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

Hypothalamic neuropeptide Y (NPY) has been implicated in the regulation of energy balance and reproduction, and chronically elevated NPY levels in the hypothalamus are associated with obesity and reduced reproductive function. However, it is not known which one of the five cloned Y receptors mediates these effects. Here we show that crossing the Y4 receptor knockout mouse (Y4(-/-)) onto the ob/ob background restores the reduced plasma testosterone levels of ob/ob mice as well as the reduced testis and seminal vesicle size and morphology to control values. Fertility in the sterile ob/ob mice was greatly improved by Y4 receptor deletion, with 100% of male and 50% of female Y4(-/-),ob/ob double knockout mice producing live offspring. Development of the mammary ducts and lobuloalveoli was significantly enhanced in pregnant Y4(-/-) and Y4(-/-),ob/ob females. Consistent with the improved fertility and enhanced mammary gland development, gonadotropin releasing hormone (GnRH) expression was significantly increased in Y4(-/-) and Y4(-/-),ob/ob animals. Y4(-/-) mice displayed lower body weight and reduced white adipose tissue mass accompanied by increased plasma levels of pancreatic polypeptide (PP). However, Y4 deficiency had no beneficial effects to reduce body weight or excessive adiposity of ob/ob mice. These data suggest that central Y4 receptor signaling specifically inhibits reproductive function under conditions of elevated central NPY-ergic tonus.
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PMID:Y4 receptor knockout rescues fertility in ob/ob mice. 1200 Jul 91

Neuropeptide Y is implicated in energy homeostasis, and contributes to obesity when hypothalamic levels remain chronically elevated. To investigate the specific role of hypothalamic Y2 receptors in this process, we used a conditional Y2 knockout model, using the Cre-lox system and adenoviral delivery of Cre-recombinase. Hypothalamus-specific Y2-deleted mice showed a significant decrease in body weight and a significant increase in food intake that was associated with increased mRNA levels for the orexigenic NPY and AgRP, as well as the anorexic proopiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART) in the arcuate nucleus. These hypothalamic changes persisted until at least 34 days after Y2 deletion, yet the effect on body weight and food intake subsided within this time. Plasma concentrations of pancreatic polypeptide and corticosterone were 3- to 5-fold increased in hypothalamus-specific Y2 knockout mice. Germ-line Y2 receptor knockout also produced a significant increase in plasma levels of pancreatic polypeptide. However, these mice differed from conditional knockout mice in that they showed a sustained reduction in body weight and adiposity associated with increased NPY and AgRP but decreased POMC and CART mRNA levels in the arcuate nucleus. The transience of the observed effects on food intake and body weight in the hypothalamus-specific Y2 knockout mice, and the difference of this model from germ-line Y2 knockout mice, underline the importance of conditional models of gene deletion, because developmental, secondary, or extrahypothalamic mechanisms may mask such effects in germ-line knockouts.
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PMID:Important role of hypothalamic Y2 receptors in body weight regulation revealed in conditional knockout mice. 1207 62

Neuropeptide Y (NPY) in the central nervous system is a major regulator of food consumption and energy homeostasis. It also regulates blood pressure, induces anxiolysis, enhances memory retention and affects circadian rhythms, as well as modulates hormone release. Five Y receptors are known that mediate the action of NPY and its two other family members, peptide YY and pancreatic polypeptide. Increased NPY signaling due to elevated NPY expression in the hypothalamus leads to the development of obesity and its related phenotypes, type 2 diabetes and cardiovascular disease. Dysregulation in NPY signaling also causes alterations in bone formation. The large number of Y receptors has made it difficult to delineate their individual contributions to these physiological processes. However, recent studies analyzing Y-receptor knockout models have started to unravel some of the individual functions of these Y receptors. Particularly, the use of conditional knockout models has made it possible to pinpoint a specific functional contribution to an individual Y receptor in a particular location. From these studies, the predominantly presynaptically expressed Y2 receptor in the arcuate nucleus of the hypothalamus has emerged as a prime candidate for mediating satiety as well as a candidate for regulating bone formation. (c) 2002 Prous Science. All rights reserved.
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PMID:Hypothalamic Y2 Receptors: Central Coordination of Energy Homeostasis and Bone Mass Regulation. 1267 89

Neuropeptide Y regulates numerous physiological processes via at least five different Y receptors, but the specific roles of each receptor are still unclear. We previously demonstrated that Y2 receptor knockout results in a lean phenotype, increased cancellous bone volume, and an increase in plasma pancreatic polypeptide (PP), a ligand for Y4 receptors. PP-overexpressing mice are also known to have a lean phenotype. Deletion of the Y4 receptor also produced a lean phenotype and increased plasma PP levels. We therefore hypothesized that part of the Y2 phenotype results from increased PP action on Y4 receptors and tested this in PP transgenic Y4(-/-) and Y2(-/-) Y4(-/-) double knockout mice. Bone mass was not altered in Y4 knockout mice. Surprisingly, despite significant hyperphagia, Y2(-/-) Y4(-/-) mice retained a markedly lean phenotype, with reduced body weight, white adipose tissue mass, leptinemia, and insulinemia. Furthermore, bone volume was also increased threefold in Y2(-/-) Y4(-/-) mice, and this was associated with enhanced osteoblastic activity. These changes were more pronounced than those observed in Y2(-/-) mice, suggesting synergy between Y2 and Y4 receptor pathways. The lack of bone changes in PP transgenic mice suggests that PP alone is not responsible for the bone mass increases but might play a major role in the lean phenotype. However, a synergistic interaction between Y2 and Y4 pathways seems to regulate bone volume and adiposity and could have important implications for possible interventions in obesity and for anabolic treatment of osteoporotic bone loss.
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PMID:Synergistic effects of Y2 and Y4 receptors on adiposity and bone mass revealed in double knockout mice. 1286 Oct 9

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

There is evidence from animal models of obesity and type 2 diabetes that increased parasympathetic vagal input to the pancreas contributes to hyperinsulinemia. Compared with Caucasians, Pima Indians have a high risk of type 2 diabetes and exhibit marked hyperinsulinemia and elevated plasma levels of pancreatic polypeptide (PP), an islet hormone considered a surrogate marker of parasympathetic nervous system (PNS) drive to the pancreas. To test if hyperinsulinemia in Pima Indians is due to increased vagal input to the beta-cell, we examined the effect of PNS blockade in 17 Caucasian (aged 35 +/- 8 years, body fat 23 +/- 7% [mean +/- SD]) and 17 Pima Indian males (aged 28 +/- 8 years, body fat 29 +/- 5%) with normal glucose tolerance. Each participant underwent four consecutive standardized liquid meal tests (64% carbohydrate, 22% fat, and 14% protein) during which a primed infusion of atropine was administered for 120 min at the following doses: 0, 2.5, 5, and 10 micro g. kg fat-free mass (FFM)(-1). h(-1). Areas under the curve for early (AUC(0-30 min)) and total (AUC(0-120 min)) postprandial insulin and PP secretory responses were calculated. Early postprandial insulin and PP secretory responses were higher in Pima Indians compared with those of Caucasians (both P = 0.01). Secretion of insulin and PP was inhibited by atropine (both P < 0.001). Increasing doses of atropine attenuated the ethnic difference in PP (P = 0.01) but not in early insulin secretory responses (P = 0.6), an effect that was not due to differences in gastric emptying rate (acetaminophen test) and/or circulating glucose. Similar results were observed for total secretory responses. These results confirm that compared with Caucasians, Pima Indians have an exaggerated PNS drive to pancreatic F-cells that secrete PP. However, the hyperinsulinemia of this population does not appear to be due to increased vagal input to pancreatic beta-cells.
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PMID:Parasympathetic blockade attenuates augmented pancreatic polypeptide but not insulin secretion in Pima Indians. 1498 50

The gastrointestinal tract and the pancreas release hormones regulating satiety and body weight. Ghrelin stimulates appetite, and glucagon-like peptide-1, oxyntomodulin, peptide YY, cholecystokinin, and pancreatic polypeptide inhibit appetite. These gut hormones act to markedly alter food intake in humans and rodents. Obesity is the current major cause of premature death in the United Kingdom, killing almost 1000 people per week. Worldwide, its prevalence is accelerating. There is currently no effective answer to the pandemic of obesity, but replacement of the low levels of peptide YY observed in the obese may represent an effective antiobesity therapy.
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PMID:Minireview: Gut peptides regulating satiety. 1504 53

Signals generated by the gastrointestinal tract are able to regulate appetite and influence body weight. Ghrelin is an orexigenic peptide produced by the stomach. Satiety signals derived from the intestine and pancreas include peptide YY, pancreatic polypeptide, glucagon-like peptide 1, oxyntomodulin, and cholecystokinin. Signals from the gut and adipose tissue are integrated in the central nervous system to provide energy homeostasis. Knowledge of the body's control of appetite is important because we strive to combat obesity in man.
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PMID:The gut and regulation of body weight. 1518 Oct 26

Obesity is one of the greatest threats to the health of the developed world. In order to design effective drugs to treat the alarming increase in obesity, it is essential to understand the physiology of normal appetite control and the pathophysiology of obesity. The hypothalamus interprets and integrates neural and humoral inputs to provide a coordinated feeding and energy expenditure response. Recent evidence suggests that certain gut hormones - ghrelin, polypeptide YY, pancreatic polypeptide, glucagon-like-peptide 1 and oxyntomodulin - have a physiological role in governing satiety via the hypothalamus. Gut hormone appetite-regulatory systems represent a potential target for the design of antiobesity drugs.
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PMID:Gut hormones in the control of appetite. 1518 57

Neuropeptide Y (NPY) in the central nervous system is a major regulator of food consumption and energy homeostasis. It also regulates blood pressure, induces anxiolysis, enhances memory retention, affects circadian rhythms and modulates hormone release. Five Y receptors (Y1, Y2, Y4, Y5 and Y6) are known to mediate the action of NPY and its two other family members, peptide YY (PYY) and pancreatic polypeptide (PP). Increased NPY signaling due to elevated NPY expression in the hypothalamus leads to the development of obesity and its related phenotypes, Type II diabetes and cardiovascular disease. Dysregulation in NPY signaling also causes alterations in bone formation, alcohol consumption and seizure susceptibility. The large number of Y receptors has made it difficult to delineate their individual contributions to these physiological processes. However, recent studies analysing NPY and Y receptor overexpressing and knockout models have started to unravel some of the different functions of these Y receptors. Particularly, the use of conditional knockout models has made it possible to pinpoint a specific function to an individual Y receptor in a particular location.
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PMID:NPY and Y receptors: lessons from transgenic and knockout models. 1533 71


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