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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

Weight loss in humans requires, except during an illness, some form of imposed restriction on food intake or increase in energy expenditure. This necessitates overcoming powerful peripheral and central signals that serve to protect against negative energy balance. The identification of the systems and pathways involved has come from mouse models with genetic and targeted mutations, e.g., ob/ob and MC4 R(-/-) as well as rat models of obesity. Study of seasonal animals has shown that they undergo annual cycles of body fattening and adipose tissue loss as important adaptations to environmental change, yet these changes appear to involve mechanisms distinct from those known already. One animal model, the Siberian hamster, exhibits marked, but reversible, weight loss in response to shortening day length. The body weight is driven by a decrease in food intake with the magnitude of the loss of body weight being directly related to the length of time of exposure to short photoperiod. The most important facet of this response is that the point of energy balance is continuously re-adjusted during the transition in body weight reflecting an apparent 'sliding set point'. Studies have focused on identifying the neural basis of this mechanism. Initial studies of known genes (e.g., NPY, POMC, and AgRP) both through the measurement of gene expression in the arcuate nucleus as well as following intracerebroventricular (i.c.v.) injection indicated that the systems involved are not those involved in restoring energy balance following energy deficits. Instead, a novel mechanism of regulation is implied. Recent studies have begun to explore the neural basis of the seasonal body weight response. A discrete and novel region of the posterior arcuate nucleus, the dorsal medial posterior arcuate nucleus (dmpARC) has been identified, where a battery of gene expression changes for signalling molecules (vgf and histamine H3 receptor) and transcription factors (RXRgamma and RAR) occur in association with seasonal changes in body weight. This work provides the basis of a potentially novel mechanism of energy balance regulation.
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PMID:What can we learn from seasonal animals about the regulation of energy balance? 1687 84

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.
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PMID:Deletion of the serotonin 2c receptor from transgenic mice overexpressing leptin does not affect their lipodystrophy but exacerbates their diet-induced obesity. 1706 60

Energy homeostasis and fuel metabolism undergo significant modifications in the course of ageing. During the second half of life many humans increase their body mass and develop glucose intolerance that may lead to obesity and type 2 diabetes. However, many old people suffer from being underweight, and this "anorexia of elderly" may seriously compromise their health under certain circumstances. Experimental studies into the causes of ageing-related impairments of food intake regulation were performed mainly on rat, and to some extent, on non-human primates. It was found that the expression of NPY, the most potent orexigenic peptide, and of NPY receptors, is highly suppressed in the hypothalamus of old rats. Moreover, the increase of NPY mRNA after fasting was severely blunted in old as compared to young rats. Similar reductions, although of lower magnitude, were reported for other hypothalamic orexigenic compounds such as, AgRP and orexins. Interestingly, ageing does not significantly alter hypothalamic mRNA levels of important anorexigens such as CART and aMSH. The presented findings suggest that, at least in rodents, ageing is associated with the general down-regulation of hypothalamic peptides that stimulate food intake and unchanged expression of anorexigenic peptides. This situation may be responsible for the decreased appetite drive in senescent animals and loss of weight at the end-of-life period. If similar changes of the central control of food intake underly "anorexia of ageing" observed in some elderly, it is possible that therapeutic intervention at this regulatory level may be possible in the future.
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PMID:Central regulation of food intake in ageing. 1722 84

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

We investigated whether ghrelin depletion (by gastrectomy surgery) and/or treatment/replacement with the gastric hormone ghrelin alters the expression of key hypothalamic genes involved in energy balance, in a manner consistent with ghrelin's pro-obesity effects. At 2 weeks after surgery mice were treated with ghrelin (12 nmol/mouse/day, sc) or vehicle for 8 weeks. Gastrectomy had little effect on the expression of these genes, with the exception of NPY mRNA in the arcuate nucleus that was increased. Ghrelin treatment (to gastrectomized and sham mice) increased the mRNA expression of orexigenic peptides NPY and AgRP while decreasing mRNA expression of the anorexigenic peptide POMC. Two weeks gavage treatment with the ghrelin mimetic, MK-0677, to rats increased NPY and POMC mRNA in the arcuate nucleus and MCH mRNA in the lateral hypothalamus. Thus, while predicted pro-obesity ghrelin signalling pathways were activated by ghrelin and ghrelin mimetics, these were largely unaffected by gastrectomy.
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PMID:Hypothalamic gene expression following ghrelin therapy to gastrectomized rodents. 1793 72

A combination of pharmacological and genetic studies in mice confirmed that the Y1 and Y5 receptors mediate the potent orexigenic actions of exogenous NPY. Although the physiological role of NPY in causing obesity is less clear, potent and selective antagonists of both Y1 and Y5 have been developed. Some of the NPY antagonists have suitable pharmacokinetic (PK) properties that allowed them to be evaluated in various rodent models of obesity. Several different Y1 and Y5 antagonists cause weight loss in rodent models, though confirmation that these effects are mechanism based has been limited. One Y5 antagonist, MK-0557 was evaluated in a 1-yr clinical trial and found to cause modest weight loss. Optimal NPY antagonist therapeutics for obesity may require blockade of both the Y1 and Y5 receptors.
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PMID:NPY Y1 and Y5 receptor selective antagonists as anti-obesity drugs. 1797 81

Cholecystokinin (CCK) is a brain gut peptide that plays an important role in satiety. CCK inhibits food intake by reducing meal size. CCK's satiety actions are mediating through its interaction with CCK1 receptors. Otsuka Long Evans Tokushima Fatty (OLETF) rats are a CCK1 receptor knockout model that allows the study of multiple CCK functions. OLETF rats are hyperphagic with the hyperphagia expressed as a significant increase in the size of meals. OLETF rat obesity is secondary to the hyperphagia and has been proposed to derive from two regulatory deficits. One is secondary to the loss of a feedback satiety signal. The other results from increased dorsomedial hypothalamic NPY expression. Recent studies have examined developmental aspects of altered feeding, body weight and orexigenic signaling in OLETF rats. OLETF rats demonstrate increases in meal size in independent ingestion tests as early as two days of age. OLETF pups are also more efficient in suckling situations. Consistent with such developmental differences, examinations of patterns of hypothalamic gene expression in OLETF pups indicate significant increases in DMH NPY expression as early as postnatal day 15. Access to a running wheel and the resulting exercise have age dependent effects on OLETF food intake and obesity. With running wheel access shortly after weaning, food intake decreases to the levels of LETO controls. When running wheel access is discontinued, food intake temporarily increases resulting in an intermediate phenotype and the absence of diabetes. Together these data demonstrate roles for peripheral CCK and CCK in feeding and body weight control and support the use of the OLETF rat as a model for examining obesity development and for investigating how interventions at critical developmental time points can alter genetic influences on food intake and body weight.
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PMID:Unraveling the obesity of OLETF rats. 1819 Sep 34

Hypothalamic-pituitary-adrenal (HPA) axis hyperactivity occurs in type 2 diabetes, and stress is assumed to play a causal role. However, intermittent restraint stress, a model mimicking some mild stressors, delays development of hyperglycemia in Zucker diabetic fatty (ZDF) rats. We examine whether such stress delays hyperglycemia independent of stress-induced reductions in hyperphagia and is due to adaptations in gene expression of HPA-related peptides and receptors that ameliorate corticosteronemia and thus hyperglycemia. ZDF rats were intermittently restraint stressed (1 h/d, 5 d/wk) for 13 wk and compared with obese control, pair fed, and lean ZDF rats. After 13 wk, basal hormones were repeatedly measured over 24 h, and HPA-related gene expression was assessed by in situ hybridization. Although restraint initially induced hyperglycemia, this response habituated over time, and intermittent restraint delayed hyperglycemia. This delay was partly related to 5-15% decreased hyperphagia, which was not accompanied by decreased arcuate nucleus NPY or increased POMC mRNA expression, although expression was altered by obesity. Obese rats demonstrated basal hypercorticosteronemia and greater corticosterone responses to food/water removal. Basal hypercorticosteronemia was further exacerbated after 13 wk of pair feeding during the nadir. Importantly, intermittent restraint further delayed hyperglycemia independent of food intake, because glycemia was 30-40% lower than after 13 wk of pair feeding. This may be mediated by increased hippocampal MR mRNA, reduced anterior pituitary POMC mRNA levels, and lower adrenal sensitivity to ACTH, thus preventing basal and stress-induced hypercorticosteronemia. In contrast, 24-h catecholamines were unaltered. Thus, rather than playing a causal role, intermittent stress delayed deteriorations in glycemia and ameliorated HPA hyperactivity in the ZDF rat.
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PMID:Adaptation to mild, intermittent stress delays development of hyperglycemia in the Zucker diabetic Fatty rat independent of food intake: role of habituation of the hypothalamic-pituitary-adrenal axis. 1832 96

Detailed knowledge of the pathways by which ghrelin and leptin signal to AMPK in hypothalamic neurons and lead to regulation of appetite and glucose homeostasis is central to the development of effective means to combat obesity. Here we identify CaMKK2 as a component of one of these pathways, show that it regulates hypothalamic production of the orexigenic hormone NPY, provide evidence that it functions as an AMPKalpha kinase in the hypothalamus, and demonstrate that it forms a unique signaling complex with AMPKalpha and beta. Acute pharmacologic inhibition of CaMKK2 in wild-type mice, but not CaMKK2 null mice, inhibits appetite and promotes weight loss consistent with decreased NPY and AgRP mRNAs. Moreover, the loss of CaMKK2 protects mice from high-fat diet-induced obesity, insulin resistance, and glucose intolerance. These data underscore the potential of targeting CaMKK2 as a therapeutic intervention.
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PMID:Hypothalamic CaMKK2 contributes to the regulation of energy balance. 1846 Mar 26


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