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Query: UMLS:C0020505 (hyperphagia)
 6,116 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Leptin is an adipocyte-secreted hormone that binds hypothalamic receptors and potently decreases food intake. Leptin receptor defects in homozygous mutant Zucker fatty ( fa/fa) rats lead to massive obesity, hyperphagia, decreased energy expenditure, and insulin resistance, while the phenotype of heterozygous ( Fa/fa) lean rats lies between lean ( Fa/Fa) and obese ( fa/fa) rats. Whether heterezygotes exhibit specific changes in lipid metabolism in a diet-responsive manner is not clear. Thus, the specific aim of this study was to test whether the presence of one fa allele modulates lipid metabolism and leptin, and whether these effects are exacerbated by high-fat diet. We demonstrate that the presence of one fa allele significantly increases lipogenesis in adipose tissue assessed by glycerol-3-phosphate dehydrogenase (GPDH) and fatty acid synthase (FAS) activities. FAS is more responsive to high-fat diets than GPDH in Fa/fa rats. Adipose tissue leptin levels are significantly higher in fat pads of Fa/fa compared to Fa/Fa rats. Moreover, Fa/fa rats fed high-fat diet show an additional two-fold increase in leptin levels compared to wild type rats on the same diet. Collectively, these results indicate that the presence of one fa allele increase adipocyte lipogenic enzyme activities, which results in hyperleptinemia concurrent with increased adiposity.
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PMID:Effects of fatty (fa) allele and high-fat diet on adipose tissue leptin and lipid metabolism. 1266 Aug 83

The incidence of obesity has increased dramatically in recent years, making it one of the most pressing public health concerns worldwide. Obesity is commonly associated with comorbid conditions, most notably diabetes, coronary artery disease, and hypertension, and the coexistence of these diseases has been termed the Metabolic Syndrome. The identification of the hormone leptin provided a molecular link to obesity. Leptin is recognized as the central mediator in an endocrine circuit regulating energy homeostasis. Leptin administration leads to hypophagia, increased energy expenditure, and weight loss, while leptin deficiency enacts an adaptive response to starvation manifested by hyperphagia, decreased energy expenditure, and suppression of the neuroendocrine axis. While elucidation of leptin's role has permitted a more detailed view of the biology underlying energy homeostasis, most obese individuals are leptin resistant. A more complete understanding of the molecular components of the leptin pathway is necessary to develop effective treatment for obesity and the Metabolic Syndrome. The identification and role of one such component, stearoyl-CoA desaturase-1 (SCD-1), is reviewed here. Leptin's actions are not due to its anorectic effects alone. Leptin also mediates specific metabolic effects, including the potent depletion of triglyceride from liver and other peripheral tissues. To explore the molecular basis by which leptin depletes hepatic lipid, we used oligonucleotide arrays to identify genes in liver whose expression was modulated by leptin treatment. An algorithm was created that identified and ranked genes specifically repressed by leptin. The gene ranking at the top of this list was SCD-1, the rate limiting enzyme in the biosynthesis of monounsaturated fats. SCD-1 was specifically repressed during leptin-mediated weight loss, and mice lacking SCD-1 showed markedly reduced adiposity on both a lean and ob/ob background (ab(J)/ab(J); ob/ob), despite higher food intake. ab(J)/ab(J); ob/ob mice also showed a complete correction of the hypometabolic phenotype and hepatic steatosis of ob/ob mice, suggesting that fatty acid oxidation is enhanced in the absence of SCD-1. These findings indicate that pharmacologic manipulation of SCD-1 may be of benefit in the treatment of obesity, diabetes, hepatic steatosis, and other components of the Metabolic Syndrome.
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PMID:Stearoyl-CoA desaturase-1 and the metabolic syndrome. 1468 58

Leptin has been postulated to comprise part of an adipostat, whereby during states of excessive energy storage, elevated levels of the hormone prevent further weight gain by inhibiting appetite. A physiological role for leptin in this regard remains unclear because the presence of excessive food, and therefore the need to restrain overeating under natural conditions, is doubtful. We have previously shown that CRH-deficient (Crh(-/-)) mice have glucocorticoid insufficiency and lack the fasting-induced increase in glucocorticoid, a hormone important in stimulating leptin synthesis and secretion. We hypothesized that these mice might have low circulating leptin. Indeed, Crh(-/-) mice exhibited no diurnal variation of leptin, whereas normal littermates showed a clear rhythm, and their leptin levels were lower than their counterparts. A continuous peripheral CRH infusion to Crh(-/-) mice not only restored corticosterone levels, but it also increased leptin expression to normal. Surprisingly, 36 h of fasting elevated leptin levels in Crh(-/-) mice, rather than falling as in normal mice. This abnormal leptin change during fasting in Crh(-/-) mice was corrected by corticosterone replacement. Furthermore, Crh(-/-) mice lost less body weight during 24 h of fasting and ate less food during refeeding than normal littermates. Taken together, we conclude that glucocorticoid insufficiency in Crh(-/-) mice results in impaired leptin production as well as an abnormal increase in leptin during fasting, and propose that the fast-induced physiological reduction in leptin may play an important role to stimulate food intake during the recovery from fasting.
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PMID:Impaired leptin expression and abnormal response to fasting in corticotropin-releasing hormone-deficient mice. 1503 10

The obese gene product, leptin, plays a central role in food intake and energy metabolism. The physiological roles of leptin in human bodily function have been broadened over the past decade since leptin was first discovered in 1994. Evidence has suggested that leptin plays a specific role in the intricate cascade of cardiovascular events, in addition to its well-established metabolic effects. Leptin, a hormone linking adiposity and central nervous circuits to reduce appetite and enhance energy expenditure, has been shown to increase overall sympathetic nerve activity, facilitate glucose utilization and improve insulin sensitivity. In addition, leptin is capable of regulating cardiac and vascular contractility through a local nitric oxide-dependent mechanism. However, elevated plasma leptin levels or hyperleptinemia, have been demonstrated to correlate with hyperphagia, insulin resistance and other markers of the metabolic syndrome including obesity, hyperlipidemia and hypertension, independent of total adiposity. Elevated plasma leptin levels may be an independent risk factor for the development of cardiovascular disease. Although mechanisms leading to hyperleptinemia have not been well described, factors such as increased food intake and insulin resistance have been shown to rapidly enhance plasma leptin levels and subsequently tissue leptin resistance. These findings have prompted the speculation that leptin in the physiological range may serve as a physiological regulator of cardiovascular function whereas elevated plasma leptin levels may act as a pathophysiological trigger and/or marker for cardiovascular diseases due to tissue leptin resistance.
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PMID:Leptin and hyperleptinemia - from friend to foe for cardiovascular function. 1507 62

The adipose-derived hormone leptin was first described as a satiety factor, but recent studies have demonstrated that leptin acts on various physiologic processes and plays an important role in obesity and the associated hypertension. In this article, we review recent data on leptin signaling as it relates to nutrition. Plasma leptin levels are positively correlated to body fat and adipocyte size and, therefore, levels are higher during obesity. The hyperphagia in the presence of hyperleptinemia in obesity is a paradoxical effect. Leptin signaling primarily depends on the leptin receptor (Ob-R). The suppressor of cytokine-signaling (SOCS) protein, in particular SOCS-3, was shown as a leptin-regulated inhibitor of proximal leptin signaling, although its role during obesity remains uncertain.
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PMID:Nutritional regulation of leptin signaling. 1568 81

Food restriction and weight loss result in reduced plasma leptin, which is associated with a pleiotropic biologic response. However, because weight loss itself is also associated with changes in numerous other humoral and metabolic signals, it can be difficult to determine the precise features of the biologic response to acute leptin deficiency. To study this response in the absence of changes in nutritional state, we have developed a protocol that allows such analysis in normal, non-food-restricted animals. Wild-type mice are treated with high-dose leptin until fat mass is depleted and, as a consequence, endogenous leptin production is reduced. At this point, exogenous leptin is abruptly withdrawn, thus inducing a state of leptin deficiency in otherwise normal mice. Leptin deficiency is sustained by feeding the animals only as much as they consumed voluntarily before leptin withdrawal. The biologic response to leptin deficiency induced in this manner includes altered neuropeptide levels, decreased energy expenditure, and impaired reproductive and immune function. Replacement of leptin at physiological concentrations after withdrawal of high-dosage leptin blunts, but does not completely block, the hyperphagia and weight regain caused by acute leptin deficiency, nor does it correct the resulting reproductive and immune dysfunction. This suggests that high-dosage leptin treatment induces a state of partial leptin resistance. In aggregate, these studies establish the role of acute hypoleptinemia in regulating energy balance, the immune system, and reproductive function, and further suggest that high-dosage leptin treatment can induce a state of acquired leptin resistance.
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PMID:Acute leptin deficiency, leptin resistance, and the physiologic response to leptin withdrawal. 1569 32

Leptin deficiency has been associated with extreme obesity and hyperphagia in rodents and humans. A rare genetic disorder in humans yields the absence of the hormone leptin, extreme obesity, and a ravenous appetite. Reports on these rare cases have indicated that therapy using leptin injections can yield significant weight loss and changes in appetite. The aim of this report on acute leptin therapy in three leptin deficient adults was to provide a microanalysis of changes in eating behavior and ratings of hunger and satiety. In addition to substantial weight loss, 15 weeks of leptin therapy was associated with approximately 50% reduction in food intake and substantial changes in ratings of hunger and satiety before most meals. After short-term leptin therapy, the three participants ate until ratings indicated they were satiated, which was comparable to the ratings before leptin therapy. These findings suggest that one of the primary effects of acute leptin therapy may be to reduce the ravenous hunger associated with leptin deficiency, resulting in reduced food intake and significant weight loss. These results are discussed in the context of the scientific literature pertaining to leptin and its effects on appetite and obesity.
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PMID:Microanalysis of eating behavior of three leptin deficient adults treated with leptin therapy. 1594 71

Ectopic fat accumulation has been implicated as a contributing factor in the abnormal metabolic state of obesity. One human model of ectopic fat deposition is generalized lipodystrophy. Generalized lipodystrophy is a rare disorder characterized by a profound deficiency of adipose tissue with resultant loss of triglyceride storage capacity and reduced adipokines, including leptin. Subjects with generalized lipodystrophy and reduced leptin levels often have an increased appetite leading to hyperphagia. Excess fuel consumption, coupled with a lack of adipose tissue, contributes to the significant ectopic triglyceride accumulation in the muscle and liver seen in these subjects. This ectopic fat, along with the deficiency in leptin signaling and perhaps other adipokines, likely contributes to insulin resistance, diabetes, and hepatic steatosis. We report here the long-term effects of leptin replacement in a cohort of these subjects. Fifteen patients with generalized lipodystrophy were treated with twice-daily recombinant methionyl human leptin (r-metHuLeptin) for 12 months. We evaluated metabolic parameters at baseline and every 4 months. Antidiabetes medications were decreased or discontinued as necessary. Reductions were seen in serum fasting glucose (from 205 +/- 19 to 126 +/- 11 mg/dl; P < 0.001), HbA1c (from 9 +/- 0.4 to 7.1 +/- 0.5%; P < 0.001), triglycerides (from 1,380 +/- 500 to 516 +/- 236 mg/dl; P < 0.001), LDL (from 139 +/- 16 to 85 +/- 7 mg/dl; P < 0.01), and total cholesterol (from 284 +/- 40 to 167 +/- 21 mg/dl; P < 0.01). HDL was unchanged (from 31 +/- 3 to 29 +/- 2 mg/dl; P = 0.9). Liver volumes were significantly reduced (from 3,663 +/- 326 to 2,190 +/- 159 cm3; P < 0.001), representing loss of steatosis. Decreases were seen in total body weight (from 61.8 +/- 3.6 to 57.4 +/- 3.4 kg; P = 0.02) and resting energy expenditure (from 1,929 +/- 86 to 1,611 +/- 101 kcal/24 h; P < 0.001). R-metHuLeptin led to significant and sustained improvements in glycemia, dyslipidemia, and hepatic steatosis. Leptin represents the first novel, effective, long-term treatment for severe forms of lipodystrophy.
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PMID:Long-term efficacy of leptin replacement in patients with generalized lipodystrophy. 1598 99

An adverse prenatal environment may induce long-term metabolic consequences, in particular obesity and insulin resistance. Although the mechanisms are unclear, this programming has generally been considered an irreversible change in developmental trajectory. Adult offspring of rats subjected to undernutrition during pregnancy develop obesity, hyperinsulinemia, and hyperleptinemia, especially in the presence of a high-fat diet. Reduced locomotor activity and hyperphagia contribute to the increased fat mass. Using this model of maternal undernutrition, we investigated the effects of neonatal leptin treatment on the metabolic phenotype of adult female offspring. Leptin treatment (rec-rat leptin, 2.5 microg/g.d, sc) from postnatal d 3-13 resulted in a transient slowing of neonatal weight gain, particularly in programmed offspring, and normalized caloric intake, locomotor activity, body weight, fat mass, and fasting plasma glucose, insulin, and leptin concentrations in programmed offspring in adult life in contrast to saline-treated offspring of undernourished mothers who developed all these features on a high-fat diet. Neonatal leptin had no demonstrable effects on the adult offspring of normally fed mothers. This study suggests that developmental metabolic programming is potentially reversible by an intervention late in the phase of developmental plasticity. The complete normalization of the programmed phenotype by neonatal leptin treatment implies that leptin has effects that reverse the prenatal adaptations resulting from relative fetal undernutrition.
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PMID:Neonatal leptin treatment reverses developmental programming. 1616 32

Leptin activates the long form of the leptin receptor (LRb) to control feeding and neuroendocrine function and thus regulate adiposity. While adiposity influences insulin sensitivity, leptin also regulates glucose homeostasis independently of energy balance. Disruption of the LRb/STAT3 signal in s/s mice results in hyperphagia, neuroendocrine dysfunction, and obesity similar to LRb null db/db mice. Insulin resistance and glucose intolerance are improved in s/s compared to db/db animals, however, suggesting that LRb/STAT3-independent signals may contribute to the regulation of glucose homeostasis by leptin. Indeed, caloric restriction normalized glycemic control in s/s animals, but db/db mice of similar weight and adiposity remained hyperglycemic. These differences in glucose homeostasis were not attributable to differences in insulin production between s/s and db/db animals but rather to decreased insulin resistance in s/s mice. Thus, in addition to LRb/STAT3-mediated adiposity signals, non-LRb/STAT3 leptin signals mediate an important adiposity-independent role in promoting glycemic control.
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PMID:Roles for leptin receptor/STAT3-dependent and -independent signals in the regulation of glucose homeostasis. 1605 60


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