. Metabolic adjustments are reviewed in maintenance of energy balance, neural regulation, and humoral regulation are discussed. Experiments with rats indicate that genetically obese rats respond differently to hypergravity than lean rats.

Topics: Adaptation, Physiological; Adipose Tissue; Animals; Appetite Stimulants; Autonomic Nervous System; Body Mass Index; Energy Intake; Energy Metabolism; Humans; Hypergravity; Leptin; Neuropeptide Y; Obesity; Paraventricular Hypothalamic Nucleus; Proteins; Rats; Rats, Zucker; Space Flight; Weightlessness

Topics: Adipocytes; Gene Expression; Humans; Hypothalamus; Leptin; Neuropeptide Y; Obesity; Proteins; RNA, Messenger

Correction of the obese state induced by genetic leptin deficiency reduces elevated levels of both blood glucose and hypothalamic neuropeptide Y (NPY) mRNA in ob/ob mice. To determine whether these responses are due to a specific action of leptin or to the reversal of the obese state, we investigated the specificity of the effect of systemic leptin administration to ob/ob mice (n = 8) on levels of plasma glucose and insulin and on hypothalamic expression of NPY mRNA. Saline-treated controls were either fed ad libitum (n = 8) or pair-fed to the intake of the leptin-treated group (n = 8) to control for changes of food intake induced by leptin. The specificity of the effect of leptin was further assessed by 1) measuring NPY gene expression in db/db mice (n = 6) that are resistant to leptin, 2) measuring NPY gene expression in brain areas outside the hypothalamus, and 3) measuring the effect of leptin administration on hypothalamic expression of corticotropin-releasing hormone (CRH) mRNA. Five daily intraperitoneal injections of recombinant mouse leptin (150 micrograms) in ob/ob mice lowered food intake by 56% (P < 0.05), body weight by 4.1% (P < 0.05), and levels of NPY mRNA in the hypothalamic arcuate nucleus by 42.3% (P < 0.05) as compared with saline-treated controls. Pair-feeding of ob/ob mice to the intake of leptin-treated animals produced equivalent weight loss, but did not alter expression of NPY mRNA in the arcuate nucleus. Leptin administration was also without effect on food intake, body weight, or NPY mRNA levels in the arcuate nucleus of db/db mice. In ob/ob mice, leptin did not alter NPY mRNA levels in cerebral cortex or hippocampus or the expression of CRH mRNA in the hypothalamic paraventricular nucleus (PVN). Leptin administration to ob/ob mice also markedly reduced serum glucose (8.3 +/- 1.2 vs. 24.5 +/- 3.8 mmol/l; P < 0.01) and insulin levels (7,263 +/- 1,309 vs. 3,150 +/- 780 pmol/l), but was ineffective in db/db mice. Pair-fed mice experienced reductions of glucose and insulin levels that were < 60% of the reduction induced by leptin. The results suggest that in ob/ob mice, systemic administration of leptin inhibits NPY gene overexpression through a specific action in the arcuate nucleus and exerts a hypoglycemic action that is partly independent of its weight-reducing effects. Furthermore, both effects occur before reversal of the obesity syndrome. Defective leptin signaling due to either leptin deficiency (in ob/ob mice) or leptin res

Topics: Animals; Arcuate Nucleus of Hypothalamus; Blood Glucose; Cerebral Cortex; Corticotropin-Releasing Hormone; Cricetinae; Gene Expression; Hippocampus; Hypothalamus; In Situ Hybridization; Insulin; Insulin Secretion; Kidney; Leptin; Mice; Mice, Inbred C57BL; Mice, Obese; Neuropeptide Y; Obesity; Proteins; Recombinant Proteins; RNA, Messenger; Transfection

Several studies suggest neuroendocrine abnormalities in, particularly, abdominal, central obesity in humans, a condition with high morbidity and mortality. Therefore the concentrations of neuropeptides and catecholamines in cerebrospinal fluid (CSF) were analysed in 48 obese women, subdivided into groups with central, abdominal and gluteo-femoral distribution of body fat, utilising the waist-to-hip circumference ratio (WHR) for division.. In comparisons with non-obese control women concentration of 5-hydroxyindol acetic acid (5-HIAA), methoxyhydroxyphenylglycol (MHPG), corticotropin releasing hormone (CRH), beta-endorphins (END) and neuropeptide Y (NPY) were lower, while homovanillic acid (HVA) was not different in obese women, HIAA, HVA and END correlated negatively with the WHR only in abdominally obese women, suggesting a threshold effect. HIAA vs HVA as well as CRF vs END correlated strongly in the total and both subgroups. An interrelationship between all these four substances was found in abdominal but not in gluteo-femoral obesity, suggesting a tighter functional coupling in the former group. Several correlations were found between CSF substance levels and appetite registrations, including END vs voracious eating, and for carbohydrate craving vs HIAA and vs HVA (negatively). This was also found only in abdominally obese women.. Although the concentrations of monoamine metabolites and neuropeptides in the CSF sampled at the level of the lumber spine might not be representative for those at regulatory centers in the brain, the findings suggest that low 5-HIAA is characteristic of human obesity, and coupled to CRH as well as eating abnormalities, particularly in abdominal obesity. Since CRH is regulating the balance between the autonomic nervous systems, insulin secretion and thermogenesis in animals, corresponding anomalies in abdominal obesity in humans may have a central origin.

Topics: Adipose Tissue; Adult; beta-Endorphin; Biogenic Monoamines; Body Composition; Body Constitution; Body Mass Index; Corticotropin-Releasing Hormone; Female; Homovanillic Acid; Humans; Hydroxyindoleacetic Acid; Methoxyhydroxyphenylglycol; Middle Aged; Neuropeptide Y; Obesity

Topics: Adipocytes; Animals; Carrier Proteins; Humans; Leptin; Mice; Mice, Obese; Neuropeptide Y; Obesity; Proteins; Receptors, Cell Surface; Receptors, Cytokine; Receptors, Leptin; RNA, Messenger

Topics: Animals; Drug Implants; Feeding Behavior; Humans; Leptin; Mice; Mice, Inbred C57BL; Neuropeptide Y; Obesity; Proteins

Topics: Animals; Body Weight; Feeding Behavior; Leptin; Neuropeptide Y; Obesity; Proteins; Receptors, Neuropeptide Y

Evidence suggests that serotonin and neuropeptide Y neurons in the hypothalamus, which respectively inhibit and stimulate food intake, may interact to control energy homoeostasis. We therefore investigated the effects of fluoxetine, which inhibits serotonin reuptake, on food intake and the activity of the neuropeptide Yergic arcuato-paraventricular projection in lean Wistar and Zucker rats. We also studied its effects in obese Zucker rats, in which obesity is postulated to be due to overactivity of the arcuato-paraventricular projection. Fluoxetine significantly reduced food intake in lean and obese rats, both during continuous subcutaneous infusion and (10 mg/kg/day for seven days) and acutely after a single injection (10 mg/kg). Fluoxetine also significantly reduced neuropeptide Y levels in the paraventricular nucleus, a major site of neuropeptide Y release which is highly sensitive to the appetite-stimulating actions of neuropeptide Y. Push-pull sampling in lean and fatty Zucker rats showed that neuropeptide Y secretion in the paraventricular nucleus was significantly reduced after acute fluoxetine treatment. Furthermore, seven days fluoxetine treatment prevented the significant increases in hypothalamic neuropeptide Y messenger RNA which were induced in lean rats by food restriction which precisely matched the hypophagia induced by the drug. We conclude that fluoxetine inhibits various aspects of the activity of the neuropeptide Yergic arcuato-paraventricular neurons, and suggest that reduced neuropeptide Y release in the paraventricular nucleus may mediate, at least in part, the drug's hypophagic action. We further suggest that serotonin may influence food intake and energy balance by inhibiting the arcuato-paraventricular projection, and that the two neurotransmitters may act together to regulate feeding and energy homoeostasis.

Topics: Animals; Arcuate Nucleus of Hypothalamus; Autoradiography; Blood Glucose; Body Weight; Eating; Fluoxetine; Hormones; Hypothalamus; Male; Neural Pathways; Neurons; Neuropeptide Y; Obesity; Paraventricular Hypothalamic Nucleus; Rats; Rats, Wistar; Rats, Zucker; RNA, Messenger; Selective Serotonin Reuptake Inhibitors

A single intracerebroventricular injection of dexamethasone (DEX) rapidly (within 30 min) suppresses brown adipose tissue thermogenesis and increases plasma insulin concentrations in adrenal-ectomized (ADX) ob/ob mice but not in ADX lean mice. Intracerebroventricular neuropeptide Y (NPY) administered intracerebroventricularly causes these same metabolic changes within 30 min in both ob/ob and lean ADX mice. We therefore hypothesized that DEX exerts these rapid-onset metabolic actions in ob/ob mice via a phenotype-specific enhancement of NPY secretion within the central nervous system. In support of this hypothesis, DEX (a type II glucocorticoid receptor agonist) administered intracerebroventricularly selectively lowered NPY concentrations in the whole hypothalamus of ADX ob/ob mice by 35% and in the arcuate nucleus region by approximately 70% within 30 min but not in the brain stem or hippocampus or in any of these regions of lean mice. DEX also functioned in vitro to enhance depolarization-dependent release of NPY from hypothalamic blocks of ADX ob/ob mice but not of ADX lean mice. Thus DEX acts in the hypothalamus of ob/ob mice in a phenotype-specific manner to evoke rapid transport of NPY from cell bodies within the arcuate nucleus to terminal regions including the dorsomedial and ventromedial hypothalamic regions for release.

Topics: Adrenal Glands; Adrenalectomy; Aldosterone; Animals; Arcuate Nucleus of Hypothalamus; Corticotropin-Releasing Hormone; Dexamethasone; Electrophysiology; Hypothalamus; Injections, Intraventricular; Male; Mice; Mice, Obese; Neuropeptide Y; Obesity; Osmolar Concentration; Potassium Chloride; Receptors, Corticotropin-Releasing Hormone; Reference Values

Elevated hypothalamic neuropeptide Y (NPY) expression is found in several rodent genetic models of obesity, but any association in nongenetic models of obesity is unclear. Consequently, we have measured NPY mRNA levels in the ventromedial hypothalamus of a well-characterized model of obesity, the gold thioglucose (GTG)-injected mouse. Fourteen days after injection (early stage), animals were hyperphagic but not obese, hyperglycemic, or overtly hyperinsulinemic. Ten weeks after treatment (late stage), animals were obese, markedly hyperinsulinemic, and hyperglycemic. In both the early and late stages, NPY mRNA levels were reduced in the arcuate nucleus of GTG-injected animals. Although overnight fasting doubled NPY mRNA levels in control animals, there was no change at either stage in GTG-injected animals. NPY mRNA levels in the deep layers of the cerebral cortex and in the dentate gyrus were not affected by GTG treatment or overnight fasting. We conclude that GTG treatment reduces the expression of NPY mRNA in the arcuate nucleus and that, therefore, increased hypothalamic NPY expression is unlikely to be an important factor causing the obesity and other metabolic changes found in this model.

Topics: Animals; Arcuate Nucleus of Hypothalamus; Aurothioglucose; Hyperglycemia; Hyperinsulinism; Hyperphagia; In Situ Hybridization; Male; Mice; Mice, Inbred CBA; Neuropeptide Y; Obesity; RNA, Messenger; Ventromedial Hypothalamic Nucleus

The effect of different doses of leptin, given as an intracerebroventricular (ICV) bolus, on body weight gain and food intake was investigated during refeeding, following a 24-h fast in lean (FA/fa) rats. It was observed that ICV leptin resulted in a dose-dependent decrease in body weight gain, compared with vehicle injection, a difference that persisted for at least 6 days. This was associated with a transient reduction in food intake over the first 2 days after leptin injection. More importantly, the effect of leptin was also observed in genetically obese fa/fa rats but at the expense of two to ten times higher leptin concentrations, indicating the presence of decreased leptin sensitivity. Furthermore, ICV leptin injections were able to decrease neuropeptide Y (NPY) levels in the arcuate and paraventricular hypothalamic nuclei in both lean and genetically obese fa/fa rats, although a higher leptin dose was again needed in the obese group. These observations provide further evidence for the implication of NPY and leptin in a regulatory loop controlling body homeostasis. This loop is functional in lean and genetically obese fa/fa rats, provided that leptin levels in the central nervous system are high enough in the obese group, in particular. Since human obesity is frequently associated with elevated circulating leptin levels, a state of decreased leptin sensitivity (i.e., leptin resistance), similar to that described here in fa/fa rats, could possibly occur in human syndromes as well.

Topics: Animals; Appetite; Body Weight; Cerebral Ventricles; Dose-Response Relationship, Drug; Eating; Fasting; Humans; Hypothalamus; Injections, Intraventricular; Leptin; Male; Neuropeptide Y; Obesity; Proteins; Rats; Rats, Mutant Strains; Thinness; Time Factors

Topics: Amyloid; Colipases; Diabetes Mellitus, Type 2; Diet; Disease Models, Animal; Enzyme Precursors; Humans; Islet Amyloid Polypeptide; Leptin; Neuropeptide Y; Neurotransmitter Agents; Obesity; Protein Precursors; Proteins; Serotonin; Tryptophan

We determined the changes in neuropeptide Y (NPY) mRNA expression of the arcuate nucleus (ARC) in sham-operated (SHAM) and bilaterally ovariectomized (OVX) rats with estradiol (E2) supplement. Ovariectomy increases body weight gain for 3 weeks, accompanied by an increase of daily food intake. Ovariectomy significantly reduced serum corticosterone levels. E2 supplement reversed the effects of ovariectomy on body weight gain, food intake and serum corticosterone levels. Ovariectomy significantly increased NPY mRNA expression in the ARC. E2 supplement decreased NPY mRNA expression in the ARC of OVX rats. The present findings indicated that hypothalamic NPY mRNA expression, which involves the regulation of feeding behavior, are in parallel with circulating estrogen levels. Hypothalamic NPY mRNA expression may be important in the induction of hyperphagia after the withdrawal of estrogen by bilateral ovariectomy.

Topics: Animals; Arcuate Nucleus of Hypothalamus; Base Sequence; DNA Primers; Estradiol; Female; Hyperphagia; Hypothalamus; Molecular Sequence Data; Neuropeptide Y; Obesity; Ovariectomy; Rats; Rats, Wistar; RNA, Messenger; Stimulation, Chemical

Topics: Eating; Humans; Interleukin-1; Leptin; Neuropeptide Y; Obesity; Proteins

The obesity syndrome of ob/ob mice results from lack of leptin, a hormone released by fat cells that acts in the brain to suppress feeding and stimulate metabolism. Neuropeptide Y (NPY) is a neuromodulator implicated in the control of energy balance and is overproduced in the hypothalamus of ob/ob mice. To determine the role of NPY in the response to leptin deficiency, ob/ob mice deficient for NPY were generated. In the absence of NPY, ob/ob mice are less obese because of reduced food intake and increased energy expenditure, and are less severely affected by diabetes, sterility, and somatotropic defects. These results suggest that NPY is a central effector of leptin deficiency.

Topics: Adipose Tissue; Animals; Blood Glucose; Body Composition; Body Height; Body Weight; Diabetes Mellitus; Diabetes Mellitus, Type 2; Eating; Energy Metabolism; Female; Fertility; Insulin-Like Growth Factor I; Leptin; Male; Mice; Mice, Mutant Strains; Mice, Obese; Neuropeptide Y; Obesity; Oxygen Consumption; Proteins; RNA, Messenger

Recently Zhang et al. cloned a gene that is expressed only in adipose tissue of the mouse. The obese phenotype of the ob/ob mouse is linked to a mutation in the obese gene that results in expression of a truncated inactive protein. Human and rat homologues for this gene are known. Previous experiments predict such a hormone to have a hypothalamic target. Hypothalamic neuropeptide Y stimulates food intake, decreases thermogenesis, and increases plasma insulin and corticosterone levels making it a potential target. Here we express the obese protein in Escherichia coli and find that it suppresses food intake and decreases body weight dramatically when administered to normal and ob/ob mice but not db/db (diabetic) mice, which are thought to lack the appropriate receptor. High-affinity binding was detected in the rat hypothalamus. One mechanism by which this protein regulated food intake and metabolism was inhibition of neuropeptide-Y synthesis and release.

Topics: Animals; Body Weight; Cell Membrane; Diabetes Mellitus, Experimental; Eating; Escherichia coli; Humans; Hypothalamus; In Vitro Techniques; Leptin; Mice; Neuropeptide Y; Obesity; Proteins; Rats; Recombinant Proteins

Neuropeptide Y administered intracerebroventricularly and into the paraventricular nucleus of the hypothalamus stimulates feeding and decreases brown adipose tissue thermogenesis. Although specific neuropeptide Y antagonists are not yet available, previous studies had shown that the opioid antagonist naloxone blocked neuropeptide Y-induced feeding when both drugs were injected intracerebroventricularly. We wanted to find out if naloxone injected into specific brain sites would block neuropeptide Y effects on feeding and brown fat thermogenesis. Rats were double injected in specific brain sites with neuropeptide Y and either naloxone or naltrexone (a congener of naloxone). Food intake and brown fat measures were assessed. Naloxone or naltrexone in the paraventricular nucleus weakly decreased paraventricular nucleus neuropeptide Y-induced feeding and did not affect neuropeptide Y-induced reductions in brown fat activity. Peripheral naloxone blocked intracerebroventricular neuropeptide Y-induced feeding and brown fat alterations. Fourth ventricular naloxone decreased paraventricular nucleus neuropeptide Y-induced feeding, and naltrexone given into the nucleus of the solitary tract blocked paraventricular nucleus neuropeptide Y-induced alterations in feeding and brown fat. These data indicate that neuropeptide Y in the paraventricular nucleus may act on feeding and brown fat thermogenesis through opioidergic pathways in the nucleus of the solitary tract.

Topics: Adipose Tissue, Brown; Animals; Brain; Energy Metabolism; Feeding Behavior; Male; Naloxone; Naltrexone; Neuropeptide Y; Obesity; Paraventricular Hypothalamic Nucleus; Rats; Rats, Sprague-Dawley; Solitary Nucleus

Numerous hypothalamic peptides are involved in the control of eating behaviour. We assessed plasma and cerebrospinal fluid (CSF) levels of SRIH, beta-endorphin (beta-EP), CRH, NPY and GHRH in a group of massively obese patients and in normal weight subjects. In the obese patients, CSF SRIH and beta-EP levels were significantly reduced and increased, respectively, compared with controls (20.6 +/- 2.62, mean +/- s.e.m., vs 34.5 +/- 2.14 pg/ml, P < 0.05, for SRIH and 111.2 +/- 5.00 vs 80.4 +/- 5.32 pg/ml, P < 0.001, for beta-EP). Considering the data of obese and control subjects altogether, SRIH and beta-EP concentrations correlated negatively and positively, respectively, with BMI values (r = -0.641, P < 0.005 and r = 0.518, P < 0.05). No significant differences were observed in CSF levels of CRH, NPY and GHRH between obese and normal weight subjects, though GHRH levels were close to the assay sensitivity. CSF concentrations of CRH were positively correlated with those of SRIH in obese patients (r = 0.60, P < 0.05) and with those of NPY both in obese (r = 0.69, P < 0.02) and in control subjects (r = 0.83, P < 0.005). Plasma levels of SRIH, beta-EP, NPY and GHRH did not differ significantly in the two groups of subjects; plasma CRH was undetectable. Our results argue against the hypothesis of an enhanced SRIH tone as the cause of impaired GH secretion in obese patients, a primary defect in GHRH or GH release seems more likely. Moreover, they emphasise the importance of an increased tone of endogenous opioids in the pathophysiology of human obesity.

Topics: Adult; Aged; beta-Endorphin; Corticotropin-Releasing Hormone; Female; Gonadotropin-Releasing Hormone; Humans; Middle Aged; Neuropeptide Y; Obesity; Reference Values; Somatostatin

The hypothalamic neuropeptide Y content and preproneuropeptide Y mRNA expression were studied in metformin-treated (300 mg/kg orally for 12 days), in pair-fed and in ad libitum-fed obese Zucker rats in order to elucidate possible mechanisms involved in the anorectic and body weight reducing effect of chronic metformin treatment in genetically obese Zucker rats. In addition the acute influence of metformin on food intake was studied by comparing its effects after oral and parenteral administration. The concentration of neuropeptide Y in the hypothalamic paraventricular nucleus was significantly higher in the metformin-treated and pair-fed rats when compared to the control animals. The expression of preproneuropeptide Y mRNA in the arcuate nucleus was similar in all three treatment groups. Both chronic metformin treatment and pair-feeding markedly lowered hyperinsulinaemia in these animals. A single subcutaneous dose of metformin (300 mg/kg) reduced food intake only in obese animals, while the same dose of metformin given orally did not affect food intake in either lean or obese animals. It is concluded that the treatment with metformin and pair-feeding, which results in comparable reductions in food intake, body weight gain and hyperinsulinaemia, similarly increase neuropeptide Y concentrations in the paraventricular nucleus while not affecting preproneuropeptide Y mRNA expression in the arcuate nucleus. The increase in hypothalamic neuropeptide Y content may be secondary to the reduction in hyperinsulinaemia during metformin treatment and pair-feeding. Thus, the anorectic effect of chronic metformin treatment cannot be explained by changes in content or expression of hypothalamic neuropeptide Y.

Topics: Administration, Oral; Animals; Appetite Depressants; Blood Glucose; Body Weight; Drinking; Eating; Hypothalamus; Injections, Subcutaneous; Insulin; Male; Metformin; Neuropeptide Y; Obesity; Rats; Rats, Zucker; RNA, Messenger

NPY is synthesized in the hypothalamic arcuate nucleus (ARC), and NPY injected into the paraventricular nucleus (PVN), the main site of NPY release, induces hyperphagia and reduces energy expenditure. Hypothalamic NPY mRNA and NPY levels are increased in fatty Zucker rats, consistent with increased NPY release. This could explain the hyperphagia and reduced energy expenditure, which lead to obesity in the fatty Zucker rat. We have therefore compared NPY secretion in the PVN of conscious fatty and lean Zucker rats using push-pull sampling. The NPY secretory profile was consistently higher in fatty Zucker rats than in lean rats throughout the 3-h study period (P < 0.01), and mean NPY secretion over the whole 3 h was increased 2-fold in the fatty rats (P < 0.001). We conclude that fatty Zucker rats have increased NPY release in the PVN. This observation further supports the hypothesis that increased activity of the NPYergic ARC-PVN pathway may contribute to obesity in the fatty Zucker syndrome.

Topics: Animals; Body Weight; Eating; Male; Neuropeptide Y; Obesity; Paraventricular Hypothalamic Nucleus; Rats; Rats, Zucker; Reference Values

Acute central administration of galanin has been reported to increase fat consumption. These experiments were designed to test the hypothesis that repeated injections of galanin would elicit hyperphagia and weight gain and that this response would depend on the available diet. Male Sprague-Dawley rats were fed high (56% energy) or low (10% energy) fat diets. Galanin (300 pmol) or saline vehicle was injected into the third ventricle twice daily for 7 days and three times daily for another 6 days. On both the high-carbohydrate and high-fat diets, twice daily galanin increased daytime food intake, but there was a compensatory decrease in nighttime intake. The addition of a third, nighttime injection of galanin was ineffective in producing an increase in total 24-h intake. There was no significant increase in body weight during galanin treatment in rats eating either diet although animals eating the high-fat diet gained more weight as reflected by a significant increase in epididymal fat pad weight. Galanin treatment had no effects on serum insulin, glucose or corticosterone concentrations, measured at the end of the experiment. However, animals fed the high-fat diet had significantly higher insulin concentrations at the time of sacrifice. Although repeated central infusions of galanin reliably stimulated daytime intake of both diets, they failed to increase total daily energy intake or body weight.

Topics: Animals; Blood Glucose; Body Weight; Corticosterone; Dietary Carbohydrates; Dietary Fats; Eating; Galanin; Hyperphagia; Injections, Intraventricular; Insulin; Male; Neuropeptide Y; Obesity; Peptides; Rats; Rats, Sprague-Dawley

A central dysregulation of several neuropeptides could be at the origin of the marked hyperphagia of the obese Zucker rat, a well-known animal model used for the study of obesity. Neuropeptide Y (NPY), which strongly stimulates food intake and increases early in life in obese rats, plays a major role in the development of this hyperphagia. The aim of our experiment was to measure the feeding responses of lean (n = 8) and obese (n = 17) male Zucker rats to several doses of exogenous NPY injected in the lateral brain ventricle. We analyzed the microstructure of the rats' feeding behavior with an automatic device for 8 h post-injection. NPY stimulated food intake both in the lean and obese rats in a dose-dependent manner (P < 0.001). However, the minimal effective dose was always 3-4 times greater in the obese rats than in the lean ones (range: 0.43-0.53 vs. 0.12-0.18 microgram/brain; P < 0.001). Meal size, meal duration and time spent eating significantly increased in the lean rats (P < 0.05 or less). The last two parameters also increased in the obese rats but with the highest dose (5 micrograms) only. The obese Zucker rats were therefore less sensitive to NPY than the lean ones, probably because of their already high endogenous NPY levels. The modifications in the eating behavior indicate that NPY could overcome the satiety signals.

Topics: Animals; Differential Threshold; Dose-Response Relationship, Drug; Eating; Feeding Behavior; Male; Neuropeptide Y; Obesity; Osmolar Concentration; Rats; Rats, Zucker; Reference Values

1. The effects of chronic treatments with a selective beta 3-adrenoceptor agonist and a selective alpha 2-adrenoceptor antagonist and their interactions with physical exercise training were studied in experimental obesity. 2. BRL 35135 (beta 3-agonist, 0.5 mg kg-1 day-1 p.o.), atipamezole (alpha 2-antagonist, 4.0 mg kg-1 day-1 p.o.) and placebo were given to genetically obese male Zucker rats. Half of the rats were kept sedentary whereas the other half were subjected to moderate treadmill exercise training. Body weight gain, cumulative food intake, the neuropeptide Y content of the hypothalamic paraventricular nucleus, brown adipose tissue thermogenic activity (measured as GDP binding), plasma insulin and glucose levels were measured after 3 weeks' treatment and exercise. 3. Treatment with BRL 35135 reduced weight gain by 19%, increased brown adipose tissue thermogenic activity 45-fold and reduced plasma insulin by 50%. Atipamezole slightly increased food intake and neuropeptide Y content in the paraventricular hypothalamic nucleus but had no effect on the other measured parameters. Exercise alone had no effect on weight gain, food intake or thermogenic activity, whereas it reduced plasma insulin and glucose levels. 4. The effect of BRL 35135 on weight gain and thermogenic activity was significantly potentiated by exercise; the reduction in weight gain was 56% in comparison with 19% in sedentary animals. Food intake was significantly reduced in the BRL 35135-treated-exercise-trained animals, although neither beta 3-agonist nor exercise alone affected it. 5. Based on the present results in genetically obese Zucker rats, combination of 03-agonist treatment with a moderate physical training may offer a new feasible approach to the therapy of obesity.-. BRL 35135; atipamezole; P3-adrenoceptor agonism; M2-adrenoceptor antagonism; brown adipose tissue; thermogenesis;genetic obesity; Zucker rat; exercise; neuropeptide Y

Topics: Adipose Tissue; Adipose Tissue, Brown; Adrenergic alpha-Agonists; Adrenergic beta-Agonists; Animals; Blood Glucose; Body Temperature Regulation; Feeding Behavior; Guanosine Diphosphate; Imidazoles; Insulin; Male; Neuropeptide Y; Obesity; Paraventricular Hypothalamic Nucleus; Phenethylamines; Physical Conditioning, Animal; Rats; Rats, Zucker; Weight Gain

Adult genetically obese (ob/ob) mice display a number of metabolic alterations, the primary cause of which may be a defect in their central nervous system (CNS). The protein encoded by the protooncogene c-fos, c-Fos, functions as a nuclear transcription factor, and also serves as a marker of neuronal activity. The specific objectives of this study were (1) to use c-Fos immunohistochemistry to identify regions with altered neuronal activity in 6-7 week old male lean and ob/ob mice; (2) to examine c-fos relative mRNA abundance by northern blot analysis in brains of these mice and compare it with that of neuropeptide Y (NPY), a peptide well known to alter feeding and (3) determine changes in c-Fos immunoreactivity and mRNA caused by food deprivation. Fos-like immunoreactivity (FLI) tended to be higher in ad libitum fed ob/ob mice than in lean controls in most brain regions examined. The most prominent and consistent differences were in the paraventricular nuclei (PVN) where the numbers of Fos-positive nuclei were approximately 3 fold higher in ob/ob mice. Food deprivation for 24 h increased FLI in the PVN in lean mice but did not further augment FLI in the PVN of ob/ob mice. Arcuate nuclei of lean and ob/ob mice showed minimal FLI staining under ad libitum fed conditions. Food deprivation however, induced FLI in arcuate nuclei of both lean and ob/ob mice. The abundance of c-fos mRNA in whole brain of ob/ob mice averaged several fold higher than in leans under both fed and fasted conditions.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Arcuate Nucleus of Hypothalamus; Blotting, Northern; Brain Chemistry; Food Deprivation; Gene Expression; Genes, fos; Immunohistochemistry; Male; Mice; Mice, Obese; Neurons; Neuropeptide Y; Obesity; Paraventricular Hypothalamic Nucleus; Phenotype; RNA, Messenger

Intracerebroventricular neuropeptide Y (NPY) administration to normal rats for 7 days produced a sustained, threefold increase in food intake, resulting in a body weight gain of more than 40 g. Basal plasma insulin and triglyceride levels were increased in NPY-treated compared to vehicle-infused rats by about four- and two-fold, respectively. The glucose utilization index of white adipose tissue, measured by the labelled 2-deoxy-D-glucose technique was four times higher in NPY-treated rats compared to controls. This change was accompanied by an increase in the insulin responsive glucose transporter protein (GLUT 4). In marked contrast, muscle glucose utilization was decreased in NPY-treated compared to vehicle-infused animals. This change was accompanied by an increase in triglyceride content. When NPY-treated rats were prevented from overeating, there was no decrease in muscle glucose uptake, nor was there an increase in muscle triglyceride content. This suggests that muscle insulin resistance of ad libitum-fed NPY-treated rats is due to a glucose-fatty acid (Randle) cycle. When intracerebroventricular NPY administration was stopped and rats kept without any treatment for 7 additional days, all the abnormalities brought about by the neuropeptide were normalized. A tonic central effect of NPY is therefore needed to elicit and maintain most of the hormonal and metabolic abnormalities observed in the present study. Such abnormalities are analogous to those seen in the dynamic phase of obesity syndromes in which high hypothalamic NPY levels have been reported.

Topics: Adipose Tissue; Animals; Blood Glucose; Cerebral Ventricles; Deoxyglucose; Feeding Behavior; Female; Glucose Clamp Technique; Infusions, Parenteral; Insulin; Muscle, Skeletal; Neuropeptide Y; Obesity; Rats; Rats, Zucker; Reference Values; Triglycerides; Weight Gain

A central dysregulation of several neuropeptides could be at the origin of the marked hyperphagia of the obese Zucker rat, a well-known animal model used for the study of obesity. Neuropeptide Y (NPY), which stimulates food intake and increases early in life in obese rats, plays a major role in the development of this hyperphagia. The aim of our experiment was to test a proposed NPY antagonist namely PYX-2 in obese hyperphagic Zucker rats in order to know if it could be an interesting drug for limiting their food intakes. Four doses of PYX-2 (50-1000 pmol) were injected in a counterbalanced order in the lateral brain ventricles of 10 adult male Zucker rats. Food intake was recorded 0.5, 1, 2, 3, 6, and 23 h after PYX-2 injection and compared either to the rat's spontaneous food intake or to the food intake following injection of artificial CSF (vehicle) only. It was not modified by any dose of PYX-2 whatever the time considered (1 h after injection: 4.3 +/- 0.5 (1000 pmol) vs 4.6 +/- 0.8 (CSF) g; 23 h period: 27.0 +/- 1.9 (1000 pmol) vs 26.6 +/- 2.9 (CSF) g; N.S.). Thus, PYX-2, the putative NPY antagonist, totally failed to inhibit food intake in the obese rats. The absence of effect of PYX-2 on food intake can be explained by the structure of PYX-2, a modified 27-36 amino acid sequence that may not be recognized by the Y1-type NPY receptors which are involved in the regulation of feeding behavior.

Topics: Amino Acid Sequence; Animals; Eating; Hyperphagia; Injections, Intraventricular; Male; Neuropeptide Y; Obesity; Peptide Fragments; Rats; Rats, Zucker

Neuropeptide Y (NPY) induces a robust feeding response when it is injected in the hypothalamus. It stimulates both carbohydrate and fat intakes. Diets rich in either macronutrient are known to induce obesity and to modify feeding behavior. The aim of the present study was to determine the effects of long-term ingestion of these diets on hypothalamic NPY in relation with food intake and body weight gain and composition. For this purpose, three groups of weanling Long-Evans rats were fed either a well-balanced diet, a high-carbohydrate (HC) diet (high starch plus 25% sucrose solution), or a high-fat (HF) diet during 14 weeks. Body weight and food intake were recorded during this period. At the end of the experiment, NPY was measured in several microdissected brain areas, and some adipose tissues (AT) depots were sampled. HF rats weighed significantly more than the two other groups (p < 0.02). They were also fattier (+ 30-50% in AT weights; p < 0.01). Energy intake (EI) of the HC rats was significantly greater than that of the control (+ 15%; p < 0.02) and HF rats (+ 34%; p < 0.01) during the week preceding killing. EI of HF rats over the whole experiment was lower than that of the two groups (p < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Dietary Carbohydrates; Dietary Fats; Feeding Behavior; Hypothalamus; Male; Neuropeptide Y; Obesity; Rats

The obese hyperglycaemic ob/ob mouse exhibits hyperphagia and other abnormalities of hypothalamic function. We measured hypothalamic concentrations of four peptides implicated in the control of appetite and energy expenditure, neuropeptide-Y (NPY), neurotensin, galanin, and somatostatin, by RIA and their respective mRNAs using semiquantitative Northern blotting. Using lean (+/+) mice as controls, we found unchanged concentrations of NPY, galanin, and somatostatin and a 25% reduction in neurotensin (P < 0.01). Neurotensin mRNA was similarly decreased (by 30%; P < 0.02), while NPY mRNA was increased 3-fold (P < 0.01). Centrally administered neurotensin decreases food intake, whereas NPY potently stimulates food intake. An increase in NPY gene expression together with reductions in neurotensin concentration and mRNA in the hypothalamus may be implicated in the development of hyperphagia and other neuroendocrine abnormalities seen in the ob/ob mouse.

Topics: Animals; Blotting, Northern; Chromatography, High Pressure Liquid; Galanin; Hypothalamus; Male; Mice; Mice, Obese; Neuropeptide Y; Neurotensin; Obesity; Peptides; RNA, Messenger; Somatostatin

We have investigated, by Northern blot analysis, the hypothalamic gene expression [messenger RNA (mRNA)] of two appetite stimulating neuropeptides, neuropeptide Y (NPY) and galanin (GAL) in lean (+/+) and genetically obese (fa/fa) Zucker rats at 11, 24 and 40 weeks of age and their responsiveness to food deprivation. At 11 weeks of age, hypothalamic NPY mRNA levels of fa/fa rats were similar to those observed in lean littermates. However, NPY mRNA levels of fa/fa rats were significantly greater than those of lean rats at 24 (+126%; P < 0.01) and 40 (+65%; P < 0.05) weeks of age. Food deprivation caused a significant increase in NPY mRNA levels in both lean and fa/fa Zucker rats at 11 and 24 weeks of age, but not at 40 weeks old rats. Hypothalamic GAL mRNA showed a different pattern of change. The relative content of GAL mRNA in 11 week old obese rats was significantly lower (-68%; P < 0.05) than that of lean rats, while GAL mRNA was significantly higher in 40 week old (+57%; P < 0.05) obese rats compared to their lean littermates. At 24 weeks of age, hypothalamic GAL mRNA levels did not differ between lean and obese rats. Food deprivation induced no change in hypothalamic GAL mRNA in lean rats of all 3 ages; however, it caused an increase of GAL mRNA in obese rats at 11 (+60%; P < 0.05) and 24 (+44%; P < 0.05) weeks, but not at 40 weeks.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Aging; Animal Nutritional Physiological Phenomena; Animals; Blood Glucose; Body Weight; Food Deprivation; Galanin; Gene Expression; Hypothalamus; Insulin; Male; Neuropeptide Y; Neuropeptides; Obesity; Peptides; Rats; Rats, Zucker; Reference Values

Galanin (GAL), a 29 aminoacid peptide, is widely distributed in the central nervous system and especially in the hypothalamus. It strongly stimulates food intake when it is injected in the paraventricular nucleus (PVN) of normal rats. The obese Zucker rat with a well-established hyperphagia is characterized by a general dysregulation of some important neuropeptides involved in the regulation of feeding behavior e.g. neurotensin, NPY or CCK and the aim of this study was to measure GAL in different microdissected brain areas in lean (Fa/Fa) and obese (fa/fa) male Zucker rats. As feeding status may modulate the central peptide concentrations, it was measured in ad libitum fed rats and in 48-h fasted rats of both genotypes. GAL was measured by a specific radioimmunoassay in the arcuate nuclei (ARC) and parvocellular (PVNp) and magnocellular (PVNm) parts of the PVN as well as in the median eminence (ME), median preoptic area (MPOA), supraoptic (SON) and dorsomedian (DMN) nuclei. Two-way analysis of variance revealed a very significant effect of genotype in the PVNp (P < 0.001), SON (P < 0.001) and in the ME (P < 0.02). No significant variations at all were noted in the ARC, PVNm, MPOA and DMN. GAL concentrations were more than doubled in the PVNp and SON of ad lib obese rats when compared to the ad lib lean rats (P < 0.005). On the other hand, in the ME where GAL concentration was about 4-fold greater than in the other areas, there was a 20 to 30% decrease in GAL concentrations in the obese rat (P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Analysis of Variance; Animals; Arcuate Nucleus of Hypothalamus; Body Weight; Eating; Energy Intake; Fasting; Galanin; Genotype; Hypothalamus; Male; Neuropeptide Y; Neuropeptides; Obesity; Paraventricular Hypothalamic Nucleus; Peptides; Rats; Rats, Zucker

Topics: Animals; Female; Hypothalamus; Insulin; Insulin Secretion; Male; Mutation; Neuropeptide Y; Obesity; Protoporphyrins; Rats; Rats, Mutant Strains; RNA, Messenger

Neuropeptide Y (NPY) is a 36 amino-acid peptide. It is localized within the brain but is also present peripherally. It is a well substantiated orexigenic peptide with several other endocrine and behavioural effects. In this study NPY mRNA levels were measured, using the polymerase chain reaction amplification technique, in the hypothalamus of pre-obese (unweaned 13-day-old), young (weaned 28-day-old) and adult (11-week-old) obese fa/fa rats and compared to those of lean age-matched controls. Before weaning, pre-obese pups had the same NPY mRNA levels as controls. After weaning NPY mRNA levels were increased 2-fold in young 28-day-old and 4-fold in adult obese rats, relative to corresponding controls. When adult obese rats were intracerebroventricularly-treated with ovine corticotropin-releasing hormone (oCRF) for 7 days, they stopped gaining body weight relative to vehicle-infused obese controls. Upon measuring NPY mRNA levels in the hypothalamus of these two groups of animals, it was shown that the high NPY mRNA levels of vehicle-treated (control) obese rats were decreased by 3-fold following the intracerebroventricular oCRF administration. It is proposed that: 1) hypothalamic NPY may play a role in the establishment and maintenance of the genetic obesity syndrome of the fa/fa rat, and 2) maintenance of the genetic obesity syndrome of the fa/fa rat, and 2) hypothalamic NPY could be partly regulated by central CRF.

Topics: Adipose Tissue; Aging; Animals; Base Sequence; Brain; Corticosterone; Corticotropin-Releasing Hormone; Fatty Acids, Nonesterified; Hypothalamus; Lipoprotein Lipase; Male; Molecular Sequence Data; Neuropeptide Y; Obesity; Polymerase Chain Reaction; Rats; Rats, Mutant Strains; RNA, Messenger; Triglycerides; Weaning

Chronic intracerebroventricular (icv) administration of neuropeptide-Y (NPY; 10 micrograms/day) was performed in normal female rats to investigate its hormonal and metabolic consequences. Intracerebroventricular NPY produced hyperphagia, increased basal insulinemia, as well as liver and adipose tissue lipogenic activity. It also increased basal morning corticosteronemia. When NPY-induced hyperphagia was prevented by pair-feeding, the icv NPY treatment resulted in the same increases in basal insulinemia and corticosteronemia, and liver and white adipose tissue lipogenesis was still higher than that in respective controls. Under the ad libitum and pair-feeding conditions, icv NPY stimulated glucose uptake as well as total lipoprotein lipase activity in white adipose tissue; it resulted in an increase total activity of hepatic and white adipose tissue acetyl coenzyme-A-carboxylase. As all hormonal and metabolic changes elicited by icv NPY remained present (at the same or to a lesser extent depending upon the parameter considered) when hyperphagia was prevented by pair-feeding, it was, thus, shown that icv NPY per se induces peripheral hormonal and metabolic alterations via efferent routes, which remain to be determined. The effects of icv NPY reported in this study are similar to the defects observed in the early phase of genetic obesity in rodents, the hypothalamus of which has increased NPY levels. NPY could, thus, be of relevance in the occurrence of genetically induced obesity.

Topics: Adipose Tissue; Animals; Brain; Female; Glucose; Hormones; Injections, Intraventricular; Insulin; Lipid Metabolism; Liver; Neuropeptide Y; Obesity; Rats; Rats, Zucker; Reference Values; Time Factors

A single intracerebroventricular (icv) injection of dexamethasone (250 ng) lowers brown adipose tissue (BAT) thermogenesis and whole body metabolic rates and raises plasma insulin concentrations within 30 min in adrenalectomized ob/ob mice with minimal effects in adrenalectomized lean mice. The present study was conducted to determine if intracerebroventricular neuropeptide Y (NPY), a neuropeptide regulated in part by glucocorticoids, would mimic effects of dexamethasone in these mice. NPY lowered BAT metabolism and whole body oxygen consumption and raised plasma insulin concentrations within 30 min in adrenalectomized ob/ob mice similarly to dexamethasone; but, unlike dexamethasone, NPY was as effective in modulating these metabolic responses in adrenalectomized lean mice as in ob/ob mice. Further, intracerebroventricular NPY increased food intake equally in both ob/ob and lean mice, whereas dexamethasone did not alter food intake during the 30 min postinjection period. These data are consistent with the hypothesis that NPY mediates some of the effects of intracerebroventricular dexamethasone action in ob/ob mice and that the divergence between ob/ob and lean mice lies in glucocorticoid control of NPY release/synthesis rather than in NPY action mechanisms.

Topics: Adipose Tissue, Brown; Adrenalectomy; Animals; Dexamethasone; Eating; Energy Metabolism; Guanosine Diphosphate; Injections, Intraventricular; Insulin; Male; Mice; Mice, Inbred C57BL; Mitochondria; Neuropeptide Y; Obesity; Reference Values

Neuropeptide Y (NPY) mediates feeding behavior through a local hypothalamic network formed by the arcuate and paraventricular nuclei (the AP axis). In the hypothalamus, NPY is mainly synthesized in neurons of the arcuate nucleus. These neurons project to the paraventricular nucleus, the site where NPY has the strongest stimulatory effects on food intake of Sprague-Dawley rats. In the adult Zucker fatty rat (a genetic model of obesity with a well-established hyperphagia), NPY concentrations in these nuclei are higher than in its lean counterpart. We measured hypothalamic NPY before the appearance of altered eating behavior, e.g., in very young (16-d-old) lean and obese Zucker pups, and in pups at an age when overeating had begun, e.g., a few days after weaning at 30 d. At 30 d, NPY concentrations were significantly higher in obese than in lean rats in the arcuate nucleus (14.2 +/- 0.7 vs. 11.6 +/- 0.5 pmol/mg protein, P < 0.01). This difference was not observed at 16 d. A 160% increase was noted in the paraventricular nuclei of obese rats between 16 and 30 d of life compared with a 100% increase in the lean rats (P < 0.001). Neuropeptide Y concentration was greater in 30-d-old rats than in 16-d-old rats in other areas involved in the regulation of feeding behavior, such as the dorsomedian nuclei and lateral hypothalamus, but the values did not differ between genotypes. Higher NPY concentration was therefore detected early in young obese rats in the main hypothalamic site of NPY synthesis.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Aging; Animals; Arcuate Nucleus of Hypothalamus; Dorsomedial Hypothalamic Nucleus; Feeding Behavior; Hypothalamic Area, Lateral; Neuropeptide Y; Obesity; Paraventricular Hypothalamic Nucleus; Rats; Rats, Zucker

Neuropeptide Y (NPY), a member of the pancreatic polypeptide family, strongly stimulates food intake when injected centrally in animals. It is found in abundance in the brain and particularly in areas involved in the regulation of feeding behaviour. Moreover, in these areas, NPY concentrations are higher in the obese hyperphagic Zucker rat. The aim of the present experiment was to reproduce in normal Long-Evans rats the high central levels of NPY measured in Zucker rats. We therefore continuously infused NPY in the brain lateral ventricle through osmotic mini-pumps and studied the effects of this infusion on different parameters of the feeding behaviour. Male adult Long-Evans rats were fed ad libitum on a high carbohydrate (HC) diet and on a high fat (HF) diet given simultaneously in two separate cups. NPY was infused at a rate of 0.44 micrograms/h (n = 11) and rats infused with artificial cerebrospinal fluid (n = 11) served as controls. The infusions lasted 14 days. Total food intake markedly increased in NPY infused rats starting on the first day after pump installation (33.7 +/- 1.7 vs. 14.8 +/- 0.6 g/day; P less than 0.0001). This effect lasted for nine days. In these rats, the average food intake during the infusion period (21.0 +/- 1.6 g/day) was also significantly greater than during the pre-infusion period (13.1 +/- 0.5 g/day; P less than 0.0001) and the post-infusion period (10.6 +/- 0.4 g/day; P less than 0.0001).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Circadian Rhythm; Eating; Food Preferences; Infusion Pumps, Implantable; Male; Neuropeptide Y; Obesity; Rats; Rats, Zucker; Weight Gain

Topics: Adipose Tissue; Animals; Autonomic Nervous System; Brain; Diabetes Mellitus; Diabetes Mellitus, Type 2; Disease Models, Animal; Glucocorticoids; Glucose; Humans; Hyperinsulinism; Insulin; Insulin Resistance; Insulin Secretion; Lipids; Liver; Muscles; Neuropeptide Y; Obesity; Rats; Weight Gain

The Obese Zucker rat is a model of genetic obesity characterized by hyperphagia, hyperinsulinemia and other endocrine abnormalities. In order to elucidate pathogenetic mechanisms contributing to disturbed feeding behavior in these animals, the effect of food restriction on three hypothalamic neuropeptides involved in the control of food intake was studied. Eighteen male obese and 18 lean Zucker rats were randomly divided into two groups: half of the animals were food-restricted for 2 weeks, while the other half served as controls and were fed ad libitum. The levels of preproneuropeptide Y (preproNPY), preprocorticotropin releasing factor (preproCRF) and preprosomatostatin (preproSOM) mRNAs were determined using in situ hybridization technique. In addition, plasma insulin and corticosterone concentrations were analyzed. Food restriction significantly increased the expression of preproNPY mRNA in the arcuate nucleus in both Zucker phenotypes, while the expressions of preproCRF mRNA in the paraventricular nucleus (PVN) and preproSOM mRNA in the periventricular nucleus (PeV) were not altered. The expression of preproNPY mRNA was significantly greater in control obese animals compared to control lean animals. Food restriction lowered plasma insulin levels, but did not change plasma corticosterone levels. It is concluded that food restriction specifically activates NPY gene transcription in the arcuate nucleus the response being similar in both Zucker phenotypes. The results suggest that orexigenic NPY plays a role in the adaptation to altered feeding status.

Topics: Animals; Blood Glucose; Corticotropin-Releasing Hormone; Food Deprivation; Gene Expression Regulation; Hypothalamus; Image Processing, Computer-Assisted; In Situ Hybridization; Insulin; Male; Neuropeptide Y; Obesity; Protein Precursors; Rats; Rats, Zucker; Somatostatin; Time Factors; Transcriptional Activation

Neuropeptide Y (NPY) is the most powerful appetite stimulant known, and chronic administration leads to obesity. The hypothalamic content of NPY varies with nutritional status, suggesting that it is of physiological importance. We measured NPY in specific hypothalamic nuclei and NPY mRNA in the hypothalamus by Northern blotting in rats made obese by feeding a highly palatable diet compared with controls fed standard chow. In animals fed the palatable diet, NPY concentrations were increased in the paraventricular nucleus (mean +/- S.E.M.; 19.5 +/- 2.3 vs 11.1 +/- 1.1 fmol/micrograms protein, P less than 0.02), the arcuate nucleus (20.4 +/- 3.3 vs 9.3 +/- 0.6 fmol/micrograms protein, P less than 0.01), the medial preoptic area (9.1 +/- 0.9 vs 5.9 +/- 0.7 fmol/micrograms protein, P less than 0.02) and the anterior hypothalamus (2.7 +/- 0.2 vs 2.0 +/- 0.1 fmol/micrograms, P less than 0.02). Hypothalamic NPY mRNA measured by Northern blot analysis was, however, unchanged. These results suggest that the increase in NPY was due to decreased release rather than increased NPYergic activity. The findings are in accord with the neuroendocrine disturbance and increased thermogenesis observed in this model of obesity.

Topics: Animals; Blood Glucose; Blotting, Northern; Diet; Hypothalamus; Insulin; Male; Neuropeptide Y; Obesity; Rats; Rats, Inbred Strains; RNA, Messenger

Neuropeptide Y strongly stimulates food intake when it is injected in the hypothalamic paraventricular (PVN) and ventromedian (VMN) nuclei. In Sprague-Dawley (SD) rats, NPY synthesis in the arcuate nucleus (ARC) is increased by food deprivation and is normalized by refeeding. We have previously shown that the obese hyperphagic Zucker rat is characterized by higher NPY concentrations in this nucleus. NPY might therefore play an important role in the development of hyperphagia. The aim of the present study was to determine if the regulation by the feeding state works in the obese Zucker rat. For this purpose, 10 weeks-old male lean (n = 30) and obese (n = 30) Zucker rats were either fed ad libitum, either food-deprived (FD) for 48 hours or food-deprived for 48 h and refed (RF) for 6 hours. NPY was measured in several microdissected brain areas involved in the regulation of feeding behavior. NPY concentrations in the ARC was about 50% greater in obese rats than in lean rats (p less than 0.02) whatever the feeding state. In the VMN, NPY concentrations were higher in the lean FD rats than in the obese FD rat (p less than 0.001). Food deprivation or refeeding did not modify NPY in the ARC, in the VMN or in the dorsomedian nucleus whatever the genotype considered. On the other hand, food deprivation induced a significant decrease in NPY concentrations in the PVN of lean rats. This decrease was localized in the parvocellular part of this nucleus (43.0 +/- 1.9 (FD) vs 54.2 +/- 2.1 (Ad lib) ng/mg protein; p less than 0.005). Ad lib levels were restored by 6 hours of refeeding. These variations were not observed in the obese rat. The regulation of NPY by the feeding state in the Zucker rat was therefore very different from that described in the SD rats. Strain or age of the animals used might explain these differences. High NPY levels and absence of regulation in obese Zucker rats could contribute to the abnormal feeding behavior of these rats.

Topics: Animals; Arcuate Nucleus of Hypothalamus; Body Weight; Dorsomedial Hypothalamic Nucleus; Eating; Feeding Behavior; Food Deprivation; Hyperphagia; Hypothalamus; Male; Neuropeptide Y; Obesity; Paraventricular Hypothalamic Nucleus; Radioimmunoassay; Random Allocation; Rats; Rats, Zucker; Ventromedial Hypothalamic Nucleus

Hyperphagia in the obese Zucker rat is characterized by the early modification of the dark/light (D/L) rhythm of food intake. This rhythm is mainly driven by the suprachiasmatic nucleus (SCN) and, more controversially, by the ventromedian nucleus (VMN). In the SCN of adult obese Zucker rat, the concentrations of neuropeptide Y (NPY), a potent stimulator of food intake, are increased whereas those of neurotensin (NT), an anorexigenic peptide, are decreased. However, nothing is actually known about the synchronicity of the dysregulation of the D/L rhythm and variations of these peptides. That is why we measured NPY and NT in the microdissected SCN and VMN of lean (n = 16) and obese (n = 15) Zucker rats before the occurrence of hyperphagia (day 16 of age) and a few days after weaning (day 30 of age) when the modifications are apparent. For NPY, there was a very significant effect of age (P less than 0.001) for both nuclei and a significant effect of genotype (P less than 0.02) for the SCN only. NPY concentrations increased between 16 and 30 days in both nuclei (+74% (SCN) and +70% (VMN) in the obese rat; +57% (SCN) and +67% (VMN) in the lean rat; P less than 0.001). NPY in the SCN was not different at 16 days of age between lean and obese rats but significantly increased at 30 days in the obese rat (22.6 +/- 1.2 vs. 18.6 +/- 1.5 ng/mg protein; P less than 0.05). NT was not detected in the SCN of either group at 16 days or at 30 days.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Feeding Behavior; Neuropeptide Y; Neurotensin; Obesity; Rats; Rats, Zucker; Suprachiasmatic Nucleus; Ventromedial Hypothalamic Nucleus

We examined the effect of acute third intraventricular (IVT) injections of either saline or NPY (0.95, 3.0, 9.5, or 30.0 micrograms in 1 microliter) on the 1-, 4-, and 22-hour postinjection food and water intake of female obese (fa/fa), heterozygous lean (Fa/fa), and homozygous lean (Fa/Fa) Zucker rats. None of the doses of NPY had an effect on either food or water intake of fa/fa rats. A significant increase of food intake was seen in Fa/Fa rats at 1 and 4 hours after the 3.0 micrograms injection of NPY and at 1, 4, and 22 hours after the 9.5 micrograms injection of NPY. Both 3.0 and 9.5 micrograms of NPY also stimulated 1- and 4-hour postinjection food intake of Fa/fa rats, although this effect was significant only at 4 hours after the 3.0 micrograms dose. NPY had a less reliable effect on water intake; 3.0 micrograms of NPY stimulated 1-hour postinjection water intake of Fa/fa rats and 4-hour postinjection water intake of Fa/Fa rats. These results indicate that lean, but not obese Zucker rats, respond by eating more to centrally administered NPY. This deficit is similar to the effects seen with IVT insulin injections and may be a result of a common receptor-mediated mechanism.

Topics: Animals; Body Weight; Drinking; Eating; Female; Injections, Intraventricular; Insulin; Neuropeptide Y; Obesity; Rats; Rats, Zucker; Stimulation, Chemical

Neuropeptide Y (NPY) is an important hypothalamic regulator of feeding behavior. In this study we have investigated the regulation of the expression of preproNPY mRNA in male obese and lean Zucker rats by in situ hybridization. These animals represent a model of genetic obesity with hyperphagia, hyperinsulinemia and altered endocrine functions. Obese Zucker rats, treated for 12 days with 0.9% saline, had about 210% higher level of basal preproNPY mRNA expression in the arcuate nucleus when compared to their lean littermate controls. Repeated administrations of 8-hydroxy-dipropylaminotetralin (8-OH-DPAT), a serotonergic 5-HT1A agonist, or mifepristone, a glucocorticoid receptor antagonist, did not modify the basal expression of preproNPY mRNA in the Zucker phenotypes. The 8-OH-DPAT treatment significantly reduced hyperinsulinemia in obese Zucker rats without changing plasma glucose levels. The mifepristone treatment significantly increased plasma corticosterone levels in lean animals, but not in obese animals. The present study demonstrates enhanced expression of preproNPY mRNA in the arcuate nucleus in obese Zucker rats suggesting an involvement of NPY in the pathophysiology of the hyperphagic syndrome and genetically determined obesity in Zucker rats. Neither the antagonism of glucocorticoid receptors by mifepristone, nor repeated treatment with 8-OH-DPAT resulting in reduced insulin levels in obese Zucker rats, modified the basal expression of preproNPY mRNA in the arcuate nucleus.

Topics: 8-Hydroxy-2-(di-n-propylamino)tetralin; Animals; Arcuate Nucleus of Hypothalamus; Corticosterone; Gene Expression; Insulin; Male; Mifepristone; Neuropeptide Y; Nucleic Acid Hybridization; Obesity; Protein Precursors; Rats; Rats, Zucker; Reference Values; RNA, Messenger; Tetrahydronaphthalenes

Neuropeptide Y (NPY) concentrations were measured by radioimmunoassay in eight microdissected hypothalamic regions of obese (fa/fa) and lean (Fa/?) Zucker rats. Freely fed obese rats showed significant (40-100%) increases in NPY concentrations in several regions, notably the paraventricular, ventromedial, and dorsomedial nuclei and the arcuate nucleus/median eminence, compared with lean rats. Hypothalamic NPY concentrations were not affected in either obese or lean rats by food restriction, which caused 25% weight loss over 3 wk. Refeeding to initial weight significantly increased NPY levels in the ventromedial and dorsomedial nuclei in lean rats but did not significantly alter NPY concentrations in any hypothalamic region in obese rats. These observations indicate fundamental differences in the regulation of hypothalamic NPY between obese and lean Zucker rats. NPY injected into the paraventricular nucleus and other regions causes hyperphagia, obesity, and increased secretion of insulin, glucagon, ACTH, and corticosterone. These behavioral and neuroendocrine abnormalities all occur in the obese Zucker syndrome and may be due to increased NPY-ergic activity in the hypothalamus.

Topics: Adrenocorticotropic Hormone; Animal Nutritional Physiological Phenomena; Animals; Arcuate Nucleus of Hypothalamus; Blood Glucose; Corticosterone; Diet; Dorsomedial Hypothalamic Nucleus; Hypothalamus; Insulin; Male; Median Eminence; Neuropeptide Y; Neurosecretory Systems; Obesity; Paraventricular Hypothalamic Nucleus; Radioimmunoassay; Rats; Rats, Zucker; RNA, Messenger; Ventromedial Hypothalamic Nucleus

Increased hypothalamic neuropeptide Y levels have previously been demonstrated in several hypothalamic nuclei of the (fa/fa) Zucker rat. This study set out to characterise hypothalamic NPY receptors in both genotypres and to study the effect of exogenous NPY on feeding behavior in these rats. Spontaneous daytime food intake was raised in the obese rat (p less than 0.05). Total hypothalamic receptor density (Bmax) was reduced in the obese rat compared with the lean rat (by 56%, p less than 0.005), but affinity remained unaltered. The lowest dose of NPY tested (23.5 pmol) stimulated daytime feeding in lean rats after 1, 2 and 3 hours but was inaffective in the obese rat (p less than 0.05). At two higher doses (235 pmol and 2.35 nmol), NPY was equipotent in both genotypes over 1 and 2 hours but NPY-induced feeding was attenuated over 3 hours in the obese rat. These results suggest an overactive endogenous NPYergic system in the obese (fa/fa) rat which might contribute to hyperphagia and obesity in this strain.

Topics: Animals; Binding, Competitive; Eating; Feeding Behavior; Hypothalamus; Male; Neuropeptide Y; Obesity; Rats; Rats, Zucker; Receptors, Neuropeptide Y; Receptors, Neurotransmitter

1. Hypothalamic concentrations of nine peptides with experimental effects on energy balance were compared in obese (fa/fa) and lean (Fa/?) male Zucker rats. To determine whether any peptide differences between obese and lean rats might be due to the overweight condition per se, separate groups of obese rats were food-restricted to reduce their body weight to lean values. 2. Concentrations of neuromedin B, a bombesin-like peptide, in the central hypothalamus were significantly higher in obese than in lean rats. This difference was not affected in food-restricted obese rats. 3. Hypothalamic levels of neuropeptide Y, an extremely potent central appetite stimulant, were similar in lean and freely fed obese rats but central hypothalamic levels of neuropeptide Y rose significantly in food-restricted obese rats. 4. These findings suggest that disturbances in hypothalamic neuromedin B concentrations may be involved in the obesity syndrome of the fa/fa Zucker rat. Increased central hypothalamic levels of neuropeptide Y in food-restricted rats suggest that this peptide may help to defend body weight by stimulating eating after weight loss.

Topics: Animals; Bombesin; Calcitonin Gene-Related Peptide; Food Deprivation; Galanin; Hypothalamus; Hypothalamus, Middle; Neurokinin B; Neuropeptide Y; Neuropeptides; Neurotensin; Obesity; Peptides; Radioimmunoassay; Rats; Rats, Zucker; Somatostatin; Substance P; Vasoactive Intestinal Peptide

By acting in the brain, insulin suppresses food intake, whereas neuropeptide Y (NPY) has the opposite effect. Since fasting increases NPY gene expression in the hypothalamic arcuate nucleus (ARC) and also lowers circulating insulin levels, we hypothesized that the anorexiant effect of insulin could result from insulin inhibition of NPY gene transcription in the ARC. Therefore, we determined whether the administration of insulin (200 mU per 12 hrs) into the 3rd cerebral ventricle of lean (Fa/Fa) female Zucker rats (n = 5) during 48 hrs of food deprivation reduces the expression of preproNPY mRNA in the ARC compared to vehicle-treated controls (n = 5). Coronal sections of rat brain were hybridized with an oligonucleotide probe complementary to preproNPY mRNA and apposed to x-ray film. Hybridization was quantified in both the ARC and the hippocampal dentate gyrus by computerized image analysis of the resulting autoradiographs. Central insulin significantly reduced the area of hybridization in the ARC (0.235 +/- 0.017 mm2; mean +/- SE) compared to vehicle-treated controls (0.331 +/- 0.037 mm2; p less than 0.05), but was without effect in the hippocampus. Thus, insulin reduced the expression of mRNA for NPY specifically in the ARC. Since the genetically obese (fa/fa) Zucker rat is insensitive to the anorexiant effect of insulin and over-expresses NPY in the ARC, we next tested the hypothesis that insulin does not suppress NPY mRNA expression in the ARC of these rats. Consistent with this hypothesis, central insulin administration to obese Zucker rats during 48 hrs of food deprivation (n = 6) did not lower hybridization area in the ARC compared to vehicle alone (n = 4) (0.286 +/- 0.036 vs. 0.248 +/- 0.019 mm2; p greater than 0.05). We conclude that insulin suppresses the expression of mRNA for NPY in the ARC of fasted lean but not obese Zucker rats. Regulation of hypothalamic NPY gene expression by insulin may account for its anorexiant effect, and a defect in this action may contribute to certain forms of obesity.

Topics: Animals; Arcuate Nucleus of Hypothalamus; Autoradiography; Brain; Female; Food Deprivation; Injections, Intraventricular; Insulin; Neuropeptide Y; Nucleic Acid Hybridization; Obesity; Rats; Rats, Zucker; Reference Values; RNA, Messenger

Central and lateral hypothalamic concentrations of 9 regulatory peptides implicated in the control of feeding behaviour were measured in corpulent (cp/cp) JCR:LA-cp rats which develop spontaneous obesity, hyperinsulinaemia and hyperlipidaemia, and in lean (+/?) controls. In female cp/cp rats, central hypothalamic levels of neuropeptide Y (NPY), neurotensin, somatostatin and substance P were significantly lower (p less than 0.02) than in lean female controls. Following food restriction with a 16% reduction in body weight, these differences were apparently reversed and there were also significant rises in the lateral hypothalamic concentrations of neurotensin and of galanin. The other 4 peptides examined (bombesin, calcitonin gene-related peptide, neuromedin B and vasoactive intestinal peptide) did not differ significantly between cp/cp and lean females, either fed freely or food-restricted. Male cp/cp rats showed no significant differences from lean males in central or lateral hypothalamic concentrations of any of the 9 peptides. NPY and galanin are powerful and specific central appetite stimulants, whereas neurotensin, substance P and somatostatin inhibit feeding when injected centrally. Disturbances in these putative appetite-regulating peptides may be involved in the hyperphagia and other hypothalamic abnormalities in this spontaneous obesity syndrome. The apparent absence of differences between the male corpulent and lean groups may relate to sexual dimorphism of the syndrome, which is more marked in the females.

Topics: Animals; Diet, Reducing; Female; Galanin; Hypothalamus; Insulin; Neuropeptide Y; Neuropeptides; Neurotensin; Obesity; Organ Specificity; Peptides; Rats; Rats, Mutant Strains; Reference Values; Somatostatin; Substance P; Weight Loss

Neuropeptide Y (NPY), a peptide of the pancreatic polypeptide family, is actually considered to be the most potent stimulator of food intake in rats when centrally injected. It has also suppressive effects on several components of sexual behavior. It was measured in discrete microdissected brain nuclei in obese hyperphagic Zucker fa/fa rats also characterized by a deficient reproductive function, as well as in their lean homozygous (Fa/Fa) and heterozygous (Fa/fa) counterparts. When compared with the lean (Fa/Fa) rats, NPY concentrations were significantly increased in the obese rats in the arcuate nucleus-median eminence (ARCME, +300%), in the paraventricular (PVN, +60%), suprachiasmatic (SCH, +90%), accumbens (+100%) and supraoptic (+40%) nuclei, as well as in the median preoptic area (MPOA, +70%). As PVN is one of the most important nuclei involved in the control of food intake and one site of NPY action, the high levels found in this nucleus might be a major component at the origin of hyperphagia in the obese animals. Food intake might be overstimulated by a sustained production of NPY as shown by the high concentrations found in the ARCME. NPY might also intervene in the pattern of food intake, for NPY contents were also largely modified in the SCH, the nucleus regulating feeding periodicity and in the MPOA, which is possibly involved in the regulation of energy balance. Finally, as the MPOA is the only site of action of NPY on sexual behavior, the higher levels measured in this area might contribute to the defective reproductive function of the obese Zucker fa/fa rat.

Topics: Animals; Brain; Feeding Behavior; Hyperphagia; Hypothalamus; Male; Neuropeptide Y; Obesity; Rats; Rats, Zucker; Sexual Behavior, Animal; Species Specificity

Hyperphagia and obesity are often associated, and the origins of the biochemical modifications leading to these syndromes might be in the hypothalamus. Indeed, food intake is regulated by numerous neuropeptides in various hypothalamic nuclei, including the paraventricular (PVN), arcuate (ARC), ventromedian (VMN) and suprachiasmatic (SCH) nuclei. Among these peptides, neuropeptide Y (NPY) is the most potent inducer of food intake whereas neurotensin (NT) decreases food intake. We measured these two peptides in microdissected hypothalamic nuclei in obese Zucker rats that ate 30% more food than their lean counterparts. Neuropeptide Y and neurotensin levels varied in opposite directions: In the hyperphagic obese Zucker rats, the NPY concentrations were significantly greater than those in the lean normophagic rats in the ARC (+30%), PVN (+60%) and SCH (+94%) nuclei, whereas the NT levels were significantly lower in the ARC (-40%), PVN (-31%) VMN (-66%) and SCH (-47%) nuclei. Both these variations tend to increase food intake. Feeding periodicity might also be modified because large variations of the two peptides have been measured in the supra-chiasmatic nucleus, which is considered the most important regulator of feeding rhythm. The results reinforce the hypothesis that hyperphagia in obesity is associated with a biochemical modification in the central nervous system because the peripheral status of NT and NPY was not modified in the obese rats. Because levels of other hypothalamic peptides, such as opioid peptides and somatostatin, are also slightly modified, it can be concluded that hyperphagia in obesity is associated with a central peptidergic dysregulation. Research on drugs reacting specifically with the receptor of these peptides might have interesting implications for the treatment of hyperphagia and, therefore, of obesity.

Topics: Animals; Arcuate Nucleus of Hypothalamus; Disease Models, Animal; Hyperphagia; Hypothalamus; Neuropeptide Y; Neurotensin; Obesity; Paraventricular Hypothalamic Nucleus; Rats; Rats, Zucker; Ventromedial Hypothalamic Nucleus

Neuropeptide Y (NPY) is a potent orexigenic agent capable of producing hyperphagia and obesity. NPY-containing neurons project from the hypothalmic arcuate nucleus to the paraventricular nucleus, an area known to be sensitive to the orexigenic effects of NPY. In this study we investigated the possibility that preproNPY messenger RNA (mRNA) content may be altered in obese Zucker rats compared to that of their lean littermates. Total RNA was isolated from hypothalamic dissections from male and female, obese and lean Zucker rats. RNA was also isolated from dissections of: olfactory bulb, entorhinal cortex, hippocampus, and striatum of female obese and lean rats. PreproNPY mRNA content was determined by solution hybridization-RNase protection analysis. The results revealed a 2- to 3-fold increase in preproNPY mRNA levels in the hypothalamus of obese animals compared to lean. The increase was observed in both sexes and was specific to the hypothalamus. In situ hybridization localized this increase to the arcuate nucleus. An additional RNase protection study was pursued to investigate the effects of 72 h food deprivation on hypothalamic preproNPY mRNA levels in lean and obese animals. Lean animals displayed an approximate 2-fold increase in preproNPY mRNA content, whereas obese animals showed no significant increase after food deprivation. These data are consistent with the hypothesis that NPY projections within the hypothalamus are involved in regulating feeding behavior and weight gain, and that disturbed regulation of hypothalamic NPY expression may play a role in the etiology of obesity in the genetically obese Zucker rat.

Topics: Animals; Brain; Fasting; Female; Gene Expression; Hypothalamus; Male; Neuropeptide Y; Nucleic Acid Hybridization; Obesity; Organ Specificity; Protein Precursors; Rats; Rats, Mutant Strains; Rats, Zucker; RNA, Messenger

Topics: Galanin; Humans; Neuropeptide Y; Obesity; Peptides