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

Obesity is a major risk factor for morbidity and mortality, and a series of pharmacologic approaches are available for helping to manage the problem. Obesity is caused by an imbalance between caloric intake and energy expenditure, which is influenced by both environmental and genetic factors. Pharmacologic treatments include anorexigenic agents, which fall into two broad categories: those that act via brain catecholamine pathways and those that act via serotonin pathways. The most recent oral agents approved are dexfenfluramine, which is currently being marketed, and sibutramine. Both agents inhibit the control reuptake of serotonin but in addition may have effects on thermogenesis. Under investigation are agents that increase energy expenditure: the beta 3-adrenergic receptor agonists and drugs that prevent the intestinal absorption of free fatty acids and cholesterol. In development are innovative approaches to influence leptin and its receptors, various obesity genes, and biologic substances thought to influence satiety (neuropeptide Y, enterostatin, cholecystokinin, bombesin, and amylin). Obesity has now become a major target for drug development not only for affecting obesity per se but also for managing and preventing comorbid conditions such as diabetes and cardiovascular disease.
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PMID:The pharmacologic approach to the treatment of obesity. 920 52

Synthesis and release of neuropeptide Y (NPY) are both regulated by leptin binding to its hypothalamic receptor mediating some of the effects of leptin on food intake. Moreover, NPY administration is a powerful stimulant of feeding behaviour. Thus, we investigated the potential implication of NPY, NPY-Y1 and -Y5 subtype receptors [rNPY-Y1/-Y5] in the development of human obesity. Two complementary genetic approaches were used: 1) linkage analyses between obesity and polymorphic markers located nearby NPY and rNPY-Y1/-Y5 genes (respectively on chromosomes 7p15.1 and 4q[31.3-32]) in 93 French Caucasian morbidly obese families; 2) single strand conformation polymorphism (SSCP) scanning of the coding region of the NPY and rNPY-Y1 genes performed in 50 unrelated obese patients ascertained on the basis of a body mass index of 27 kg/m2 or more and a family history of obesity. No evidence of linkage between morbid obesity or obesity-related quantitative traits and NPY and rNPY-Y1/ Y5 regions was found in this population. Moreover, SSCP scanning revealed no mutation in the coding region of NPY and rNPY-Y1 genes among obese subjects. These results suggest that NPY and NPY-Y1/ Y5 receptors are unlikely to be implicated in the development of human morbid obesity, at least in the French Caucasian population.
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PMID:Genetic studies of neuropeptide Y and neuropeptide Y receptors Y1 and Y5 regions in morbid obesity. 922 46

The discovery of both neuropeptide Y and of leptin has led to a better understanding of the pathophysiology of obesity syndromes in animal models. It has strengthened the concept of the importance of the hypothalamus in the etiology of these syndromes. Due to alterations in the regulation of the hypothalamus, e.g. by insulin, by leptin or by decreases in the availability of glucose in specific brain areas, most animal models of obesity have higher than normal hypothalamic neuropeptide Y levels. As neuropeptide Y is a potent orexigenic agent, this hypothalamic defect explains why obese rodents are hyperphagic. Increased hypothalamic neuropeptide Y levels produce hyperinsulinemia and hypercorticism, two abnormalities previously reported in obesity, but whose origin is now known to be driven by neuropeptide Y. As hyperinsulinemia favors lipid accretion and muscle insulin resistance, and as hypercorticism favors the occurrence of both high circulating triglyceride levels and muscle insulin resistance, it may be appreciated that most disorders previously reported in obesity can now be explained by high hypothalamic neuropeptide Y levels. Leptin, produced and secreted by adipose tissue, is a potent anorectic agent whose main action is exerted within the hypothalamus in which it has been shown to decrease neuropeptide Y, therefore food intake. Leptin secretion is favored, in particular, by insulin as well as by glucocorticoids. When leptin is administered to obese mice of the ob/ob strain (which do not produce nor secrete leptin due to a gene mutation), their food intake, body weight and most metabolic abnormalities are normalized. However, in the majority of genetically obese rodents, as well as in obese humans, circulating levels of leptin are high. This is related to hyperinsulinemia- and hypercorticosteronemia-induced leptin oversecretion, as well as to central leptin receptor dysfunctions preventing normal leptin access to and action within specific brain areas. Under these conditions and to prevent the effects of elevated hypothalamic neuropeptide Y levels, neuropeptide Y antagonists or active leptin agonists must be found. Neuropeptide Y and leptin further underline the existence of functional relationship between the brain (hypothalamus) and the periphery (adipose tissue, muscle). Lack of leptin (mutated leptin gene) or inefficient leptin action (leptin receptor defect) results in increased hypothalamic neuropeptide Y levels. The latter favor hyperinsulinemia and hypercorticism both producing oversecretion of leptin which, when inefficient, cannot decrease neuropeptide Y: a vicious circle is created which maintains either a "thrifty phenotype" favoring fat depot or overt obesity, depending on the degree of hyperphagia.
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PMID:Central nervous system and body weight regulation. 923 33

The role of neuropeptide Y (NPY), leptin and 5-HT and other neurotransmitters implicated in the regulation of energy balance are only now being fully investigated. Little is known about how they may interact with each other in this complex process. In evolutionary terms, the availability of excess food, and the risk of obesity, is only a recent occurrence in humans. Man, and perhaps other species, may not have developed a specialised neurochemical system for adjusting food intake during obesity. Hence perturbation of a single system, such as hypothalamic NPY or leptin, is unlikely to be directly responsible for the development of most obesity. In contrast, periods of food deprivation and partial starvation have been common in the animal kingdom and the multitude of neurotransmitters implicated in energy balance are more likely to be directed towards increasing food consumption and conserving energy than reducing appetite and increasing thermogenesis in the presence of excess. The last few years have witnessed rapid advances in the understanding of the fundamental mechanisms that regulate body weight and fat content. This progress will undoubtedly continue in the future, and it is hoped that this will be rewarded with the development of new drugs to treat obesity. At present, however, it is unclear whether NPY, leptin, or other apparently strong candidates will be the winner in the lucrative race for the ideal anti-obesity drug.
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PMID:Neurobiology. 924 37

The fatty Zucker rat has impaired heat production and fails to mount an adequate thermogenic response to cold exposure, partly because of decreased sympathetic drive to thermogenesis in brown adipose tissue. Neuropeptide Y, synthesized in neurons of the hypothalamic arcuate nucleus and released in the paraventricular nucleus, stimulates feeding and inhibits brown adipose tissue activity. The neuropeptide Y neurons are overactive in fatty Zucker rats and are thought to contribute to hyperphagia, reduced energy expenditure and obesity. We have examined the relationship between thermogenic activity in brown adipose tissue (measured as uncoupling protein messenger RNA levels) and hypothalamic neuropeptide Y and neuropeptide Y messenger RNA levels in response to cold exposure (4 degrees C) for 2.5 and 18 h, in fatty and lean Zucker rats. In lean Zucker rats, cold exposure at 4 degrees C for 2.5 and 18 h significantly increased uncoupling protein messenger RNA levels by 3.5-fold (P<0.01) and 3.3-fold (P<0.01), respectively, compared with warm-maintained controls. Exposure to cold for 18 h also increased neuropeptide Y concentrations in the paraventricular nucleus (P<0.01) and ventromedial nucleus (P<0.001) in lean rats, with no change in neuropeptide Y messenger RNA after either 2.5 or 18 h. By contrast, fatty Zucker rats showed no significant changes in uncoupling protein messenger RNA (P>0.05) at either duration of cold exposure. There were also no significant changes in neuropeptide Y levels in any region nor in neuropeptide Y messenger RNA, with cold exposure for either period (P>0.05). In lean rats, cold exposure therefore stimulates brown fat uncoupling protein messenger RNA and also increases neuropeptide Y concentrations in its hypothalamic sites of release. We suggest that increased brown fat thermogenic capacity induced by cold in lean rats may be mediated, at least in part, by decreased neuropeptide Y release in the paraventricular nucleus, resulting in its accumulation in this site. Defective thermogenic responses in fatty rats may result from central dysregulation of brown adipose tissue due to sustained and non-suppressible overactivity of hypothalamic neuropeptide Y neurons.
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PMID:Role of hypothalamic neuropeptide Y neurons in the defective thermogenic response to acute cold exposure in fatty Zucker rats. 925 38

Leptin, the ob gene product, is released from adipose tissue and likely acts in the central nervous system, particularly within the hypothalamus, to exert many of its effects. Obesity in C57BL/6J ob/ob mice is caused by a mutation in the ob gene resulting in a lack of functional leptin. In this study, we first compared effects of a single intracerebroventricular (ICV) injection of 3 pmol (50 ng) or 60 pmol (1 microg) leptin on food intake and oxygen consumption of lean and ob/ob mice deprived of food for 4 h during the 48-h period postinjection. Injection of 3 pmol leptin minimally lowered food intake in these mice without influencing oxygen consumption. Injection of 60 pmol of leptin rapidly lowered food intake within 30 min in both lean and ob/ob mice, with effects persisting for 24 h. Lean and ob/ob mice treated with leptin consumed 40 and 60% less food, respectively, in 24 h than vehicle-treated controls. Injection of leptin (60 pmol ICV) suppressed food intake of adrenalectomized mice as well (by 25 and 40% in lean mice and by 20 and 68% in ob/ob mice at 3 and 24 h, respectively), indicating that glucocorticoids are not essential for leptin to suppress food intake. Leptin increased oxygen consumption in conditions in which diet-induced thermogenesis was low, i.e., in fed ob/ob mice and in food-deprived lean mice, but not in fed adrenalectomized ob/ob mice or in fed lean mice. ICV injection of 60 pmol leptin along with 230 pmol (2 microg) of neuropeptide Y (NPY) attenuated NPY-induced feeding in ob/ob, but not in lean mice, suggesting an enhanced potential for crosstalk between the leptin and NPY signaling systems in ob/ob mice lacking endogenous leptin. Leptin exerts rapid-onset actions within the central nervous system to coordinate control of food intake and metabolic rate.
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PMID:Leptin rapidly lowers food intake and elevates metabolic rates in lean and ob/ob mice. 931 66

Despite the increase in body fat and obesity that occurs with aging, there is a linear decrease in food intake over the life span. This conundrum is explained by decreased physical activity and altered metabolism with aging. Thus, older persons fail to adequately regulate food intake and develop a physiologic anorexia of aging. This physiologic anorexia depends not only on decreased hedonic qualities of feeding with aging (an area that remains controversial) but also on altered hormonal and neurotransmitter regulation of food intake. Findings in older animals and humans have provided clues to the causes of the anorexia of aging. An increase in circulating concentrations of the satiating hormone, cholecystokinin, occurs with aging in humans. In addition, animal studies suggest a decrease in the opioid (dynorphin) feeding drive and possibly in neuropeptide Y and nitric oxide. The physiologic anorexia of aging puts older persons at high risk for developing protein-energy malnutrition when they develop either psychologic or physical disease processes. Despite its high prevalence, however, protein-energy malnutrition in older persons is rarely recognized and even more rarely treated appropriately. Screening tools for the early detection of protein-energy malnutrition in older persons have been developed. Multiple treatable causes of pathologic anorexia have been identified. There is increasing awareness of the importance of depression as a cause of severe weight loss in older persons. Approaches to the management of anorexia and weight loss in older persons are reviewed. Although many drugs exist that can enhance appetite, none of these are ideal for use in older persons currently.
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PMID:Anorexia of aging: physiologic and pathologic. 973 60

Leptin is the product of OB gene. This 16 kDa protein is produced by mature adipocytes and is secreted in plasma. Its plasma levels are strongly correlated with adipose mass in rodents as well as in humans. Leptin inhibits food intake, reduces body weight and stimulates energy expenditure. It has been suggested that leptin could be the link between obesity and diabetes. Recent experiments in rodents have shown that leptin expression in adipocytes is also regulated at short-term by hormones and nutrients. Leptin expression increases after food intake and decreases during fasting and diabetes. Insulin and glucocorticoids increase leptin expression, whereas catecholamines, via beta-adrenergic receptors and cAMP, and long-chain fatty acids (and thiazolidinediones), via PPARy, inhibit leptin expression. Leptin is a cytokine that binds to transmembrane receptors similar to the receptors of cytokine family (type IL-6), and transmit their information inside the cell, after dimerisation. A short-form of leptin receptor (with a cytoplasmic domain of 34 amino residues) has been identified in the choroid plexus. This type of receptor should be used for leptin transport across the blood-brain barrier. Then leptin binds to a long-form of leptin receptor in the hypothalamus (with a cytoplasmic domain of 302 amino residues) and decreases the production of neuropeptide Y, a neuromediator of food intake. The long-form of leptin receptor, transmits its information via the Janus Kinases (JAK) who subsequently phosphorylate transcription factors of the STAT family. Intermediary forms of leptin receptor have been identified in other tissues: liver, heart, skeletal muscles, endocrine pancreas. The role of leptin receptors in these tissues remains obscure, but is of considerable interest. Recent studies have shown that leptin inhibits insulin secretion and have anti-insulin effects on liver and adipose tissue. If these effects are confirmed, leptin could play a role similar to TNF alpha and could participate in the insulin-resistance of obesity and type II diabetes.
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PMID:Is leptin the link between obesity and insulin resistance? 934 38

Administration of neuropeptide Y (NPY) into the hypothalamus or cerebral ventricles has been shown to increase food intake, the secretion of hormones such as insulin, glucagon and corticosterone and to alter the metabolism of carbohydrate and lipids. It has been suggested that metabolic effects of hypothalamic NPY may contribute to fat accretion in some types of obesity and to the metabolic and behavioural adaptation to food deprivation. However, it is currently unknown if different nutritional states alter the responses to hypothalamic NPY. Consequently, we have compared the effects of NPY injected into the third ventricle (ICV) in the fed and overnight-fasted state on ingestive behaviour, on insulin, glucagon and corticosterone secretion before, and following, an IV glucose bolus (IVGTT) and on blood glucose following an intra-arterial insulin bolus (ITT). Studies were performed on conscious, unrestrained adult female rats. In the fed state, 2 and 6 micrograms ICV NPY produced a potent orexigenic and dypsogenic effect. In the fasted state, the 2 micrograms dose had a dypsogenic effect, while only the 6 micrograms dose had a significant orexigenic effect. In the fed but not fasted state, 3 micrograms ICV NPY increased plasma glucagon and corticosterone levels and attenuated the decline in blood glucose during the ITT. By contrast, in both fed and fasted groups, 3 micrograms ICV NPY potentiated the insulin secretory responses during the IVGTT. We conclude that, apart from stimulating insulin secretion, the acute metabolic and orexigenic responses to ICV NPY in this study were substantially reduced or abolished by overnight fasting. Therefore, behavioural and metabolic responses to endogenous hypothalamic NPY may also be more significant in the fed than the fasted state.
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PMID:Metabolic and orexigenic effects of intracerebroventricular neuropeptide Y are attenuated by food deprivation. 935 48

The recently discovered rat neuropeptide Y (NPY) receptor, the Y5 subtype, has been proposed to mediate the NPY-induced feeding response and therefore plays a central role in the regulation of food intake. These conclusions were based on studies with peptidic agonists. We now report studies in which phosphothioate end-protected antisense oligodeoxynucleotides (ODNs) targeted to prepro NPY (prepro NPY antisense ODNs) or to the Y5 receptor (Y5 antisense ODNs) were used to assess the functional importance of this novel receptor subtype in vivo. NPY antisense ODNs given intracerebroventricularly to rats prevented the increase in hypothalamic NPY levels during food deprivation and inhibited fasting-induced food intake. Likewise, repeated intracerebroventricular injections of Y5 antisense ODNs prevented fasting-induced food intake in rats. Moreover, two Y5 antisense ODNs, targeted to different sequences of the receptor, significantly decreased basal food intake and inhibited the increase in food intake after intracerebroventricular injection of NPY. These effects proved to be selective, since the feeding response to galanin was not affected. Analysis of the structure of feeding behavior revealed that prepro NPY and Y5 receptor antisense ODNs reduced food intake by inducing decreases in meal size and meal duration analogous to the orexigenic effects of NPY that are mediated by increases in these parameters. Although changes in Y5 receptor density could not be measured, the results with Y5 antisense ODNs strongly suggest that this receptor subtype mediates the feeding response to exogenous and endogenous NPY. Selective Y5 antagonists may therefore be of therapeutic value for the treatment of obesity and eating disorders.
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PMID:Inhibition of food intake by neuropeptide Y Y5 receptor antisense oligodeoxynucleotides. 935 28


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