Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Obesity shortens life expectancy. The peripheral administration of peptide YY3-36 (PYY3-36) inhibits food intake in mice and rats. The effects of PYY3-36 on food intake have been assessed in obese and lean subjects in a double-blind, placebo-controlled, cross-over study. In fasting obese and lean subjects, infusion of PYY3-36 reduced the caloric intake in 24 h by 17 and 24%, respectively. Long-term studies to determine whether PYY3-36 reduces food intake in freely fed humans are now required.
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PMID:Can food intake be reduced with peptide YY3-36? 1501 46

Batterham et al. report that the gut peptide hormone PYY3-36 decreases food intake and body-weight gain in rodents, a discovery that has been heralded as potentially offering a new therapy for obesity. However, we have been unable to replicate their results. Although the reasons for this discrepancy remain undetermined, an effective anti-obesity drug ultimately must produce its effects across a range of situations. The fact that the findings of Batterham et al. cannot easily be replicated calls into question the potential value of an anti-obesity approach that is based on administration of PYY3-36.
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PMID:Physiology: does gut hormone PYY3-36 decrease food intake in rodents? 1216 64

Prader-Willi syndrome (PWS) is characterized by life-threatening childhood-onset hyperphagia, obesity and, uniquely, high plasma levels of ghrelin, the orexigenic gastric hormone. Somatostatin suppresses ghrelin secretion in normal subjects. We therefore examined the effect of somatostatin on plasma ghrelin and appetite in four male PWS adults fasted overnight in a double-blind, placebo-controlled, randomized cross-over study. Subjects received an intravenous infusion of somatostatin (250 microg/hr) or saline for 300 min, and had blood samples taken every 30 min for measurement of plasma ghrelin and PYY3-36 (anorexigenic intestinal hormone) by radio-immunoassay, and glucose. Appetite was measured by counting sandwiches eaten over a 60 min free food access period from +120 min. Despite somatostatin lowering fasting plasma ghrelin by 60 +/- 2% (P = 0.04) to levels seen in non-PWS men, there was no associated reduction in food intake (105 +/- 9% of food intake during saline infusion, P = 0.6). Somatostatin also lowered plasma PYY levels by 45 +/- 16% (P = 0.04), and produced post-prandial hyperglycemia (P = 0.04). We conclude that either hyperghrelinemia may not contribute to hyperphagia in PWS adults, or perhaps concomitant reductions in anorexigenic gastrointestinal hormones by somatostatin counteracted any anorexigenic effect of lowering orexigenic ghrelin. Somatostatin analogues may therefore not be an effective therapy for obesity in PWS. Larger chronic studies with long-acting somatostatin analogues will be needed to determine their benefits and risks in treating PWS obesity.
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PMID:Somatostatin infusion lowers plasma ghrelin without reducing appetite in adults with Prader-Willi syndrome. 1529 65

Many peptides are synthesised and released from the gastrointestinal tract. Although their roles in the regulation of gastrointestinal function have been known for some time, it has become increasingly evident that they also influence eating behaviour. Peptide YY (PYY) is released postprandially from gastrointestinal L-cells with glucagon-like peptide 1 (GLP-1) and oxyntomodulin. Following peripheral administration of PYY3-36, the circulating form of PYY, to mouse, rat or human there is marked inhibition of food intake. Obese subjects have lower basal fasting PYY levels and have a smaller postprandial rise. However, obesity does not appear to be associated with resistance to PYY (as it is with leptin) and exogenous infusion of PYY3-36 results in a reduction in food intake by 30% in an obese group and 31% in a lean group at a buffet meal. Overall PYY significantly reduced 24-h caloric intake in both obese (16.5%) and lean groups (23.5%). Obesity is the current major cause of premature death in the UK, killing almost 1000 people a week. Worldwide its prevalence is accelerating. The administration of the naturally occurring gut hormone may offer a long-term therapeutic approach to weight control. Here, the therapeutic potential of PYY is considered.
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PMID:The therapeutic potential of gut hormone peptide YY3-36 in the treatment of obesity. 1592 70

Obesity is taking on pandemic proportions. The laws of thermodynamics, however, remain unchanged, as energy will be stored if less energy is expended than consumed; the storage is usually in the form of adipose tissue. Several neural, humeral and psychological factors control the complex process known as appetite. Recently, a close evolutionary relationship between the gut and brain has become apparent. The gut hormones regulate important gastrointestinal functions such as motility, secretion, absorption, provide feedback to the central nervous system on availability of nutrients and may play a part in regulating food intake. Peptide YY (PYY) is a thirty-six amino acid peptide related to neuropeptide Y (NPY) and is co-secreted with glucagon-like peptide 1. Produced by the intestinal L-cells, the highest tissue concentrations of PYY are found in distal segments of the gastrointestinal tract, although it is present throughout the gut. Following food intake PYY is released into the circulation. PYY concentrations are proportional to meal energy content and peak plasma levels appear postprandially after 1 h. PYY3-36 is a major form of PYY in both the gut mucosal endocrine cells and the circulation. Peripheral administration of PYY3-36 inhibits food intake for several hours in both rodents and man. The binding of PYY3-36 to the Y2 receptor leads to an inhibition of the NPY neurones and a possible reciprocal stimulation of the pro-opiomelanocortin neurones. Thus, PYY3-36 appears to control food intake by providing a powerful feedback on the hypothalamic circuits. The effect on food intake has been demonstrated at physiological concentrations and, therefore, PYY3-36 may be important in the everyday regulation of food intake.
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PMID:Peptide YY, appetite and food intake. 1596 Aug 66

The Center for Business Intelligence (CBI) presented this 2-day conference as part of its business of discovery series. The meeting, which targeted senior level industry personnel, highlighted the latest developments in the search for effective and safe obesity drugs. The adverse health consequences and growing prevalence of obesity make this condition a major worldwide public health concern. Consistent with the multi-faceted nature of the body weight regulatory system, the presentations featured a variety of approaches aimed at different neuroendocrine and peripheral tissue targets. Clinical as well as basic data on agents in various stages of development were presented. These included rimonabant, an inhibitor of the endocannabinoid system, which has undergone extensive phase III clinical testing, and two selective 5-HT(2C) agonists, ATH-88651 (Athersys Inc) and APD-356 (Arena Pharmaceuticals Inc), which are in earlier stage development. Synthetic analogs of the gut and islet peptide hormones, PYY3-36 and amylin, which are in early-stage development as anorexigenic agents, were also discussed. More basic research-oriented presentations featured the potential therapeutic utility of melanocortin 4 receptor agonists and the inhibition of the gastric peptide ghrelin and the enzymes diacylglycerol acyltransferase 1 and 11beta-hydroxysteroid dehydrogenase 1. Another presentation addressed the problem of leptin resistance. A novel technology that measures extracellular flux rates and its application in screening obesity agents that target thermogenesis was also discussed.
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PMID:Obesity Drug Development Summit. 21-22 July, 2005, Arlington, VA, USA. 1611 85

The neuropeptide Y (NPY)/peptide YY (PYY) system has been implicated in the physiology of obesity for several decades. More recently ignited enormous interest in PYY3-36, an endogenous Y2-receptor agonist, as a promising anti-obesity compound. Despite this interest, there have been remarkably few subsequent reports reproducing or extending the initial findings, while at the same time studies finding no anti-obesity effects have surfaced. Out of 41 different rodent studies conducted (in 16 independent labs worldwide), 33 (83%) were unable to reproduce the reported effects and obtained no change or sometimes increased food intake, despite use of the same experimental conditions (i.e. adaptation protocols, routes of drug administration and doses, rodent strains, diets, drug vendors, light cycles, room temperatures). Among studies by authors in the original study, procedural caveats are reported under which positive effects may be obtained. Currently, data speak against a sustained decrease in food intake, body fat, or body weight gain following PYY3-36 administration and make the previously suggested role of the hypothalamic melanocortin system unlikely as is the existence of PYY deficiency in human obesity. We review the studies that are in the public domain which support or challenge PYY3-36 as a potential anti-obesity target.
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PMID:PYY3-36 as an anti-obesity drug target. 1624 16

A number of anti-obesity drugs are currently undergoing clinical development. These include: (i) centrally-acting drugs, such as the noradrenergic and dopaminergic reuptake inhibitor radafaxine, the endocannabinoid antagonist rimonabant, the selective serotonin 5-HT2c agonist APD-356, and oleoyl-estrone; (ii) drugs that target peripheral episodic satiety signals, such as glucagon-like peptide-1 (exenatide, exenatide-LAR and liraglutide), peptide YY (intranasal PYY3-36 and AC-162325) and amylin (pramlintide); (iii) drugs that block fat absorption, such as the novel lipase inhibitors cetilistat and GT-389255; and (iv) a human growth hormone fragment (AOD-9604) that increases adipose tissue breakdown. Of these, only rimonabant has got as far as completing phase III clinical trials. This review will provide an overview of the most prominent drugs currently undergoing clinical development as potential anti-obesity therapies.
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PMID:Obesity drugs in clinical development. 1662 17

Appetite and satiety are subject to complex regulation, with neuroendocrine mechanisms playing an important role. The central nervous system is attracting increasing attention as a target tissue for many hormones such as leptin, PYY3-36, ghrelin, glucagon-like-peptide 1 and many others. Among its many well-known functions, insulin is also a potent anorexigenic hormone, and insulin receptors are widely distributed throughout the central nervous system. One way to advance our understanding of central nervous regulation of hunger and satiety in humans is to develop suitable neuroimaging techniques for use in various clinical and experimental conditions. Several studies have been performed using functional magnetic resonance imaging and positron emission tomography to identify areas of the brain that are differentially activated by alteration of the feeding state. These preliminary data are taking shape as a complex neuronal network involving the hypothalamus, thalamus, limbic and paralimbic areas including the insular cortex and the anterior cingulate gyrus and the orbitofrontal cortex. Continuous efforts to understand hormonal effects on these pathways may advance our understanding of human obesity.
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PMID:The effects of insulin on the central nervous system--focus on appetite regulation. 1693 79

Obesity represents the most prevalent nutritional problem worldwide which in the long run predisposes to development of diabetes mellitus, hypertension, endometrial carcinoma, osteoarthritis, gall stones and cardiovascular diseases. Despite significant reductions in dietary fat consumption, the prevalence of obesity is on a rise and is taking on pandemic proportions. Obesity develops when energy intake exceeds energy expenditure over time. Recently, a close evolutionary relationship between the peripheral and hypothalamic neuropeptides has become apparent. The hypothalamus being the central feeding organ mediates regulation of short-term and long-term dietary intake via synthesis of various orexigenic and anorectic neuropeptides. The structure and function of many hypothalamic peptides (neuropeptide Y (NPY), melanocortins, agouti-related peptide (AGRP), cocaine and amphetamine regulated transcript (CART), melanin concentrating hormone (MCH), orexins have been characterized in rodent models The peripheral neuropeptides such as cholecystokinin (CCK), ghrelin, peptide YY (PYY3-36), amylin, bombesin regulate important gastrointestinal functions such as motility, secretion, absorption, provide feedback to the central nervous system on availability of nutrients and may play a part in regulating food intake. The pharmacological potential of several endogenous peripheral peptides released prior to, during and/or after feeding are being explored. Long-term regulation is provided by the main circulating hormones leptin and insulin. These systems implicated in hypothalamic appetite regulation provide potential targets for treatment of obesity which could potentially pass into clinical development in the next 5 years. This review summarizes various effects and interrelationship of these central and peripheral neuropeptides in metabolism, obesity and their potential role as targets for treatment of obesity.
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PMID:Role of neuropeptides in appetite regulation and obesity--a review. 1693 29


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