neuropeptide-y and Metabolic-Syndrome

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

The prevalence rates of obesity and metabolic syndrome are on the rise in the United States. Epidemiological surveys suggest that the rates of these medical conditions are especially high among persons with psychiatric disorders, including post-traumatic stress disorder (PTSD). A variety of factors are thought to contribute to the risk for metabolic syndrome, including excessive caloric intake, decreased activity and energy expenditure, use of certain medications, stress and genetic influences. Recent research demonstrates that stress, acting through the neuropeptide Y (NPY) and glucocorticoid systems, potentiates the development of obesity and other aspects of metabolic syndrome in mice fed a high caloric, fat and sugar diet. Alterations in the NPY and glucocorticoid systems also impact behavioral adaptation to stress, as indicated by studies in animals and persons exposed to severe, life-threatening or traumatic stress. The following review examines the biology of the NPY and neuroactive steroid systems as physiological links between metabolic syndrome and PTSD, a paradigmatic neuropsychiatric stress disorder. Hopefully, understanding the function of these systems from both a translational and systems biology point of view in relation to stress will enable development of more effective methods for preventing and treating the negative physical and mental health consequences of stress.

Topics: Adaptation, Physiological; Animals; Dehydroepiandrosterone; Female; Glucocorticoids; Humans; Hydrocortisone; Male; Metabolic Syndrome; Mice; Models, Biological; Neuropeptide Y; Pregnanolone; Risk Factors; Stress Disorders, Post-Traumatic; Stress, Physiological; Testosterone

Multidisciplinary research from my and my colleagues' laboratory has shown that disruption at various levels of leptin signaling to the interactive hypothalamic network of neuropeptide Y (NPY) and cohorts contributes to the antecedent pathophysiologic sequelae of the disease cluster of the metabolic syndrome. Disruptions in NPY signaling due to high or low abundance of NPY and cognate receptors dysregulate the homeostatic milieu to promote hyperinsulinemia, hyperglycemia, fat accrual, and overt diabetes. Hyperleptinemia induced by consumption of energy-rich diets inhibits leptin transport across the blood-brain barrier and thereby produces leptin insufficiency in the hypothalamus. Sustained leptin insufficiency results in loss of hypothalamic restraint on pancreatic insulin secretion and diminished glucose metabolism and energy expenditure. This chain of events culminates in hyperinsulinemia, hyperglycemia, and diabetes. Our recent studies have shown that increasing the supply of leptin centrally by gene therapy reinstates the restraint on hypothalamic NPY signaling and ameliorates diabetes and the attendant disease cluster of the metabolic syndrome. Thus, newer therapies that would enhance leptin transport across the blood-brain barrier in a timely manner or reinstate leptin restraint on NPY signaling through central leptin gene therapy or pharmacologically with leptin mimetics are likely to curtail the pathophysiologic sequelae of diabetes and related ailments of the metabolic syndrome.

Topics: Animals; Diabetes Mellitus; Hypothalamus; Leptin; Metabolic Syndrome; Mice; Neuropeptide Y; Rats

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

It is increasingly accepted that alterations of the intrauterine and early postnatal nutritional, metabolic and hormonal environment may predispose individuals to development of diseases in later life. Results from studies of the offspring of diabetic mothers strongly support this hypothesis. It has also been suggested that being light at birth leads to an increased risk of the metabolic syndrome (Syndrome X) in later life (the Barker hypothesis). The pathophysiological mechanisms that underlie this programming are unclear. However, hormones are important environment-dependent organizers of the developing neuroendocrine-immune network, which regulates all the fundamental processes of life. Hormones can act as 'endogenous functional teratogens' when present in non-physiological concentrations, induced by alterations in the intrauterine or neonatal environment during critical periods of perinatal life. Perinatal hyperinsulinism is pathognomic in offspring of diabetic mothers. Early hyperinsulinism also occurs as a result of early postnatal overfeeding. In rats, endogenous hyperinsulinism, as well as peripheral or intrahypothalamic insulin treatment during perinatal development, may lead to 'malprogramming' of the neuroendocrine systems regulating body weight, food intake and metabolism. This results in an increased disposition to become obese and to develop diabetes throughout life. Similar malprogramming may occur due to perinatal hypercortisolism and hyperleptinism. With regard to 'small baby syndrome' and the thrifty phenotype hypothesis, we propose that early postnatal overfeeding of underweight newborns may substantially contribute to their long-term risk of obesity and diabetes. In summary, a complex malprogramming of the central regulation of body weight and metabolism may provide a general aetiopathogenetic concept, explaining perinatally acquired disposition to later disease and, thereby, opening a wide field for primary prevention.

Topics: Animals; Appetite Regulation; Body Weight; Diabetes, Gestational; Eating; Female; Hormones; Humans; Hypothalamus; Infant Nutritional Physiological Phenomena; Infant, Low Birth Weight; Infant, Newborn; Metabolic Syndrome; Neuropeptide Y; Pregnancy

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

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

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

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

The objectives of this study were to evaluate the effects of maternal oral exposure to the antibacterial Triclosan (TCS) during gestation and lactation on the metabolic status of the adult offspring and on the expression of main genes controlling the appetite regulatory network. Pregnant rats were fed ad-libitum with ground food + TCS (1 mg/kg) from day 14 of gestation to day 20 of lactation (n=3) or ground food (n=3). After litter reduction, 12 males and 12 females born from the TCS exposed rats (TCS, n=24) or not (Control, n=24) were used to evaluate monthly body weight, food intake, plasma levels of cholesterol, glucose and triglycerides, and the hypothalamic mRNA expression of agouti-related protein (Agrp), neuropeptide Y (Npy) and propiomelanocortin (Pomc). Body weight for rats in the TCS group was 12.5% heavier for males at 4 months (p<0.001) and 19% heavier for females at 8 months (p=0.01). Food intake was significantly higher for rats in the TCS group at 5 months of age (p<0.01). Cholesterol and glucose levels were significantly higher for rats in the TCS group at 8 months (p<0.05). mRNA expression of Npy and Agrp were significantly increased in hypothalami of rats in the TCS group at 2 months for males or 8 months for females (p<0.05). In conclusion, low doses of oral TCS consumption by the pregnant and lactating dam increase the hypothalamic expression of the orexigenic neuropeptides Npy and Agrp in the offspring and alter their metabolic status during adulthood, resembling development of the metabolic syndrome.

Topics: Agouti-Related Protein; Animals; Animals, Newborn; Appetite; Appetite Regulation; Disease Susceptibility; Female; Gene Regulatory Networks; Male; Metabolic Syndrome; Neuropeptide Y; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Wistar; Triclosan

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

There have been few epidemiological studies that have investigated genetic susceptibility to cardiovascular risk associated with the prevalence of metabolic syndrome (MetS). Neuropeptide Y (NPY) is a strong candidate gene for coronary artery disease (CAD). Therefore, the aim of this study was to investigate the association between the NPY gene rs16147 polymorphism and the presence of MetS in a well defined group of Iranian subjects with angiographically-defined CAD.. A cross-sectional study design was used in which a total of 364 patients were recruited; 143 patients with MetS and 221 without MetS were genotyped using the ARMS-PCR technique. Logistic regression analyses were performed to determine the odds ratios (ORs) for the association of specific genotypes with the presence of MetS and related phenotypes.. The frequency of the variant G allele of the NPY gene was significantly higher in CAD patients without MetS (p = 0.032). Compared to the AA genotype of the NPY gene, individuals carrying the GG genotype had a reduced risk of MetS (OR = 0.51, 95% CI = 0.27-0.95, p = 0.034).. The rs16147 polymorphism may be associated with presence of MetS among subjects with documented CAD. Carriage of NPY A allele in patients with CAD is associated with a higher prevalence of MetS.

Topics: Adolescent; Adult; Aged; Coronary Artery Disease; Cross-Sectional Studies; Female; Genetic Predisposition to Disease; Humans; Iran; Male; Metabolic Syndrome; Middle Aged; Neuropeptide Y; Polymorphism, Genetic; Prevalence; Risk Factors; Young Adult

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

Metabolic syndrome (MS) is a cluster of complicated disorders caused by the interactive influencing factors of heredity and environment, which predisposes to many cnacers. RESULTS from epidemic research indicate that stress is tightly related to the pathogenesis of MS and neoplasia. This paper aims to investigate the association between psychological stress and MS with respect to the tumor necrosis factor alpha (TNFα) and neuropeptide Y (NPY) genes in the Han and Hui ethnic groups.. All subjects for this case-control study matched strict enrollment criteria (nationality, gender and age) and lived in the city of Wu Zhong of Ningxia Province in China. The enrolled group contained 102 matched pairs of Hui ethnic individuals and 98 matched pairs of Han ethnic individuals. Enrolled subjects completed the general Symptom Checklist-90 (SCL-90). The TNFα-308G/A variant and NPYrs16147 polymorphism were detected in case (81 males, 119 females) and control (81 males, 119 females) groups by polymerase chain reaction (PCR) amplification.. Nine factors of the SCL-90 were found to be statistically different (p<0.05) between case and control groups. The homozygous mutant genotype (AA) and the mutant allele (A) of the TNFα-308G/A gene were less frequently observed in the control population compared to the case group. The odds ratio (95% confidence interval) in "Allele" for MS was 2.28 (1.47-3.53), p=0.0001, while "OR" was 1.11 (0.83-1.47), p=0.15, for the NPYrs16147 gene polymorphism.. Psychological stress has been positively associated with MS. A previous study from our group suggested there were differences in the level of psychological stress between Hui and Han ethnic groups. Furthermore, we found that the stress-related TNFα gene was associated with MS for both Han and Hui ethnic groups. In contrast, NPY may be a possible contributor to MS and associated cancer for the Han ethnic group.

Topics: Asian People; Case-Control Studies; China; Female; Gene Frequency; Genetic Association Studies; Humans; Male; Metabolic Syndrome; Middle Aged; Neuropeptide Y; Polymorphism, Single Nucleotide; Stress, Psychological; Surveys and Questionnaires; Tumor Necrosis Factor-alpha

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

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

The metabolic syndrome (MetS) is characterized by constellation of clinical and biochemical features that increase the risk of cardiovascular disease. Neuropeptide Y (NPY) is a neurotransmitter and enhances the development of obesity and other aspects of MetS. We determined the association between NPY Leu7Pro polymorphism and features of MetS in Iranian patients with coronary artery disease (CAD). A total of 550 patients with CAD including individuals with (n = 184) and without MetS (n = 366) were genotyped by polymerase chain reaction-restriction fragment length polymorphism. A significantly higher frequency of the Leu7Pro polymorphism was found in patients with MetS compared with the non-MetS patients (P = .001). Furthermore, there was a significant difference in Pro7 frequency between diabetics versus nondiabetics (P = .005), dyslipidemic versus nondyslipidemic (P = .04), and obese versus nonobese (P = .001) in this population. Leu7Pro polymorphism is associated with the MetS in patients with CAD.

Topics: Adult; Aged; Aged, 80 and over; Amino Acid Substitution; Coronary Artery Disease; Cross-Sectional Studies; Female; Genetic Predisposition to Disease; Genotype; Humans; Male; Metabolic Syndrome; Middle Aged; Neuropeptide Y; Polymorphism, Genetic; Risk Factors

Neuropeptide Y (NPY) mediates stress-induced obesity in adult male mice by activating its Y2 receptor (Y2R) in visceral adipose tissue (VAT). Here, we studied whether the NPY-Y2R system is also activated by maternal low-protein diet (LPD) and linked to obesity in offspring. Prenatal LPD offspring had lower birth weights compared to normal-protein diet (NPD) offspring. Female prenatal and lactation stress (PLS) offspring from mothers fed an LPD developed abdominal adiposity and glucose intolerance associated with a 5-fold up-regulation of NPY mRNA and a 6-fold up-regulation of Y2R mRNA specifically in VAT, in addition to elevated platelet-rich-plasma (PRP) NPY, compared to control females fed a high-fat diet (HFD). Conversely, PLS male offspring showed lower NPY in PRP, a 10-fold decrease of Y2R mRNA in VAT, lower adiposity, and improved glucose tolerance compared to control males. Interestingly, prenatal LPD offspring cross-fostered to control lactating mothers had completely inverse metabolic and NPY phenotypes. Taken together, these findings suggested that maternal LPD activates the VAT NPY-Y2R system and increases abdominal adiposity and glucose intolerance in a sex- and time-specific fashion, suggesting that the peripheral NPY system is a potential mediator of programming for the offspring's vulnerability to obesity and metabolic syndrome.

Topics: Animals; Diet, High-Fat; Diet, Protein-Restricted; Female; Glucose Intolerance; Intra-Abdominal Fat; Lactation; Male; Maternal Nutritional Physiological Phenomena; Metabolic Syndrome; Mice; Neuropeptide Y; Obesity, Abdominal; Pregnancy; Receptors, Neuropeptide Y; Up-Regulation

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

A functional polymorphism leucine 7 proline in the human neuropeptide Y (NPY) gene leading to increased NPY release from sympathetic nerves is associated with traits of metabolic syndrome. Although hypothalamic NPY neurons play an established role in promoting positive energy balance, the role of NPY colocalized with norepinephrine in sympathetic nervous system and brain noradrenergic neurons remains obscure.. To clarify the role of NPY in noradrenergic neurons, we generated a transgenic mouse overexpressing NPY under dopamine-beta-hydroxylase promoter and characterized the metabolic phenotype of the OE-NPY(DbetaH) mouse.. NPY levels are increased by 1.3-fold in adrenal glands and 1.8-fold in the brainstem but not in the hypothalamus in OE-NPY(DbetaH) mice. They display increased white adipose tissue mass and cellularity and liver triglyceride accumulation without hyperphagia or increased body weight. Hyperinsulinemia and impaired glucose tolerance develop by the age of 6 months in the OE-NPY(DbetaH) mice. Furthermore, circulating ghrelin is significantly increased in comparison with wild-type mice.. The present study shows that even a moderate increase in NPY levels in noradrenergic neurons leads to disturbances in glucose and lipid metabolism. The OE-NPY(DbetaH) mouse is an interesting new model to investigate the pathophysiology of some key components of the cluster of abnormalities characterizing the metabolic syndrome.

Topics: Adrenal Glands; Animals; Body Weight; Brain; DNA; Dopamine beta-Hydroxylase; Female; Genotype; Ghrelin; Glucose Intolerance; Male; Metabolic Syndrome; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neurons; Neuropeptide Y; Polymerase Chain Reaction; Promoter Regions, Genetic

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

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