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

The high prevalence of obesity and its well documented association with the cardiovascular risk factors diabetes mellitus, dyslipidemia and hypertension represents a major problem for the general health status of industrialized societies. Although numerous studies have shown that genetic factors have a major influence on the regulation of energy homeostasis and the susceptibility to obesity, the genes and predisposing mutations involved are insufficiently understood. Among several known rodent models of obesity due to single gene mutations, mice homozygous for the obese (ob) gene exhibit massive early-onset obesity, hyperphagia, non-insulin-dependent diabetes mellitus, defective thermoregulation and infertility. Recently the ob gene was identified by positional cloning and shown to be mutated in ob/ob mice. Leptin, the product of the ob gene, is a 167-amino acid secreted protein that is synthesized exclusively in adipose tissue. With the exception of ob/ob mice, circulating plasma leptin is elevated in obesity. Administration of recombinant leptin to ob/ob mice reduces fat mass, food intake, hyperglycemia and hyperinsulinemia. The various effects of the hormone are mediated by leptin receptors expressed at high levels in the hypothalamus, but also in several other non-neuronal tissues. A mutation in the leptin receptor gene is responsible for the obese phenotype of db/db mice. Plasma leptin in humans is positively correlated with body fat mass, suggesting that leptin resistance rather than leptin deficiency is a common feature of human obesity. This review briefly summarizes the current status of the rapidly growing evidence that leptin plays an important role in the regulation of body weight and fat deposition.
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PMID:Regulation of energy balance by leptin. 888 45

Serum leptin concentrations and the levels of ob mRNA in adipocytes in obese humans are elevated. Hyperphagia and obesity are characteristics of hypercortisolism. We have therefore asked whether or not leptin levels were elevated in very obese children, and whether or not dexamethasone would increase leptin levels in obese children. A single dose dexamethasone suppression test was performed in ten obese children (5 girls, 5 boys; age 6 to 16 yrs, mean 12 +/- 1, median 12 yrs) to rule out hypercortisolism. Body mass index (BMI) in the ten children was calculated to be 27-45 kg/m2. Venous blood was sampled before dexamethasone was given in the evening and at 9.00 a.m. the following morning. Endogenous cortisol production was suppressed in all patients. Leptin levels, as measured by a newly developed specific radioimmunoassay, were 31.6 +/- 12.9 microg/l, range 19.2-59.9 microg/l before dexamethasone and 39.9 +/- 16.5 microg/l, range 26.3-80.3 microg/l after dexamethasone in the obese children (ANOVA, p = 0.01). Simple regression analysis revealed that serum levels correlated significantly with body mass index (r = 0.82, p < 0.001). Non-obese children (BMI < 27 kg/m2) had leptin levels between 0.1 and 33.3 microg/l, median 2.2 microg/l (N = 713). Girls (5.5 +/- 4.6 microg/l) (N = 401) had significantly higher leptin levels than boys (1.7 +/- 2.1 microg/l (N = 312) (p < 0.0001). We conclude that 1) high serum leptin concentrations are present in obese children. 2) A single dose of dexamethasone significantly increases the high leptin serum levels in these children. We hypothesize that glucocorticosteroids up-regulate leptin levels in the human.
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PMID:High leptin concentrations in serum of very obese children are further stimulated by dexamethasone. 901 47

Leptin acts on the brain to inhibit feeding, increase thermogenesis, and decrease body weight. Neuropeptide Y (NPY)-ergic neurons of the hypothalamic arcuate nucleus (ARC) that project to the paraventricular nuclei (PVN) and dorsomedial nuclei (DMH) are postulated to control energy balance by stimulating feeding and inhibiting thermogenesis, especially under conditions of energy deficit. We investigated whether leptin's short-term effects on energy balance are mediated by inhibition of the NPY neurons. Recombinant murine leptin (11 microg) injected into the lateral ventricle of fasted adult Wistar rats inhibited food intake by 20-25% between 2 and 6 h after administration, compared with saline-treated controls (P < 0.05). Uncoupling protein mRNA levels in brown adipose tissue (BAT) rose by 70% (P < 0.01). Leptin treatment significantly reduced NPY concentrations by 20-50% (P < 0.05) in the ARC, PVN, and DMH and significantly decreased hypothalamic NPY mRNA levels (0.61 +/- 0.02 vs. 0.78 +/- 0.03 arbitrary units; P < 0.01). A second study examined changes in leptin during 5 days' intracerebroventricular NPY administration (10 microg/day), which induced sustained hyperphagia and excessive weight gain. In NPY-treated rats, leptin mRNA levels in epididymal fat were comparable to those in saline-treated controls (0.94 +/- 0.17 vs. 1.0 +/- 0.28 arbitrary units; P > 0.1), but plasma leptin levels were significantly higher (4.88 +/- 0.66 vs. 2.85 +/- 0.20 ng/ml; P < 0.01). Leptin therefore acts centrally to decrease NPY synthesis and NPY levels in the ARC-PVN projection; reduced NPY release in the PVN may mediate leptin's hypophagic and thermogenic actions. Conversely, NPY-induced obesity results in raised circulating leptin concentrations. Leptin and the NPY-ergic ARC-PVN neurons may interact in a homeostatic loop to regulate body fat mass and energy balance.
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PMID:Interactions between leptin and hypothalamic neuropeptide Y neurons in the control of food intake and energy homeostasis in the rat. 903 86

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

With the exception of ob/ob mice, circulating plasma leptin is elevated in all other obese rodents as well as in obese humans, suggesting that leptin resistance rather than leptin deficiency is a characteristic feature of obesity. The exact molecular mechanisms leading to leptin resistance and the applicability of exogenous leptin to overcome resistance to the anorectic effect of the hormone, are insufficiently characterized. The aim of this study was to investigate whether chronic leptin administration could prevent the development of obesity and its associated disorders in transgenic mice with toxigene mediated ablation of brown adipose tissue (BAT). Daily injections of leptin were started at the age of 6 weeks, when body weight, food intake and plasma leptin levels of transgenics were not different from control mice. Over the next 6 weeks, leptin treated transgenics showed the same excessive body weight gain as transgenic mice injected with saline. Leptin treatment was furthermore not able to prevent the development of hyperphagia, hyperglycaemia, hyperinsulinaemia and hyperlipidaemia in transgenic mice. In contrast, control mice injected with leptin had significantly lower body weight, food intake and plasma triglycerides than those treated with saline. In summary, leptin treatment was not able to prevent the development of obesity and its associated abnormalities in transgenic mice with BAT deficiency. This data suggests that intact BAT function is of critical importance for leptin's effect on food intake and energy expenditure, and that primary dysfunction of BAT is associated with leptin resistance, even when hyperleptinaemia is not yet present.
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PMID:Chronic leptin treatment does not prevent the development of obesity in transgenic mice with brown fat deficiency. 924 2

Leptin 167 an amino acid product of the recently discovered obesity gene "ob-gene", is a tissue hormone of adipose tissue. It is a hormonal satiety signal or a signal for terminating food intake. Its level rise after a meal or after administration. Rats with a mutation of the ob-gene have zero or very low leptin levels, are hyperphagic, obese and sterile, develop diabetes as a result of overeating. Administration of recombinant leptin arrests hyperphagia, the body weight declines and sexual function improve partly, in particular in males. It seems that leptin controls not only the function of the hypothalamic satiety centre but also the output of GnRh and other liberins as well as thermoregulation, muscular and sexual activity and thus energy expenditure. In the majority of obese rats and human the leptin levels are significantly higher compared with asthenic individuals, proportionate to the percentage of body fat and BMI. Obesity promotes also insulin resistance and penetration of the H-phenomenon into the phenotype. In the insulin resistance syndrome (5H-X) it may thus be assumed that there is a parallel leptin and insulin resistance, probably of the postreceptor type, and even a causal association, as the "db" gene is identical with the gene for leptin receptors.
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PMID:[Leptin and its biological and clinical significance. Is leptin and insulin resistance in the X-5H hormonal metabolic syndrome a parallel or causally-linked phenomenon?]. 924 68

Brown adipose tissue (BAT) has the capacity for uncoupled mitochondrial respiration and is proposed to be a key site for regulating energy expenditure in rodents. To better define the role of BAT in energy homeostasis, we previously created a line of transgenic mice with deficiency of BAT (UCP promoter-driven diphtheria toxin A transgenic mice [UCP-DTA]) mice. These mice develop obesity that initially is due to decreased energy expenditure and later accompanied by hyperphagia despite increased levels of circulating leptin. In addition, the obesity of these mice is accompanied by severe insulin-resistant diabetes and hyperlipidemia. To better define the basis for leptin resistance in this model, we treated UCP-DTA mice with leptin (300 microg i.p., b.i.d.) and compared their response with that of leptin-treated ob/ob and FVB control mice (30 microg i.p., b.i.d.). Leptin treatment of FVB and ob/ob mice decreased their body weight and food intake and improved their glucose homeostasis. In contrast, tenfold higher dosages of leptin had no effect on body weight, food intake, or circulating insulin or glucose concentrations of UCP-DTA mice. Hypothalamic neuropeptide Y (NPY) mRNA expression was lower in UCP-DTA mice than in littermate control FVB mice in the fed state, and increased progressively in response to food restriction as leptin levels fell. In parallel to the levels of hypothalamic NPY, corticosterone levels were initially suppressed and rose with food restriction. Thus food intake, body weight, and insulin and glucose homeostasis of UCP-DTA mice are all extraordinarily resistant to leptin, whereas hypothalamic NPY and the hypothalamopituitary adrenal (HPA) axis may remain under leptin control. Further elucidation of the mechanisms underlying leptin resistance in UCP-DTA mice may provide valuable insights into the basis for leptin resistance in human obesity.
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PMID:Severe leptin resistance in brown fat-deficient uncoupling protein promoter-driven diphtheria toxin A mice despite suppression of hypothalamic neuropeptide Y and circulating corticosterone concentrations. 951 18

The adipocyte-specific hormone leptin, the product of the obese (ob) gene, regulates adipose-tissue mass through hypothalamic effects on satiety and energy expenditure. Leptin acts through the leptin receptor, a single-transmembrane-domain receptor of the cytokine-receptor family. In rodents, homozygous mutations in genes encoding leptin or the leptin receptor cause early-onset morbid obesity, hyperphagia and reduced energy expenditure. These rodents also show hypercortisolaemia, alterations in glucose homeostasis, dyslipidaemia, and infertility due to hypogonadotropic hypogonadisms. In humans, leptin deficiency due to a mutation in the leptin gene is associated with early-onset obesity. Here we describe a homozygous mutation in the human leptin receptor gene that results in a truncated leptin receptor lacking both the transmembrane and the intracellular domains. In addition to their early-onset morbid obesity, patients homozygous for this mutation have no pubertal development and their secretion of growth hormone and thyrotropin is reduced. These results indicate that leptin is an important physiological regulator of several endocrine functions in humans.
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PMID:A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction. 953 16

The objective was to characterize the ability of control and transgenic brown adipose tissue (BAT)-ablated uncoupling protein diphtheria toxin A chain (UCP-DTA) mice to adjust food intake in relation to changes in environmental temperature and to assess the involvement of leptin in this adjustment. We measured serum leptin in mice from a previous study of UCP-DTA mice raised at thermoneutrality (35 degrees C) or at the usual rearing temperature (24 degrees C) from weaning [Melnyk, A., M. -E. Harper, and J. Himms-Hagen. Am. J. Physiol, 272 (Regulatory Integrative Comp. Physiol. 41): R1088-R1093, 1997] and extended the study by acclimating control and obese UCP-DTA mice at 18 wk of age to cold (14 degrees C) for up to 14 days. Leptin levels did not change in control mice at 14 degrees C; however, food intake increased threefold within 1 day and remained at this level. Serum leptin level was elevated in UCP-DTA mice at 24 degrees C compared with control mice at 24 degrees C; this elevated level decreased within 1 day at 14 degrees C and was not different from the level in control mice by 14 days. Food intake of UCP-DTA mice that were hyperphagic at 24 degrees C did not change during 7 days at 14 degrees C, then increased slowly. Similar low leptin levels were present in control mice raised at 24 or 35 degrees C and in UCP-DTA mice raised at 35 degrees C. Food intake of control mice raised at 24 degrees C was two times that of control mice raised at 35 degrees C. UCP-DTA mice raised at 35 degrees C ate the same low amount as control mice raised at 35 degrees C. UCP-DTA mice at 24 degrees C were hyperphagic relative to control mice at 24 degrees C yet had elevated leptin levels in their serum. Two principal conclusions are drawn. First, adjustment of food intake over a fourfold range by control mice acclimated to temperatures from 35 down to 14 degrees C is independent of changes in serum leptin levels. Second, this adjustment of food intake in relation to temperature is defective in the UCP-DTA mouse; the defect leads to hyperphagia at 24 degrees C and a failure to increase food intake as rapidly as control mice when exposed to 14 degrees C. Because lack of UCP-1-mediated thermogenesis in BAT of knockout mice is known not to induce hyperphagia, we propose that deficiency of UCP-1-expressing brown adipocytes in BAT of UCP-DTA mice results in lack of a satiety factor, secreted by these cells in BAT of control mice in inverse relationship to sympathetic nervous system activity.
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PMID:Temperature-dependent feeding: lack of role for leptin and defect in brown adipose tissue-ablated obese mice. 957 79

Hyperphagia and obesity can be experimentally induced in rodents by microinjection of 6-hydroxydopamine (6-OHDA) into the ventral noradrenergic bundle (VNAB) to interrupt efferent catecholaminergic pathways to the hypothalamus. Since hypothalamic neuropeptide Y (NPY) is implicated in the control of ingestive behavior, we evaluated hypothalamic NPY activity in this model of obesity. Adult male rats injected bilaterally with 12 microg of 6-OHDA in the VNAB displayed an enhanced rate of body weight gain and selective dark-phase hyperphagia that started at about 10 days postinjection and persisted for the entire duration of the experiment. NPY gene expression, assessed by ribonuclease protection assay, was significantly higher in the hypothalami of 6-OHDA-treated hyperphagic rats during the dark phase (p < 0.01 vs. levels during the light phase and in control, vehicle-injected rats). We also evaluated gene expression of NPY Y and Y5 receptors, receptor subtypes reported to mediate NPY-induced feeding. The dark-phase increase in NPY mRNA was accompanied by the concomitant upregulation of NPY Y5R gene expression, but not of Y1R mRNA levels. Leptin, the peripheral hormone secreted by adipocytes, is believed to maintain body weight and inhibit food intake, most likely by suppressing hypothalamic NPY activity. Evaluation of leptin gene expression in the epididymal fat revealed that the upregulation of leptin mRNA noted during the dark phase in control rats did not occur in 6-OHDA-treated rats. These observations implied that the normal restraint on NPY and feeding exercised by leptin in control rats may be abrogated in 6-OHDA-treated hyperphagic rats due to insufficient levels of leptin. If so, administration of leptin should inhibit food intake in these rats. Indeed, injection of leptin (2 mg/kg, intraperitoneally (i.p.)) on 2 consecutive days reduced 24-h food intake by 25% and significantly reduced body weight. These results suggest that the nocturnal hyperphagia and resultant obesity induced by 6-OHDA injected into the VNAB may be attributed to leptin deficiency concomitant with increased hypothalamic NPY.
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PMID:Evidence that dark-phase hyperphagia induced by neurotoxin 6-hydroxydopamine may be due to decreased leptin and increased neuropeptide Y signaling. 961 6


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