Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020505 (hyperphagia)
 6,116 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Exercise is a mechanism for maintenance of body weight in humans. Morbidly obese human patients have been shown to possess single nucleotide polymorphisms in the melanocortin-4 receptor (MC4R). MC4R knockout mice have been well characterized as a genetic model that possesses phenotypic metabolic disorders, including obesity, hyperphagia, hyperinsulinemia, and hyperleptinemia, similar to those observed in humans possessing dysfunctional hMC4Rs. Using this model, we examined the effect of voluntary exercise of MC4R knockout mice that were allowed access to a running wheel for a duration of 8 wk. Physiological parameters that were measured included body weight, body composition of fat and lean mass, food consumption, body length, and blood levels of cholesterol and nonfasted glucose, insulin, and leptin. At the termination of the experiment, hypothalamic mRNA expression levels of neuropeptide Y (NPY), agouti-related protein (AGRP), proopiomelanocortin (POMC), cocaine- and amphetamine-regulated transcript (CART), orexin, brain-derived neurotropic factor (BDNF), phosphatase with tensin homology (Pten), melanocortin-3 receptor (MC3R), and NPY-Y1R were determined. In addition, islet cell distribution and function in the pancreas were examined. In the exercising MC4R knockout mice, the pancreatic islet cell morphology and other physiological parameters resembled those observed in the wild-type littermate controls. Gene expression profiles identified exercise as having a significant effect on hypothalamic POMC, orexin, and MC3R levels. Genotype had a significant effect on AGRP, POMC, CART, and NPY-Y1R, with an exercise and genotype interaction effect on NPY gene expression. These data support the hypothesis that voluntary exercise can prevent the genetic predisposition of melanocortin-4 receptor-associated obesity and diabetes.
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PMID:Voluntary exercise prevents the obese and diabetic metabolic syndrome of the melanocortin-4 receptor knockout mouse. 1897 Dec 58

Leptin regulates energy balance and glucose metabolism by activation of multiple signaling cascades mediated by the long-form leptin receptor Ob-Rb. However, the whole spectrum of signaling actions through the 3 cytoplasmic tyrosines of mouse Ob-Rb remains to be completely defined in vivo. Here, we generated 2 knockin lines of mice expressing mutant leptin receptors with phenylalanine substitution for all 3 tyrosines (Y123F) or for Tyr(1138) alone (Y3F). Y123F animals developed overt obesity similar to that of Y3F animals with abrogated hypothalamic activation of STAT3 by leptin, but they exhibited more severe impairment in glucose tolerance. In striking contrast to db/db mice, however, both Y123F and Y3F mice showed attenuated adiposity with reduced hyperphagia, marked improvement in physical activity and adaptive thermogenesis, and significantly ameliorated glycemic control. Further, Y123F mice had hypothalamic neuropeptide Y/agouti-related protein expression maintained at prominently lower levels compared with db/db mice. Thus, these results provide direct physiological evidence that Ob-Rb exerts crucial metabolic actions not only through tyrosine-dependent, but also tyrosine-independent mechanisms in control of energy balance and glucose homeostasis.
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PMID:Tyrosine-dependent and -independent actions of leptin receptor in control of energy balance and glucose homeostasis. 1901 22

Protein or calorie restriction during gestation and/or suckling induces hyperphagia and increases the susceptibility to develop obesity, glucose intolerance and hypertension in adulthood. The mechanisms by which early nutrient restriction affects the normal physiological regulation of feeding as well as to what extent the metabolic programming of hyperphagia contributes to the long-term risk of obesity and insulin resistance remain, however, to be determined. Here the temporal pattern of food intake and the behavioural satiety sequence were investigated in the offspring of Sprague-Dawley rats fed a control (C) or a low-protein (LP) diet throughout pregnancy and lactation. During the first two months of their post-natal life, protein-restricted animals exhibited hyperphagia characterized by a delayed appearance of satiety, an increase in meal size and reduced latency to eat. Protein-restricted pups also exhibited an enhanced expression of the orexigenic peptides Agouti-related protein and neuropeptide Y and decreased hypothalamic levels of the anorexigenic peptide pro-opiomelanocortin. At 8 months, LP rats still consumed larger meals than their control counterparts but they ingested daily the same amount of food as control offspring and exhibited enhanced abdominal fat and increased levels of triglycerides and fatty acids in serum. These observations indicate that the hyperphagia observed in young LP rats results from a decreased action of negative feedback signals critical to meal termination and an enhanced function of the positive signals that initiate and maintain eating. These results also suggest that perinatal malnutrition programmes obesity through a mechanism independent of its effects on feeding behaviour.
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PMID:Perinatal undernutrition-induced obesity is independent of the developmental programming of feeding. 1910 Jul 59

Maternal obesity due to long-term high-fat diet (HFD) consumption leads to faster growth in offspring during suckling, and increased adiposity at 20 days of age. Decreased expression of the orexigenic neuropeptide Y (NPY) and increased anorexigenic proopiomelanocortin (POMC) mRNA expression were observed in the fed state. However, hunger is the major drive to eat and hypothalamic appetite regulators change in response to meals. Therefore, it is important to compare both satiated and fasting states. Female Sprague-Dawley rats (8 weeks old) were fed a cafeteria-style HFD (15.33 kJ/g) or chow for 5 weeks before mating, with the same diet continuing throughout gestation and lactation. At postnatal day 20, male pups were killed either after overnight fasting or in the fed state. Pups from obese dams were hyperphagic during both pre- and postweaning periods. Pups from obese dams had higher hypothalamic mRNA expression of POMC and NPY Y1 receptor, but lower hypothalamic melanocortin-4 receptor (MC4R) and its downstream target single-minded gene 1 (Sim1), in the fed state. Overnight fasting reduced circulating glucose, insulin, and leptin and increased hypothalamic NPY Y1 receptor mRNA in pups from both lean and obese dams. Hypothalamic NPY and agouti-related protein (AgRP) were only increased by fasting in pups from obese dams; reductions in MC4R and Sim1 were only seen in pups from lean dams. At weaning, the suppressed orexigenic signals in offspring from obese dams were normalized after overnight fasting, although anorexigenic signaling appeared impaired in these animals. This may contribute to their hyperphagia and faster growth.
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PMID:Differential responses of orexigenic neuropeptides to fasting in offspring of obese mothers. 1928 28

Negative energy balance during lactation is reflected by low levels of insulin and leptin and is associated with chronic hyperphagia and suppressed GnRH/LH activity. We studied whether restoration of insulin and/or leptin to physiological levels would reverse the lactation-associated hyperphagia, changes in hypothalamic neuropeptide expression [increased neuropeptide Y (NPY) and agouti-related protein (AGRP) and decreased proopiomelanocortin (POMC), kisspeptin (Kiss1), and neurokinin B (NKB)] and suppression of LH. Ovariectomized lactating rats (eight pups) were treated for 48 h with sc minipumps containing saline, human insulin, or rat leptin. The arcuate nucleus (ARH) was analyzed for NPY, AGRP, POMC, Kiss1, and NKB mRNA expression; the dorsal medial hypothalamus (DMH) was analyzed for NPY mRNA. Insulin replacement reversed the increase in ARH NPY/AGRP mRNAs, partially recovered POMC, but had no effect on recovering Kiss1/NKB. Leptin replacement only affected POMC, which was fully recovered. Insulin/leptin dual replacement had similar effects as insulin replacement alone but with a slight increase in Kiss1/NKB. The lactation-induced increase in DMH NPY was unchanged after treatments. Restoration of insulin and/or leptin had no effect on food intake, body weight, serum glucose or serum LH. These results suggest that the negative energy balance of lactation is not required for the hyperphagic drive, although it is involved in the orexigenic changes in the ARH. The chronic hyperphagia of lactation is most likely sustained by the induction of NPY in the DMH. The negative energy balance also does not appear to be a necessary prerequisite for the suppression of GnRH/LH activity.
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PMID:Regulation of food intake and gonadotropin-releasing hormone/luteinizing hormone during lactation: role of insulin and leptin. 1947 Jul 5

Brandt's voles Lasiopodomys brandtii exhibit large increases in nonshivering thermogenesis to cope with chronic cold exposure, resulting in compensatory hyperphagia and fat mobilization. These physiological events are accompanied by a remarkable reduction in serum leptin levels. However, the role of hypoleptinemia in cold adaptation in this species is still unknown. In the present study, we tested the hypothesis that hypoleptinemia contributes to increases in food intake and brown adipose tissue (BAT) thermogenesis by modifying hypothalamic neuropeptides in cold-exposed Brandt's voles. Adult male voles were transferred to 5 degrees C for 28 days. Accompanied by a decrease in serum leptin levels, hypothalamic agouti-related protein (AgRP) mRNA levels were significantly increased, but there were no changes in the long form of leptin receptor (Ob-Rb), suppressor of cytokine signaling 3 (SOCS3), neuropeptide Y (NPY) mRNA, proopiomelanocortin (POMC), and cocaine- and amphetamine-regulated peptide (CART) mRNA levels in the hypothalamus. When cold-exposed voles were returned to warm (23 degrees C) for 28 days, body mass, food intake, serum leptin, and AgRP mRNA were restored to control levels. Leptin administration in cold-exposed voles decreased food intake as well as hypothalamic AgRP mRNA levels. There were no significant effects of leptin administration on hypothalamic Ob-Rb, SOCS3, NPY, POMC, CART mRNA, and uncoupling protein 1 levels under cold conditions. These results suggest that hypoleptinemia partially contributes to cold-induced hyperphagia, which might involve the elevation of hypothalamic AgRP gene expression.
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PMID:Role of hypoleptinemia during cold adaptation in Brandt's voles (Lasiopodomys brandtii). 1972 9

The amygdala is rich in melanocortin 4 receptors. Because the reduction in dietary fat intake after enterostatin is injected in the central nucleus of the amygdala (CeA) is blocked by a melanocortin 4 receptor antagonist, we investigated the role of melanocortin activity in the CeA in regulating food intake and macronutrient choice. Sprague-Dawley rats, fitted with CeA cannulas, were fed either chow, a high-fat (HF) diet, or adapted to a two-choice HF or low-fat (LF) diet. Injections of the MC4R agonist melanotan II (MTII) in the CeA had a dose-dependent inhibitory effect on food intake that lasted for at least 24 h. This response was greater in rats fed a HF diet. The inverse agonist agouti-related protein (AgRP) and antagonist SHU-9119 increased food intake in a dose-dependent manner, with the hyperphagia lasting for 60 h. In rats adapted to a two-choice HF/LF diet, MTII decreased HF consumption but had no effect on LF consumption, resulting in a long-lasting decrease in total calorie intake (-35.5% after 24 h, P < 0.05). Total calorie intake increased in both AgRP- and SHU-9119-treated rats (32 and 109% after 24 h, respectively) as the result of increased intake of HF diet. There was no modification of LF consumption with AgRP treatment and a transient nonsignificant decrease with SHU-9119 treatment. Amygdala brain-derived neurotrophic factor expression was increased by AgRP in fed rats. These results identify the amygdala as a site of action for the melanocortin system to control food intake and dietary preferences.
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PMID:Melanocortin activity in the amygdala controls appetite for dietary fat. 1992 60

c-Jun-N-terminal kinase (JNK) is a signaling molecule that is activated by proinflammatory signals, endoplasmic reticulum (ER) stress, and other environmental stressors. Although JNK has diverse effects on immunological responses and insulin resistance in peripheral tissues, a functional role for JNK in feeding regulation has not been established. In this study, we show that central inhibition of JNK activity potentiates the stimulatory effects of glucocorticoids on food intake and that this effect is abolished in mice whose agouti-related peptide (AgRP) neurons are degenerated. JNK1-deficient mice feed more upon central administration of glucocorticoids, and glucocorticoid receptor nuclear immunoreactivity is enhanced in the AgRP neurons. JNK inhibition in hypothalamic explants stimulates Agrp expression, and JNK1-deficient mice exhibit increased Agrp expression, heightened hyperphagia, and weight gain during refeeding. Our study shows that JNK1 is a novel regulator of feeding by antagonizing glucocorticoid function in AgRP neurons. Paradoxically, JNK1 mutant mice feed less and lose more weight upon central administration of insulin, suggesting that JNK1 antagonizes insulin function in the brain. Thus, JNK may integrate diverse metabolic signals and differentially regulate feeding under distinct physiological conditions.
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PMID:Functional role of c-Jun-N-terminal kinase in feeding regulation. 2002 34

Lactation is an important physiological model of the integration of energy balance and reproduction, as it involves activation of potent appetitive neuropeptide systems coupled to a profound inhibition of pulsatile GnRH/LH secretion. There are multiple systems that contribute to the chronic hyperphagia of lactation: 1) suppression of the metabolic hormones, leptin and insulin, 2) activation of hypothalamic orexigenic neuropeptide systems NPY, AGRP, orexin (OX) and melanin concentrating hormone (MCH), 3) special induction of NPY expression in the dorsomedial hypothalamus, and 4) suppression of anorexigenic systems POMC and CART. These changes ensure adequate energy intake to meet the metabolic needs of milk production. There is significant overlap in all of the systems that regulate food intake with the regulation of GnRH, suggesting there could be several redundant factors acting to suppress GnRH/LH during lactation. In addition to an overall increase in inhibitory tone acting directly on GnRH cell bodies that is brought about by increases in orexigenic systems, there are also effects at the ARH to disrupt Kiss1/neurokinin B/dynorphin neuronal function through inhibition of Kiss1 and NKB. These changes could lead to an increase in inhibitory auto-regulation of the Kiss1 neurons and a possible disruption of pulsatile GnRH release. While the low levels of leptin and insulin contribute to the changes in ARH appetitive systems, they do not appear to contribute to the suppression of ARH Kiss1 or NKB. The inhibition of Kiss1 may be the key factor in the suppression of GnRH during lactation, although the mechanisms responsible for its inhibition are unknown.
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PMID:The neuroendocrine basis of lactation-induced suppression of GnRH: role of kisspeptin and leptin. 2072 62

Sucrose-rich diets compared to starch-rich diets are known to stimulate overeating under chronic conditions. The present study in normal-weight rats established an acute "preload-to-test meal" paradigm for demonstrating sucrose-induced hyperphagia and investigating possible mechanisms that mediate this behavioral phenomenon. In this acute paradigm, the rats were first given a small (15 kcal) sucrose preload (30% sucrose) for 30 min compared to an equicaloric, starch preload (25% starch with 5% sucrose) and then allowed to freely consume a subsequent test meal of lab chow. The sucrose preload, when compared to a starch preload equal in energy density and palatability, consistently increased food intake in the subsequent test meal occurring between 60 and 120 min after the end of the preload. Measurements of hormones, metabolites and hypothalamic peptides immediately preceding this hyperphagia revealed marked differences between the sucrose vs starch groups that could contribute to the increase in food intake. Whereas the sucrose group compared to the starch group immediately after the preload (at 10 min) had elevated levels of glucose in serum and cerebrospinal fluid (CSF) along with reduced expressions of neuropeptide Y (NPY) and agouti-related protein (AgRP) in the arcuate nucleus (ARC), the subsequent effects (at 30-60 min) just preceding the test meal hyperphagia were the reverse. Along with lower levels of glucose, they included markedly elevated serum and CSF levels of corticosterone and mRNA levels of NPY and AgRP in the ARC. In addition to establishing an animal model for sucrose-induced hyperphagia, these results demonstrate peripheral and central mechanisms that may mediate this behavioral phenomenon.
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PMID:Hyperphagia induced by sucrose: relation to circulating and CSF glucose and corticosterone and orexigenic peptides in the arcuate nucleus. 2103 88


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