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

Homozygous mutations of the ob gene, encoding leptin, are associated with severe obesity, hyperphagia and insulin resistance in humans. Leptin conveys a signal from adipose tissue to hypothalamic nuclei that integrate whole body fuel metabolism, informing those nuclei about the magnitude of fuel reserves. In the absence of leptin, the brain perceives energy availability as insufficient and therefore activates powerful mechanisms to restore fuel depots. If leptin synthesis or signal transduction is perturbed in the presence of food, a severely obese phenotype ensues.
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PMID:[From gene to disease; leptin and obesity]. 1129 96

In response to moderately increased dietary fat content, melanocortin-4 receptor-null mutant (MC4R-/-) mice exhibit hyperphagia and accelerated weight gain compared to wild-type mice. An increased feed efficiency (weight gain/kcal consumed) argues that mechanisms in addition to hyperphagia are instrumental in causing weight gain. We report two specific defects in coordinating energy expenditure with food intake in MC4R-/- mice. Wild-type mice respond to an increase in the fat content of the diet by rapidly increasing diet-induced thermogenesis and by increasing physical activity, neither of which are observed in MC4R-/- mice. Leptin-deficient and MC3R-/- mice regulate metabolic rate similarly to wild-type mice in this protocol. Melanocortinergic pathways involving MC4-R-regulated neurons, which rapidly respond to signals not requiring changes in leptin, thus seem to be important in regulating metabolic and behavioral responses to dietary fat.
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PMID:Melanocortin-4 receptor is required for acute homeostatic responses to increased dietary fat. 1136 41

The administration of leptin to leptin-deficient humans, and the analogous Lepob/Lepob mice, effectively reduces hyperphagia and obesity. But common obesity is associated with elevated leptin, which suggests that obese humans are resistant to this adipocyte hormone. In addition to regulating long-term energy balance, leptin also rapidly affects neuronal activity. Proopiomelanocortin (POMC) and neuropeptide-Y types of neurons in the arcuate nucleus of the hypothalamus are both principal sites of leptin receptor expression and the source of potent neuropeptide modulators, melanocortins and neuropeptide Y, which exert opposing effects on feeding and metabolism. These neurons are therefore ideal for characterizing leptin action and the mechanism of leptin resistance; however, their diffuse distribution makes them difficult to study. Here we report electrophysiological recordings on POMC neurons, which we identified by targeted expression of green fluorescent protein in transgenic mice. Leptin increases the frequency of action potentials in the anorexigenic POMC neurons by two mechanisms: depolarization through a nonspecific cation channel; and reduced inhibition by local orexigenic neuropeptide-Y/GABA (gamma-aminobutyric acid) neurons. Furthermore, we show that melanocortin peptides have an autoinhibitory effect on this circuit. On the basis of our results, we propose an integrated model of leptin action and neuronal architecture in the arcuate nucleus of the hypothalamus.
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PMID:Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus. 1137 81

Adipose tissue performs complex metabolic and endocrine functions. This review will focus on the recent literature on the biology and actions of three adipocyte hormones involved in the control of energy homeostasis and insulin action, leptin, acylation-stimulating protein, and adiponectin, and mechanisms regulating their production. Results from studies of individuals with absolute leptin deficiency (or receptor defects), and more recently partial leptin deficiency, reveal leptin's critical role in the normal regulation of appetite and body adiposity in humans. The primary biological role of leptin appears to be adaptation to low energy intake rather than a brake on overconsumption and obesity. Leptin production is mainly regulated by insulin-induced changes of adipocyte metabolism. Consumption of fat and fructose, which do not initiate insulin secretion, results in lower circulating leptin levels, a consequence which may lead to overeating and weight gain in individuals or populations consuming diets high in energy derived from these macronutrients. Acylation-stimulating protein acts as a paracrine signal to increase the efficiency of triacylglycerol synthesis in adipocytes, an action that results in more rapid postprandial lipid clearance. Genetic knockout of acylation-stimulating protein leads to reduced body fat, obesity resistance and improved insulin sensitivity in mice. The primary regulator of acylation-stimulating protein production appears to be circulating dietary lipid packaged as chylomicrons. Adiponectin increases insulin sensitivity, perhaps by increasing tissue fat oxidation resulting in reduced circulating fatty acid levels and reduced intramyocellular or liver triglyceride content. Adiponectin and leptin together normalize insulin action in severely insulin-resistant animals that have very low levels of adiponectin and leptin due to lipoatrophy. Leptin also improves insulin resistance and reduces hyperlipidemia in lipoatrophic humans. Adiponectin production is stimulated by agonists of peroxisome proliferator-activated receptor-gamma; an action may contribute to the insulin-sensitizing effects of this class of compounds. The production of all three hormones is influenced by nutritional status. These adipocyte hormones, the pathways controlling their production, and their receptors represent promising targets for managing obesity, hyperlipidemia, and insulin resistance.
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PMID:Control of energy homeostasis and insulin action by adipocyte hormones: leptin, acylation stimulating protein, and adiponectin. 1179 Sep 63

In 1994, Zhang et al. of Rockefeller University in New York reported the first successful complementary DNA (cDNA) cloning of leptin by the positional cloning method. Leptin was identified as the gene of ob/ob mouse in genetic obesity syndromes. It has very strong food intake control, and body weight and energy expenditure. The name "leptin" derived from the Greek word leptos, meaning "thin." We hereby review major advances leading to our current finding of leptin, leptin receptor and its structure, the outline of homozygote, and also influence of leptin in the pituitary. (The structure of leptin) The mouse obese gene has been localized to chromosome 6. With human leptin gene on chromosome 7q31.3, its DNA has more than 15000 base pairs and consists of three exons and two introns. For bioactivation of leptin the importance of disulfide-binding site is suggested. Human leptin which replaced the 128-th arginine with glutamine has the function of an aldosteron antagonist, which is reported to have the function of athrocytosis inhibition. The resemblance of leptin precursor of human, mouse and rat is very high, i.e., mouse and rat homology is 96% and mouse and human homology is 83%. (The structure of leptin receptor) The mutant gene, which is the cause of obesity, was shown on map on diabetic mouse (db/db) chromosome 4, and it was proven to be the same as the leptin receptor gene cloned by Tartaglia et all. Further studies have found the Zucker fatty rat (fa/fa) to be incorporated into a linkage map of rat chromosome 5, whose region of rat is the equivalent to the region of conserved synteny of the db/db mouse gene. The leptin receptor is glycoprotein consisting of a single transmembrane-spanning component. The primary structure of leptin receptor belongs to the cytokine-class1 family, the single membrane-spanning receptor, and is highly related to the gp130 signal-transducing component of the interleukin-6 (IL-6) receptor, the granulocyte colony-stimulating factor (G-CSF) receptor, and the leukemia inhibitory factor (LIF) receptor. The leptin receptor is known to have at least six existing isoforms (Ob-Ra, b, c, d, e, f) from the difference in splicing. (Homozygote Mutation of Leptin and Leptin Receptor :Hormone Secretion Disorders) The point mutation of ob/ob mouse and the splicing mutation of db/db mouse show remarkable obesity and hyperphagia. These obesity models show a reproduction disorder with both the male and the female, and they develop with homozygote. The cause is thought to be the gonadotropin secretory abnormality in pituitary. Three family lines report the cases of this deficiency, and it is considered that the secretory abnormality in pituitary develops into hypogonadotropic. These patients show low value in plasma FSHbeta (follicle stimulating hormone-beta and LHbeta (luteinizing hormone-beta which are produced from pituitary, and the plasma GnRH (gonadotropin releasing hormone) level is also low. Furthermore, the leptin receptor deficient family line was reported in 1998, in which case only the homozygote developed. The plasma leptin concentration of normal human is about 8.0 ng/ml, and this case with leptin receptor deficiency has high value of 500-700 ng/ml, which is the equivalent to the db/db mouse. (Role of Leptin in Hypothalamus-Pituitary-Periphery Function) The role of leptin which regulates pituitary hormones suggests the promotion the GHRH (growth hormone releasing hormone) secretion in hypothalamus-pituitary axis, with the possibility of the rise in secretion of GH (growth hormone) in pituitary, i.e. effects of icv (intracerebroventricular) infusion of leptin has spontaneously stimulated GHRH, which promotes GH secretion in the normal rats. On the other hand, topical treatment of GH3 (derived from a rat pituitary GH-secreting cell line) with leptin directly inhibits cell proliferation. The obesity model animals (ob/ob, db/db, fa/fa) have equally plump body compared to the normal models, which shows signs of sufficient growth. (Localization and Functional Relevance of Leptin and Leptin Receptor in Rodents Pituitary) Aside from being the food intake inhibitor and the energy control factor, leptin takes part in controlling the pituitary hormones. Promoting the secretion of GH, PRL (prolactin), TSHbeta (thyroid stimulating hormone-beta, FSHbeta/LHbeta, and inhibiting the secretion of ACTH (adrenocorticotropic hormone) are the major changes of pituitary hormones which are brought on by leptin. The expressive localization is specific, and immunohistochemistry (IHC) method recognized leptin in granular state in FSHbeta, LHbeta and TSHbeta positive cells. In our biochemical examination, the bulk of the expression of leptin is recognized in fraction of the secretory granule. In particular, FSHbeta cells had the highest percentage rate of colocalized leptin in rat pituitary. On the other hand, leptin receptor has been reported to be found only in normal rat pituitary, human pituitary adenoma, and respective cell lines in pituitaries by the RT-PCR method until now, but we disclosed for the first time the localization of leptin receptor on the plasma membrane of GH-secreting cells with the IHC method that has not been cleared so far. These findings show that leptin and leptin receptor have been expressed in different cells, and that the rat pituitary glands entertain paracrine mechanism between leptin (FSHbeta/LHbeta cells) and leptin receptor (GH cells). The function of paracrine in this pituitary suggests a new point of view in hypothalamus-pituitary axis, and it shall be concerned with many aspects such as hormone secretions and proliferation/inhibition. (Human Pituitary Adenoma) Preliminary report of leptin and leptin-receptor relationship with pituitary adenoma that has secretion abnormality has been filed, and its manifestation is being observed by the RT-PCR. Leptin and leptin receptor are expressed in most adenoma, and it is thought to function by autocrine and paracrine pathway in the adenomas. Leptin has been located in ACTH-secreting adenoma most frequently, especially in ACTH carcinoma. The leptin receptor is detected in all adenomas with high percentage rate, with both long and short forms, and then many cases of nonfunctioning pituitary adenomas, compared with other adenomas, have been reported to be positive with both long and short forms of leptin receptor as detected by RT-PCR. The HP75 cell line is derived from the nonfunctioning pituitary adenoma, which produces FSHbeta and LHbeta. The expression of leptin receptor in nonfunctioning pituitary adenoma, and the suppression of HP75 multiplication may lead to the possible hypothesis of leptin becoming one factor for the treatment of pituitary adenoma, especially in gonadotropin adenomas.
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PMID:Leptin and the pituitary. 1182 4

Hyperphagia (overeating) is often associated with energy over-storage and obesity, which may lead to a myriad of serious health problems, including heart disease, hypertension, and type 2 diabetes. Thus, understanding the complex pathological mechanisms underlying hyperphagia and obesity has an important clinical significance. Leptin, or ob protein, is a key element in the long-term regulation of food intake and body weight homeostasis. It circulates in the blood at levels correlated with body fat mass. Leptin binds to specific receptors in the hypothalamus to mediate events that regulate feeding behavior. In light of new evidence, the initial view that leptin is an adipocyte-derived signal, which acts centrally to decrease body weight, has been modified. It has been shown that leptin may also have specific functions in the gastrointestinal tract, suggesting that feeding and energy homeostasis is regulated by both central and peripheral signals. Evidence supports the view that leptin integrates short-term, meal-related signals from the gut into long-term regulation of energy balance. In addition, the gastric leptin level is altered by the nutritional state and the administration of cholecystokinin. This commentary aims to review the evidence of the role of leptin as a peripherally acting signal in the gut in the regulation of nutrient intake, adiposity, and body weight. Based on currently available data, some potential future studies are suggested.
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PMID:Leptin, gut, and food intake. 1200 60

Leptin regulates food intake and body weight by acting primarily in the hypothalamus. In humans and rodents, obesity is associated with hyperleptinaemia, suggesting a possible state of leptin resistance. Thus, to begin to examine the mechanisms of leptin resistance, we developed a rat model in which chronic central leptin infusion results in the development of resistance to leptin's satiety action. Adult male rats were infused chronically into the lateral cerebroventricle with leptin (160 ng/h) or phosphate-buffered saline via Alzet pumps for 28 days, followed by artificial cerebrospinal fluid infusion for 3 weeks. After the initial decrease in food intake, rats developed resistance to the satiety action of leptin, and withdrawal of the chronic leptin infusion resulted in hyperphagia. During leptin infusion, body weight was gradually decreased to reach a nadir on day 12, and thereafter, body weight was sustained at a reduced level throughout the entire 28-day infusion, despite normalization in food intake. Body weight was mostly normalized by day 22 postleptin. Since neuropeptide Y (NPY) neurones are one of the targets of leptin signalling in the hypothalamus, we next examined whether the development of resistance to the satiety action of leptin was due to altered NPY gene expression. On day 3-4 of infusion, hypothalamic NPY mRNA levels, as determined by RNAse protection assay (RPA), were significantly decreased in leptin treated rats compared to controls. By contrast, on day 16 of infusion, NPY mRNA levels in the leptin treated group had returned to control levels. In situ hybridization study confirmed the results obtained with RPA and showed further that the effect of chronic leptin infusion on NPY mRNA levels was restricted to the rostral and middle parts of the arcuate nucleus. Overall, the finding that the action of continuous leptin exposure on NPY neurones was not sustained suggests that NPY neurones may be involved in the development of leptin resistance to the satiety action of leptin in the hypothalamus.
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PMID:Resistance to the satiety action of leptin following chronic central leptin infusion is associated with the development of leptin resistance in neuropeptide Y neurones. 1237 4

Extremely unusual genetic conditions can reveal normal processes governing physiologic regulation and metabolism. Children with rare homozygous mutations in the leptin gene and complete leptin deficiency develop extreme hyperphagia and obesity soon after birth but respond with normal eating and a selective loss of excess body fat upon being given small amounts of leptin. Heterozygote relatives have 30% more fat than predicted and relatively low leptin levels. This demonstrates leptin's fundamental involvement in maintaining energy balance. Leptin also seems to act as a metabolic gate allowing children to enter puberty.
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PMID:Leptin: defining its role in humans by the clinical study of genetic disorders. 1240 81

Leptin-deficient Lep(ob)/Lep(ob) mice exhibit elevations in plasma insulin early in development. The present study tested the hypothesis that absence of leptin during neonatal development permanently programs islets from these mice to hypersecrete insulin. Administration of leptin for 8 days to young adult Lep(ob)/Lep(ob) mice normalized their food intake, plasma insulin concentration, and insulin secretion in response to glucose, acetylcholine, and leptin. Restriction of food intake per se of Lep(ob)/Lep(ob) mice lowered, but did not normalize, plasma insulin concentrations. Food-restricted Lep(ob)/Lep(ob) mice continued to hypersecrete insulin in response to glucose, but islets from these mice did not hyperrespond to acetylcholine or respond to leptin as occurs in ad libitum-fed Lep(ob)/Lep(ob) mice. We conclude that neonatal leptin deficiency does not permanently program islets from mice to hypersecrete insulin. The hyperphagia associated with leptin deficiency contributes substantially to the hypersecretion of insulin, but leptin also appears to have more direct effects on regulation of insulin secretion.
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PMID:Leptin administration normalizes insulin secretion from islets of Lep(ob)/Lep(ob) mice by food intake-dependent and -independent mechanisms. 1256 25

Lactation markedly increases nutrient requirements in both rodents and ruminants. This is met mostly by increased food intake, but there are also adaptations to increase metabolic efficiency. Despite such changes, lactating animals usually experience periods of negative energy balance. This is not due to a physical constraint on food intake, at least in the rat. Leptin, a hormone secreted by adipocytes, plays an important role in the regulation of appetite and energy balance. During lactation, serum leptin concentration is decreased in both rodents and ruminants, and the nocturnal rise in concentration is lost in rats. Hypoleptinaemia in lactation is primarily a result of negative energy balance. There is also increased clearance of serum leptin, and the attenuation of the nocturnal rise in leptin in rats is at least partly due to the suckling stimulus. Hypoleptinaemia is not the major factor driving hyperphagia in lactating rats, but it probably facilitates the increased food intake. Leptin may play a more important role in this respect in lactating ruminants. Leptin is probably involved in other adaptations that increase metabolic efficiency during lactation. The ability of hypothalamic neuropeptides to respond to leptin does not appear to be altered by lactation in either rodents or ruminants. The reason why lactating animals do not respond to hypoleptinaemia with a further increase in appetite, thereby achieving energy balance, appears to be due to a failure to respond to changes in neuropeptides which mediate the effects of leptin.
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PMID:Leptin and the adaptations of lactation in rodents and ruminants. 1266 Aug 82


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