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

Leptin, the long-sought satiety factor of adipocytes origin, has emerged as one of the major signals that relay the status of fat stores to the hypothalamus and plays a significant role in energy homeostasis. Understanding the mechanisms of leptin signaling in the hypothalamus during normal and pathological conditions, such as obesity, has been the subject of intensive research during the last decade. It is now established that leptin action in the hypothalamus in regulation of food intake and body weight is mediated by a neural circuitry comprising of orexigenic and anorectic signals, including NPY, MCH, galanin, orexin, GALP, alpha-MSH, NT, and CRH. In addition to the conventional JAK2-STAT3 pathway, it has become evident that PI3K-PDE3B-cAMP pathway plays a critical role in leptin signaling in the hypothalamus. It is now established that central leptin resistance contributes to the development of diet-induced obesity and ageing associated obesity. Central leptin resistance also occurs due to hyperleptinimia produced by exogenous leptin infusion. A defective nutritional regulation of leptin receptor gene expression and reduced STAT3 signaling may be involved in the development of leptin resistance in DIO. However, leptin resistance in the hypothalamic neurons may occur despite an intact JAK2-STAT3 pathway of leptin signaling. Thus, in addition to defective JAK2-STAT3 pathway, defects in other leptin signaling pathways may be involved in leptin resistance. We hypothesize that defective regulation of PI3K-PDE3B-cAMP pathway may be one of the mechanisms behind the development of central leptin resistance seen in obesity.
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PMID:Leptin signaling in the hypothalamus: emphasis on energy homeostasis and leptin resistance. 1472 56

Obesity is a major health problem and as a result, it is reasonable to consider pharmacological approaches alongside approaches involving diet, physical activity and lifestyle change. The currently available drugs, sibutramine and orlistat, result in modest, clinically worthwhile weight loss, with demonstrable improvements in co-morbidity, but do not meet the often unrealistic expectations of patients or health care professionals managing obese patients. There is insufficient data on efficacy or safety of other agents to support their use. Many new pharmacological approaches are under investigation. These include gut hormones, such a peptide YY (3-36) and cholecystokinin that normally signal satiety, and centrally-acting agents such as serotonin agonists, the anticonvulsants topiramate and zonisamide, cannabinoid receptor antagonists and drugs that act on other peptide neurotransmitter systems such as NPY and the melanocortins. Given the multiple pathways that influence energy balance, it is likely that therapies targeting more than one control system may be required in the future to meet the expectations and needs of patients needing to lose weight for medical reasons.
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PMID:Clinical evaluation of anti-obesity drugs. 1505 16

Antagonizing the robust stimulation of food intake by neuropeptide Y represents a new potential therapeutic approach for the treatment of obesity. Earlier pharmacological studies have pointed to the Y1 and Y5 receptors as the most likely mediators of the NPY orexigenic response. In this paper, we describe a new series of small molecule Y5 antagonists derived from a 2,4-diaryl-1H-imidazole lead. The main objectives of our structural optimization efforts were to produce novel and potent Y5 antagonists with an improved oral pharmacokinetic profile and less affinity for the hERG potassium channel compared to the lead 2,4-diarylimidazole structures. These goals were accomplished by replacement of the 2-aryl ring with a cyclohexyl ring and subsequent elaboration of the 4-position of the cyclohexyl ring with a variety of hydrophilic functionalities. The resulting compound, N-(2-hydroxy-tert-butyl)(4-[4-[3-(trifluoromethyl)phenyl]imidazol-2-yl]cyclohexyl)carboxamide (20), displayed good potency at the Y5 receptor (K(i) = 3 nM), while interactions at the hERG channel were essentially eliminated (6% inhibition at a concentration of 3 microM). Importantly, the pharmacokinetic properties of 20 (F = 36%) represented a marked improvement over that of the initial 2,4-diarylimidazole structures.
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PMID:Design, synthesis, and biological evaluation of substituted 2-cyclohexyl-4-phenyl-1H-imidazoles: potent and selective neuropeptide Y Y5-receptor antagonists. 1508 30

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.
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PMID:NPY and cohorts in regulating appetite, obesity and metabolic syndrome: beneficial effects of gene therapy. 1533 72

Ghrelin is a member of the group of growth hormone secretagogues (GHSs). It is a peptide hormone, recently isolated from stomach as an endogenous ligand for the growth hormone secretagogue receptor (GHS-R). Ghrelin is mostly produced by the stomach, although its production has been proved in various tissues. It is a potent releaser of growth hormone (GH) from anterior pituitary cells, but it also stimulates the release of other hypophyseal hormones. Ghrelin stimulates food intake and induces metabolic changes leading to an increase in body weight and body fat mass. This effect seems to be independent of GH action and needs an intact NPY/AGRP (neuropeptide Y/agouti-related protein) system. Plasma ghrelin levels are decreased in obesity, elevated in cachexia and show a diurnal rhythm. Its preprandial elevation suggests, that it might be a signal for meal initiation. Ghrelin further stimulates the release of gastric acid and gastric motility and affects pancreatic functions. It has vasodilatatory, cardioprotective and antiproliferative effects. This article is focused on ghrelin's endocrine and metabolic functions.
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PMID:Endocrine and metabolic activities of a recently isolated peptide hormone ghrelin, an endogenous ligand of the growth hormone secretagogue receptor. 1549 31

Ghrelin is a peptide produced by the stomach and released into the circulation. As a natural ligand of the growth hormone secretagogue (GHS) receptor, it stimulates growth hormone secretion but it also stimulates feeding in humans and rodents. The orexigenic effect of ghrelin has been related to AgRP/NPY and orexin pathways. We proposed that ghrelin might be involved in the susceptibility to diet induced obesity and in the regulation of macronutrient selection. We have investigated these hypotheses in two strains of rat, the Osborne-Mendel (OM) rat that prefers diets high in fat and is sensitive to dietary obesity and the S5B/P1 (S5B) rat that prefers a low fat diet and is resistant to high fat diet induced obesity. OM and S5B rats were adapted to a choice of high fat (HF) and low fat (LF) diet for 2 weeks. GHRP-2, an analogue of ghrelin, was injected intraperitoneally into satiated and 24 h fasted rats at doses of 10, 30 and 90 nmol. Food intake was measured over the next 4 h period. In satiated S5B rats, GHRP-2 stimulated intake of the LF diet in a dose dependent manner but did not affect the intake of the HF diet. In satiated OM rats, 90 nmol of GHRP-2 stimulated HF intake. In contrast, neither fasted OM nor S5B rats increased the intake of either HF or LF diet in response to GHRP-2. Fasting for 18 h induced a large rise in ghrelin mRNA in stomach of OM rats but not in S5B rats. There were no significant differences in plasma total ghrelin. An increase in ghrelin mRNA in stomach immediately before the onset of the dark cycle was observed in OM but not in S5B rats. Active ghrelin level was significantly affected by different feeding conditions in both OM and S5B rats adapted on HF diet with a trend to increase after 48 h of fasting and to decline to basal levels following 10 h of refeeding. These data suggest that ghrelin stimulates the intake of the preferred macronutrient. In addition, a differential regulation of ghrelin gene expression between OM and S5B rats may be important in their differential sensitivity to HF diet-induced obesity.
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PMID:Regulation of ghrelin gene expression in stomach and feeding response to a ghrelin analogue in two strains of rats. 1557 7

The Society for Medicines Research organized a one-day meeting on antiobesity drugs on March 26, 1998, in London. Current environmental risks for obesity include an increase in the proportion of fat consumption--especially an increase in the fat-to-carbohydrate ratio--and an increase in a sedentary life-style without an appropriate lowering in food intake. Energy balance plays a pivotal role of in the control of body stores. Knowing the mechanisms of the control of energy intake and energy expenditure provides explanations for the incidence of obesity and also possible sites for drug intervention. The genetic basis for obesity is complex, with the probability of a number of interacting genes being involved (polygenic inheritance). Each of the main components of the energy balance relationship has a distinct genetic basis. The ob gene was first identified in 1994 by Friedman, and its product is leptin, which may well be a potential target for obesity treatment. Speakers at the meeting highlighted various targets that hold promise in developing pharmacological treatments for obesity: increasing the activity of satiety factors (CCK-8, GPL-1, ACTH, alphaMSH and 5-HT acting on 5-HT(2C) receptors); inhibiting orexigenic agents (NPY, MCH, galanin); targeting thermogenesis (beta(3)-adrenergic agonists and uncoupling proteins); targeting fat absorption; and targeting neuropeptides. Some of the compounds developed to act on these sites are now becoming available.
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PMID:Update on antiobesity drugs. 1561 66

Intraventricular delivery of glial cell line-derived neurotrophic factor (GDNF) results in weight loss. We hypothesized that this effect of GDNF was likely mediated via its effects on dopaminergic neurons in the hypothalamus. Continuous rAAV-mediated GDNF expression in the hypothalamus of young and senescent rats resulted in weight loss compared to controls. However, GDNF-induced weight loss was unrelated to alterations in hypothalamic dopamine levels. The weight loss was associated with decreased food intake and increased energy expenditure, but these effects were not mediated by changes in hypothalamic NPY or POMC expression. Moreover, uncoupling protein 1 levels were unchanged in brown adipose tissue (BAT). The reduction in weight and adiposity were as great or greater in the aged rats even though aged rats are generally resistant to weight loss therapies. In summary, central GDNF gene delivery reduces weight and adiposity in young and aged rats through decreased food intake and increased energy expenditure. Our observations in aged rats suggest that GDNF may be especially effective in reducing obesity in aged obese rats.
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PMID:Hypothalamic rAAV-mediated GDNF gene delivery ameliorates age-related obesity. 1596 99

Otsuka Long Evans Tokushima Fatty (OLETF) rats have a deletion in the gene encoding the cholecystokinin-1 (CCK1) receptor. This deletion prevents protein expression, making the OLETF rat a CCK1 receptor knockout model. Consistent with the absence of CCK1 receptors, OLETF rats do not reduce their food intake in response to exogenously administered CCK and consume larger than normal meals. This deficit in within-meal feedback signaling is evident in liquid as well as solid meals. Neonatal OLETF rats show similar differences in independent ingestion tests. Intake is higher and is reflected in greater licking behavior. Neonatal OLETF rats also have diminished latencies to consume and higher initial ingestion rats. Adult OLETF rats are hyperphagic and obese. Although arcuate nucleus peptide gene expression is apparently normal in OLETF rats, when obesity is prevented through pair-feeding to amounts consumed by control Long Evans Tokushima Otsuka (LETO) rats, dorsomedial hypothalamic NPY mRNA expression is significantly elevated in OLETF rats. NPY overexpression is also evident in preobese, juvenile OLETF rats suggesting a causal role for this overexpression in the hyperphagia and obesity. Running wheel exercise normalizes food intake and body weight in OLETF rats. When access to exercise is provided at a time when OLETF rats are obese, the effects are limited to the period of exercise. When running wheel access is available to younger, preobese OLETF rats, exercise results in long lasting reductions in food intake and body weight and improved glucose regulation. These lasting metabolic effects of exercise may be secondary to an exercise induced reduction in DMH NPY mRNA expression.
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PMID:Hyperphagia and obesity of OLETF rats lacking CCK1 receptors: developmental aspects. 1677 Jul 63

Obesity is a major global epidemic, with over 300 million obese people worldwide, and nearly 1 billion overweight adults. Being overweight carries significant health risks, reduced quality of life, and impaired socioeconomic success, with profound consequences for health expenditure. The most successful treatment for obesity is gastric bypass surgery, which acts in part by reducing appetite through alterations in gut hormones. Circulating gut hormones, secreted or suppressed after eating food, act in the brain, particularly the hypothalamus, to alter hunger and fullness. Stomach-derived ghrelin increases food intake even in those with anorexia from chronic illness, while pancreatic polypeptide (PP), intestinal peptide YY 3-36 (PYY), oxyntomodulin, and other hormones reduce food intake and appetite. While obese subjects have appropriate reductions in orexigenic ghrelin, other gut-hormone disturbances may contribute to obesity such as reduced anorexigenic PYY and PP. Prader-Willi syndrome (PWS) arises from the loss of paternally inherited genes on chromosome 15q11-13, leading to life-threatening insatiable hunger and obesity from early childhood, through developmental brain, particularly hypothalamic defects. The study of genetically homogenous causes of abnormal-feeding behavior helps our understanding of appetite regulation. PWS subjects have inappropriately elevated plasma ghrelin for their obesity, at least partly explained by preserved insulin sensitivity. It remains unproven if their hyperghrelinemia or other gut-hormone abnormalities contribute to the hyperphagia in PWS, in addition to brain defects. Postmortem human hypothalamic studies and generation of animal models of PWS can also provide insight into the pathophysiology of abnormal-feeding behavior. Changes in orexigenic NPY and AGRP hypothalamic neurons, or anorexigenic oxytocin neurons have been found in illness and PWS. Functional neuroimaging studies, using PET and fMRI, will also allow us to tease apart the hormonal and brain pathways responsible for controlling human appetite, and their defects in obesity.
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PMID:The hypothalamus, hormones, and hunger: alterations in human obesity and illness. 1687 68


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