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

Ghrelin is a 28-amino-acid peptide predominantly produced by the stomach, while substantially lower amounts derive from other tissues including the pancreas. It is a natural ligand of the GH secretagogue (GHS) receptor (GHS-R1a) and strongly stimulates GH secretion, but acylation in serine 3 is needed for its activity. Ghrelin also possesses other endocrine and nonendocrine actions reflecting central and peripheral GHS-R distribution including the pancreas. The wide spectrum of ghrelin activities includes orexigenic effect, control of energy expenditure, and peripheral gastroenteropancreatic actions. Circulating ghrelin levels mostly reflect gastric secretion as indicated by evidence that they are reduced by 80% after gastrectomy and even after gastric by-pass surgery. Ghrelin secretion is increased in anorexia and cachexia but reduced in obesity, a notable exception being Prader-Willi syndrome. The negative association between ghrelin secretion and body weight is emphasized by evidence that weight increase and decrease reduces and augments circulating ghrelin levels in anorexia and obesity, respectively, and agrees with the clear negative association between ghrelin and insulin levels. In fact, ghrelin secretion is increased by fasting whereas it is decreased by glucose load as well as during euglycemic clamp but not after arginine or free fatty acid load in normal subjects; in physiological conditions, however, the most remarkable inhibitory input on ghrelin secretion is represented by somatostatin as well as by its natural analog cortistatin that concomitantly reduce beta-cell secretion. This evidence indicates that the endocrine pancreas plays a role in directly or indirectly modulating ghrelin secretion.
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PMID:Ghrelin and the endocrine pancreas. 1461 Feb 95

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.
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PMID:Neuropeptide Y: a physiological orexigen modulated by the feedback action of ghrelin and leptin. 1461 Feb 98

The healthcare burden that the obesity epidemic now poses in highly significant, in part due to increased risk of secondary chronic diseases such as hypertension. A lack of physical activity and high fat diets are major factors contributing to this condition. However, increasingly apparent is the genetic predisposition of individuals and ethnic groups to obesity. Present treatment strategies are currently inadequate and unlikely to have a major effect on the future prevalence of obesity. To slow the obesity epidemic, the source needs to be tackled now through fundamental research into the mechanisms by which obesity is manifest, and education on the risks and how to prevent it. This article will describe current and emerging treatments for obesity and review the recent advances in research that may provide the antiobesity treatments of the future. Research into obesity has escalated at considerable pace, catalysed by the discovery of the obese gene product leptin. Leptin is secreted by adipose tissue and acts via specific receptors in the brain to engage central neural pathways involved in regulating energy homeostasis. Since this discovery, numerous significant advances have been made in our understanding of how the brain integrates and responds to central and peripheral signals involved in maintaining energy homeostasis, and how disruption of these signalling mechanisms can manifest as obesity. As a consequence of these findings, numerous potential sites for therapeutic intervention into this condition have and are materializing. The aim of this review is to highlight current treatment strategies for obesity, recent advances in our understanding of the central neural control of energy balance, and what the authors consider to be the most promising targets for the development of novel antiobesity drugs in the future. Thus, the review focuses on leptin, neuropeptide Y, melanocortin and ghrelin signalling at the level of the CNS, and strategies targeting the sympathetic innervation of fat cells at the periphery.
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PMID:Emerging antiobesity drugs. 1461 Sep 23

Neurons of the arcuate nucleus of the hypothalamus appear to be sites of convergence of central and peripheral signals of energy stores, and profoundly modulate activity of the melanocortin circuits, providing strong rationale for pursuing these circuits as therapeutic targets for disorders of energy homeostasis. Recent studies in our lab and those of our collaborators have shown that leptin modulates different populations of hypothalamic cells in different ways. In this report, we outline an integrated model of leptin's action in the arcuate nucleus, derived from our electrophysiological studies of brain slice preparations taken from transgenic mice bred to express a variety of fluorescent proteins in specific cell types. We also discuss the recently withdrawn obesity drug fenfluramine, which appears to act on proopiomelanocortin neurons via serotonin (2C) receptors. Finally, we review current inquiries into the ability of the hormone ghrelin to stimulate appetite by its activation of neuropeptide Y neurons and inhibition of proopiomelanocortin neurons.
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PMID:Hypothalamic melanocortin neurons integrate signals of energy state. 1462 45

A complex system has evolved to regulate food intake and to maintain energy homeostasis. A series of short-term hormonal and neural signals that derive from the gastrointestinal tract, such as cholecystokinin (CCK), pancreatic polypeptide (PP) and peptide YY-(3-36), recently discovered to regulate meal size. Others such as ghrelin initiate meals, and insulin and leptin, together with circulating nutrients, indicate long-term energy stores. All these signals act on central nervous system sites which converge on the hypothalamus, an area that contains a large number of peptide and other neurotransmitters that influence food intake with neuropeptide Y (NPY) being one of the most prominent ones. Five Y receptors are known which mediate the action of neuropeptide Y and its two other family members, peptide YY and pancreatic polypeptide. Elevated neuropeptide Y expression in the hypothalamus leads to the development of obesity and its related phenotypes, Type II diabetes and cardiovascular disease. The limited availability of specific pharmacological tools and the considerable number of Y receptors have made it difficult to delineate their individual contributions to the regulation of energy homeostasis. However, recent studies analysing transgenic and knockout neuropeptide Y and Y receptor mouse models have started to unravel some of the individual functions of these Y receptors potentially also helping to develop novel therapeutics for a variety of physiological disorders including obesity.
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PMID:Neuropeptide Y and energy homeostasis: insights from Y receptor knockout models. 1462 47

Several physiological and pathophysiological conditions, including changes in body fat, food intake, and insulin resistance, are known to be associated with variations in plasma ghrelin concentrations. We tested the hypothesis that insulin resistance exerts a primary role by measuring ghrelin in 86 patients with nonalcoholic fatty liver disease (NAFLD), a condition in which insulin resistance is relatively independent of obesity. Compared with 40 matched healthy subjects, patients with NAFLD had similar glucose levels and higher plasma insulin and insulin resistance [homeostasis model assessment (HOMA)-R index] by over 60%. Ghrelin was reduced (mean +/- SD, 226 +/- 72 pmol/liter in NAFLD vs. 303 +/- 123 in controls; P < 0.0001). In relation to quartiles of body mass index, ghrelin progressively decreased in controls (P = 0.003), but not in patients (P = 0.926). In relation to quartiles of HOMA-R, ghrelin decreased in both groups, and significantly correlated with HOMA-R. After adjustment for age and sex, HOMA-R was the sole factor significantly associated with low ghrelin in the whole group (odds ratio, 5.79; 95% confidence interval, 2.62-12.81; P < 0.0001) and specifically in NAFLD (2.96; 1.12-7.79; P = 0.028). The study suggests that insulin resistance is a major factor controlling ghrelin levels in subjects with and without NAFLD.
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PMID:Low ghrelin concentrations in nonalcoholic fatty liver disease are related to insulin resistance. 1467 Nov 52

Metabolic and nutritional derangements are prominent features of the uremic syndrome. Recent evidence suggest that several large-molecular-weight molecules that often are elevated in uremia, such as leptin, ghrelin, and proinflammatory cytokines, may have nutritional impact in this patient group. On the basis of present knowledge, these compounds could be regarded as suspected but not established uremic toxins. The discovery of the ob gene, its product leptin, and cerebral leptin receptors has undoubtedly widened our understanding of obesity and the underlying molecular and physiologic mechanisms that regulate food intake and body weight. Moreover, the recent discovery of leptin receptor isoforms in several peripheral organs suggests that leptin besides having a central function also has several important peripheral biological functions. Because uremic patients in general have an inappropriate elevation of circulatory leptin, further research is necessary to determine the potential biological effects of elevated leptin levels in end-stage renal disease. Also, because many symptoms and findings prevalent in the uremic syndrome are known to be associated with elevated levels of proinflammatory cytokines, such as interleukin-6, future studies are needed to evaluate the role of specific anti-inflammatory treatment strategies in malnourished uremic patients.
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PMID:Leptin, ghrelin, and proinflammatory cytokines: compounds with nutritional impact in chronic kidney disease? 1468 62

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.
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PMID:Endocrine and metabolic aspects of adult Prader-Willi syndrome with special emphasis on the effect of growth hormone treatment. 1470 May 52

Ghrelin, leptin and adiponectin are three hormones which are frequently associated with metabolism, obesity and appetite. Recently, it has been shown that they may possess other physiologic roles, specially in connection with the circulation. Ghrelin infusion increases forearm blood-flow in a dose-dependent manner. Leptin has been shown to be involved not only in thermogenesis but angiogenesis as well. Adiponectin, apart from its insulin-sensitizing action, appears to modulate inflammation by inhibiting monocyte adhesion to endothelial cells. Six monkeys, which had been classified as being in the pre-diabetic state, where administered a triglyceride lowering regimen. Microvascular function was assessed using a laser Doppler flow-meter during a temperature provocation test. Percent change in flow from baseline following temperature elevation, as well as percent change in flow/degree rise in temperature were used to evaluate microvascular reserve and reactivity. Using univariate analysis, it appears that increased perfusion is significantly correlated with adiponectin, followed by leptin. Flow was also positively correlated with ghrelin, but the relationship did not attain significance. As expected, flow was also negatively and significantly correlated with fibrinogen. Trends show that flow was also negatively correlated to circulating triglyceride levels (p=0.08). The data indicate that the three hormones appear to possess microvascular actions that may impact on their other physiologic functions.
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PMID:Is microvascular flow rate related to ghrelin, leptin and adiponectin levels? 1472 68

AMP-activated protein kinase (AMPK) is the downstream component of a protein kinase cascade that acts as an intracellular energy sensor maintaining the energy balance within the cell. The finding that leptin and adiponectin activate AMPK to alter metabolic pathways in muscle and liver provides direct evidence for this role in peripheral tissues. The hypothalamus is a key regulator of food intake and energy balance, coordinating body adiposity and nutritional state in response to peripheral hormones, such as leptin, peptide YY-(3-36), and ghrelin. To date the hormonal regulation of AMPK in the hypothalamus, or its potential role in the control of food intake, have not been reported. Here we demonstrate that counter-regulatory hormones involved in appetite control regulate AMPK activity and that pharmacological activation of AMPK in the hypothalamus increases food intake. In vivo administration of leptin, which leads to a reduction in food intake, decreases hypothalamic AMPK activity. By contrast, injection of ghrelin in vivo, which increases food intake, stimulates AMPK activity in the hypothalamus. Consistent with the effect of ghrelin, injection of 5-amino-4-imidazole carboxamide riboside, a pharmacological activator of AMPK, into either the third cerebral ventricle or directly into the paraventricular nucleus of the hypothalamus significantly increased food intake. These results suggest that AMPK is regulated in the hypothalamus by hormones which regulate food intake. Furthermore, direct pharmacological activation of AMPK in the hypothalamus is sufficient to increase food intake. These findings demonstrate that AMPK plays a role in the regulation of feeding and identify AMPK as a novel target for anti-obesity drugs.
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PMID:AMP-activated protein kinase plays a role in the control of food intake. 1474 38


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