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Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Adipose tissue plays a crucial role in energy homeostasis not only in storing triglyceride, but also responding to nutrient, neural, and hormonal signals, and producing factors which control feeding, thermogenesis, immune and neuroendocrine function, and glucose and lipid metabolism. Adipose tissue secretes leptin, steroid hormones, adiponectin, inflammatory cytokines, resistin, complement factors, and vasoactive peptides. The endocrine function of adipose tissue is typified by leptin. An increase in leptin signals satiety to neuronal targets in the hypothalamus. Leptin activates Janus-activating kinase2 (Jak2) and STAT 3, resulting in stimulation of anorexigenic peptides, e.g., alpha-MSH and CART, and inhibition of orexigenic peptides, e.g., NPY and AGRP. The reduction in leptin levels during fasting stimulates appetite, decreases thermogenesis, thyroid and reproductive hormones, and increases glucocorticoids. Leptin also stimulates fatty acid oxidation, insulin release, and peripheral insulin action. These effects involve regulation of PI-3 kinase, PTP-1B, suppressor of cytokine signaling-3 (SOCS-3), and AMP-activated protein kinase in the brain and peripheral organs. There is emerging evidence that leptin, adiponectin, and resistin act through overlapping pathways. Understanding the signal transduction of adipocyte hormones will provide novel insights on the pathogenesis and treatment of obesity, diabetes, and various metabolic disorders.
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PMID:Adipokines that link obesity and diabetes to the hypothalamus. 1687 74

Palatability is one of the factors that regulates food and fluid intake and contributes to overconsumption in turn contributing to obesity. To elucidate the brain mechanisms of the palatability-induced ingestion, we explored the roles of six hypothalamic orexigenic neuropeptides, orexin, melanin-concentrating hormone (MCH), neuropeptide Y (NPY), agouti-related protein (AgRP), ghrelin and dynorphin, in the intake of a palatable solution, saccharin. Of the six peptides, intracerebroventricular (i.c.v.) administrations of orexin, MCH and NPY increased the intake of saccharin. Drinking of saccharin in turn elevated the mRNA levels of orexin and NPY, but not MCH. Pre-treatments of naloxone, an opioid antagonist, blocked the orexigenic effects of orexin and NPY. Specific gastric motor responses induced by central orexin-A and NPY are well known, however, MCH did not induce such responses. The i.c.v. administration of orexin-A facilitated gastric emptying. These results suggest that the overconsumption promoted by sweet and palatable tastes is attributed to the activation of orexigenic neuropeptides, such as orexin and NPY, and a downstream opioid system together with enhanced digestive functions.
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PMID:Involvement of specific orexigenic neuropeptides in sweetener-induced overconsumption in rats. 1701 Apr 51

The Agouti-related protein (AgRP) is a central orexigenic peptide leading to increased food intake when ubiquitously overexpressed. AgRP-deficient (AgRP(-/-)) mice have either no phenotype or present an age-related leanness. In this study, AgRP(-/-) mice were fed alternate high fat or low fat diets in an effort to determine whether AgRP is a mediating factor for the effects of dietary fat on metabolic parameters. There were no striking metabolic differences between AgRP(-/-) and the equally obese wild type littermates but AgRP(-/-) mice displayed a significantly longer lifespan. The point estimate of median survival for the AgRP(-/-) group was 9.8% greater while the significantly low hazard ratio (0.494) suggests that mortality incidence of AgRP(-/-) mice is less than one-half that of the wild type reference population. It is concluded that although AgRP(-/-) mice become morbidly obese consuming a high fat diet (a landmark feature for a shortened lifespan), they seem to overcome obesity- and age-related pathologies and live significantly longer than their metabolically similar wild type littermates.
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PMID:AgRP-deficiency could lead to increased lifespan. 1709 59

The adipostat is the mechanism by which the brain detects and maintains constant levels of energy stored in adipocytes in the form of lipids. Key elements of the adipostat include the adipocyte-derived hormone leptin that is expressed in proportion to energy levels and serves to communicate this information to the central nervous system and the central circuits, which sense and respond to leptin. Blockade of one of these circuits, the central melanocortin system, disrupts leptin action and causes a distinct obesity syndrome in mice and humans, characterized by increased adiposity as well as increased linear growth. We show here that transgenic zebrafish overexpressing the endogenous melanocortin antagonist agouti-related protein (AgRP) also exhibit obesity, increased linear growth, and adipocyte hypertrophy. These findings demonstrate that key elements of the adipostat originated before the evolution of mammals. Furthermore, transgenic overexpression of AgRP in zebrafish yields a new model system for the genetic analysis of energy homeostasis in a simple vertebrate system.
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PMID:Creation of a genetic model of obesity in a teleost. 1734 84

To determine whether long-term melanocortinergic activation can attenuate the metabolic effects of a high fat diet, mice overexpressing an NH(2)-terminal POMC transgene that includes alpha- and gamma(3)-MSH were studied on either a 10% low-fat diet (LFD) or 45% high-fat diet (HFD). Weight gain was modestly reduced in transgenic (Tg-MSH) male and female mice vs. wild type (WT) on HFD (P < 0.05) but not LFD. Substantial reductions in body fat percentage were found in both male and female Tg-MSH mice on LFD (P < 0.05) and were more pronounced on HFD (P < 0.001). These changes occurred in the absence of significant feeding differences in most groups, consistent with effects of Tg-MSH on energy expenditure and partitioning. This is supported by indirect calorimetry studies demonstrating higher resting oxygen consumption and lower RQ in Tg-MSH mice on the HFD. Tg-MSH mice had lower fasting insulin levels and improved glucose tolerance on both diets. Histological and biochemical analyses revealed that hepatic fat accumulation was markedly reduced in Tg-MSH mice on the HFD. Tg-MSH also attenuated the increase in corticosterone induced by the HFD. Higher levels of Agrp mRNA, which might counteract effects of the transgene, were measured in Tg-MSH mice on LFD (P = 0.02) but not HFD. These data show that long-term melanocortin activation reduces body weight, adiposity, and hepatic fat accumulation and improves glucose metabolism, particularly in the setting of diet-induced obesity. Our results suggest that long-term melanocortinergic activation could serve as a potential strategy for the treatment of obesity and its deleterious metabolic consequences.
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PMID:Transgenic MSH overexpression attenuates the metabolic effects of a high-fat diet. 1737 95

To examine the role of the brain stem melanocortin system in long-term energy regulation, we assessed the effects of overproduction of proopiomelanocortin (POMC) in the caudal brain stem of F344xBN rats with adult-onset obesity. Recombinant adeno-associated viral vector encoding POMC gene was delivered to the nucleus of solitary tract (NTS) in the hindbrain, and food intake, body weight, glucose and fat metabolism, brown adipose tissue thermogenesis, and mRNA levels of neuropeptides and melanocortin receptors were assessed. POMC delivery resulted in sustained reduction in food intake and body weight over 42 days and improved insulin sensitivity. At death, in recombinant adeno-associated viral vector-POMC-treated rats vs. control rats, alpha-melanocyte-stimulating hormone in NTS increased nearly 21-fold, whereas hypothalamic alpha-melanocyte-stimulating hormone remained unchanged. Visceral adiposity decreased by 37%; tissue triglyceride content diminished by 26% and 47% in liver and muscle, respectively; serum triglyceride and nonesterified fatty acids were reduced by 35% and 34%, respectively; phosphorylation of acetyl-CoA carboxylase was elevated by 63% in soleus muscle; brown adipose tissue uncoupling protein 1 increased by 30%; and melanocortin 3 receptor expression declined by 60%, whereas neuropeptide Y, agouti-related protein, and MC4 receptor mRNA levels were unchanged in the NTS. In conclusion, POMC overexpression in the NTS produces a characteristic unabated hypophagia that is uniquely different from the anorexic tachyphylaxis following POMC overexpression in the hypothalamus. The sustained anorectic response may result from absence of compensatory elements in the NTS, such as increased agouti-related protein expression, suggesting melanocortin activation of the brain stem may be a viable strategy to alleviate obesity.
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PMID:Melanocortin activation of nucleus of the solitary tract avoids anorectic tachyphylaxis and induces prolonged weight loss. 1738 13

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.
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PMID:Prenatal influences on susceptibility to diet-induced obesity are mediated by altered neuroendocrine gene expression. 1740 Aug

Ghrelin, an endogenous ligand of the growth hormone secretagogue receptor, is mainly produced by the stomach, but its expression has also been demonstrated in many other tissues. It has diverse biological effects. ghrelin stimulates food intake and regulates energy homeostasis through activating the expression of the orexigenic neuropeptides NPY (neuropeptide Y)/AGRP (agouti-related protein) in hypothalamic neurons, by which it plays a key role in obesity pathogenesis. This article simply introduces the recent research on its molecular structure, distribution, physiological effects and highlights the relationship between ghrelin and food intake as well as obesity.
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PMID:[Relationship between ghrelin and food intake or obesity]. 1742 66

Dietary conjugated linoleic acid (CLA) has been investigated for its beneficial effects on disease prevention and treatment, and now obesity is one of the most perspective researching highlights. In a variety of experimental models, the results of studies on the effects of CLA on food intakes are somewhat inconsistent. Our experiment was conducted to extend these observations to hypothalamus and other regions within the central nervous system so that the mechanism of the actions of CLA might be more easily elucidated. In the experiment, a permanent cannula was inserted into the lateral ventricle of each rat. For the experiment, animals received intracerebroventricular injections of either 150nmol (n=16) CLA, or LA as non-conjugated control, or normal saline as vehicle. Hypothalamus and blood samples were collected at the 2nd, 4th, 8th, and 14th day. The results show that CLA in cerebral ventricle can inhibit food intake of experimented rats and this inhibition is related with the decreased expression of neuropeptides Y (NPY) and agouti-related protein (AgRP). The circulating leptin level was also increased by this tentative treatment (2.94+/-0.71 versus 1.18+/-0.18ng/ml). However, the glucose metabolism was not affected by ICV CLA. It is concluded that CLA in brain can inhibit the appetite of rats through the mechanism of decreasing the expression of NPY and AgRP.
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PMID:Intracerebroventricular administration of conjugated linoleic acid (CLA) inhibits food intake by decreasing gene expression of NPY and AgRP. 1746 53

Obesity is a major public health problem associated with morbidity and mortality and continues to increase worldwide. This review focuses on the regions of the brain that are important in appetite regulation and the circulating factors implicated in the control of food intake. The hypothalamus is critical in the regulation of food intake containing neural circuits, which produce a number of peptides that influence food intake. The arcuate nucleus of the hypothalamus produces both orexigenic peptides (agouti-related protein and neuropeptide Y) and anorectic peptides (alpha-melanocyte-stimulating hormone and cocaine- and amphetamine-related transcript). The lateral hypothalamus produces the orexigenic peptides (melanin-concentrating hormone and orexins). Other hypothalamic factors recently implicated in appetite regulation include the endocannabinoids, brain-derived neurotrophic factor, nesfatin-1, AMP-activated protein kinase, mammalian target of rapamycin protein, and protein tyrosine phosphatase. Circulating factors that affect food intake mediate their effects by signaling to the hypothalamus and/or brainstem. A number of circulating factors are produced by peripheral organs, for example, leptin by adipose tissue, insulin and pancreatic polypeptide by the pancreas, gut hormones (e.g., ghrelin, obestatin, glucagon-like peptide-1, oxyntomodulin, peptide YY), and triiodothyronine by the thyroid gland. Circulating carbohydrates, lipids, and amino acids also affect appetite regulation. Knowledge regarding appetite regulation has vastly expanded in recent years providing targets for antiobesity drug design.
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PMID:Appetite regulation: an overview. 1754 73


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