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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 multi-gene syndrome, expression of which is modulated not only by environmental factors but above all by a number of modified genes interacting with each other. Among candidate genes related to obesity phenotype is ghrelin gene. Ghrelin plays a significant role in feeding regulation and is the strongest stimulator of growth hormone secretion. Ghrelin acts by GHS1a receptor (growth hormone secretagogue receptor). Mutations in preproghrelin and ghrelin gene or ghrelin receptor gene could be responsible for low ghrelin levels observed in obese individuals. Among identificated mutations, two Arg51 Gln and Leu72Met are most often described and change amino-acid sequence of ghrelin (Arg51Gln) and preproghrelin (Leu72Met). Although no direct relationship between Arg51Gln mutation and obesity phenotype was found, it had been shown that carriers of Arg51Gln mutation had significantly decreased plasma ghrelin levels. Furthermore 51Gln allele carriers had higher prevalence of type 2 diabetes mellitus and hypertension than non-carriers. Met 72 carrier status is associated with higher serum IGF-1 levels and seems to be a protective factor against fat accumulation and cardiovascular complications of obesity. No evidence of relationship between ghrelin receptor gene polymorphisms and body mass regulation was found, however, until now there is no study on relationships between these polymorphisms and metabolic complications of obesity. The presence of genetic variants in ghrelin or GHS receptor gene could be responsible for impaired GH secretion in visceral type obesity and development of metabolic syndrome in some of obese subjects. On the other hand, some mutations in preproghrelin gene could be protective against metabolic syndrome.
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PMID:[Preproghrelin gene, ghrelin receptor and metabolic syndrome]. 1622 41

Ghrelin, produced in the stomach, acts on growth hormone secretagogue receptors (GHSRs) in hypothalamic neurons to potently increase food intake. However, male mice with deletions of ghrelin (Ghrl-/- mice) or GHSR (Ghsr-/- mice) display normal growth and regulation of food intake. Furthermore, adult Ghrl-/- mice display a normal sensitivity to high-fat diet-induced obesity. These findings from early studies raised the question as to whether the ghrelin system is an essential component for the regulation of food intake and body weight homeostasis. However, recent studies by Wortley et al. and Zigman et al. demonstrate that Ghrl-/- and Ghsr-/- mice are resistant to diet-induced obesity when fed a high-fat diet during the early post-weaning period. This commentary highlights 3 key issues raised by these 2 reports: (a) the impact of ghrelin on the development of metabolic systems; (b) the constitutive activity of GHSR; and (c) gender differences in the sensitivity to deletion of the ghrelin signaling system.
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PMID:Is ghrelin a signal for the development of metabolic systems? 1632 95

Ghrelin is the endogenous ligand for the growth hormone secretagogue receptor (GHSR; ghrelin receptor). Since its discovery, accumulating evidence has suggested that ghrelin may play a role in signaling and reversing states of energy insufficiency. For example, ghrelin levels rise following food deprivation, and ghrelin administration stimulates feeding and increases body weight and adiposity. However, recent loss-of-function studies have raised questions regarding the physiological significance of ghrelin in regulating these processes. Here, we present results of a study using a novel GHSR-null mouse model, in which ghrelin administration fails to acutely stimulate food intake or activate arcuate nucleus neurons. We show that when fed a high-fat diet, both female and male GHSR-null mice eat less food, store less of their consumed calories, preferentially utilize fat as an energy substrate, and accumulate less body weight and adiposity than control mice. Similar effects on body weight and adiposity were also observed in female, but not male, GHSR-null mice fed standard chow. GHSR deletion also affected locomotor activity and levels of glycemia. These findings support the hypothesis that ghrelin-responsive pathways are an important component of coordinated body weight control. Moreover, our data suggest that ghrelin signaling is required for development of the full phenotype of diet-induced obesity.
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PMID:Mice lacking ghrelin receptors resist the development of diet-induced obesity. 1632 85

Eating disorders (EDs) have a highly heterogeneous etiology and multiple genetic factors might contribute to their pathogenesis. Ghrelin, a novel growth hormone-releasing peptide, enhances appetite and increases food intake, and human ghrelin plasma levels are inversely correlated with body mass index. In the present study, we examined the 171T/C polymorphism of the ghrelin receptor (growth hormone secretagogue receptor, GHSR) gene in patients diagnosed with EDs, because the subjects having ghrelin gene polymorphism (Leu72Met) was not detected in a Japanese population, previously. In addition, beta3 adrenergic receptor gene polymorphism (Try64Arg) and cholecystokinin (CCK)-A receptor (R) gene polymorphism (-81A/G, -128G/T), which are both associated with obesity, were investigated. The subjects consisted of 228 Japanese patients with EDs [96 anorexia nervosa (AN), 116 bulimia nervosa (BN) and 16 not otherwise specified (NOS)]. The age- and gender-matched control group consisted of 284 unrelated Japanese subjects. The frequency of the CC type of the GHSR gene was significantly higher in BN subjects than in control subjects (chi(2) = 4.47, p = 0.035, odds ratio = 2.05, Bonferroni correction: p = 0.070), while the frequency in AN subjects was not different from that in controls. The distribution of neither beta3 adrenergic receptor gene nor CCK-AR polymorphism differed between EDs and control subjects. Therefore, the CC type of GHSR gene polymorphism (171T/C) is a risk factor for BN, but not for AN.
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PMID:Association of ghrelin receptor gene polymorphism with bulimia nervosa in a Japanese population. 1636 31

Ghrelin, identified as an endogenous ligand for the growth hormone secretagogue receptor, functions as a somatotrophic and orexigenic signal from the stomach. Ghrelin has a unique post-translational modification: the hydroxyl group of the third amino acid, usually a serine but in some species a threonine, is esterified by octanoic acid and is essential for ghrelin's biological activities. The secretion of ghrelin increases under conditions of negative energy-balance, such as starvation, cachexia, and anorexia nervosa, whereas its expression decreases under conditions of positive energy-balance such as feeding, hyperglycemia, and obesity. In addition to having a powerful effect on the secretion of growth hormone, ghrelin stimulates food intake and transduces signals to hypothalamic regulatory nuclei that control energy homeostasis. Thus, it is interesting to note that the stomach may play an important role in not only digestion but also pituitary growth hormone release and central feeding regulation. We summarized recent findings on the integration of ghrelin into neuroendocrine networks that regulate food intake, energy balance, gastrointestinal function and growth.
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PMID:Biological, physiological, and pharmacological aspects of ghrelin. 1661 45

Ghrelin woas recently de-orphaned as an endogenous ligand of growth hormone secretagogue receptor (GHS-R), and is implicated as a short-term meal initiator and a long-term energy balance regulator. Administration of ghrelin causes increases in food intake and body weight in both rodents and humans. Inhibiting its actions with GHS-R anti-sense oligonucleotides, anti-ghrelin antibodies, and peptide antagonists leads to decreased food intake and weight loss in rodents. Despite the much-publicized promise of providing a novel approach for anti-obesity treatment, limited progress has been made in developing small-molecule GHS-R antagonists and no such compound has been advanced to clinical trials. This review will summarize the recent progress in small-molecule GHS-R antagonists and offer some insight into this area of research based on the experience at Abbott Laboratories.
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PMID:Growth hormone secretagogue receptor antagonists as anti-obesity therapies? Still an open question. 1688 33

In humans, circulating GH levels are increased in catabolic states and suppressed in obesity. In both extremes, normalization of the metabolic environment normalizes GH release, leading to the conclusion that changes in metabolic hormones and/or metabolites promote changes in GH synthesis and release. Metabolic regulation of GH secretion can be mediated centrally by modulation of hypothalamic GHRH and somatostatin input to the pituitary and/or by direct regulation of pituitary somatotrope function. Although data are available showing glucocorticoids, free fatty acids (FFA), IGF-I, and insulin have direct effects on rat somatotrope function, little information is available regarding the direct pituitary effects of these metabolic factors in primates. Therefore, this study examined the effects of glucocorticoids (dexamethasone (0.1-100 nM) and hydrocortisone (10 nM)), FFA (oleic and linoleic acid, 100 and 400 microM each), IGF-I (0.5-50 nM), and insulin (0.5-50 nM) on GH release and GH, GHRH-receptor (GHRH-R) and ghrelin-receptor (GHS-R) mRNA levels, in primary pituitary cell cultures of baboons (Papio anubis) after 24 h treatment. A commercial ELISA kit was used to determine the amount of GH released into the media, while quantitative real-time reverse transcription-PCR was used to determine mRNA levels. To design species-specific primers for baboon GH, GHRH-R, GHS-R, insulin receptor (INSR), IGF-I receptor (IGF-IR), pituitary-specific transcription factor-1 (Pit-1), and cyclophilin A (used as a housekeeping gene) cDNA, sequence data for each baboon transcript were obtained and this data were submitted to Genbank. Glucocorticoids, FFA, insulin and IGF-I treatment did not significantly alter the expression of Pit-1, a transcription factor essential for normal somatotrope development and function. However, as previously reported in the rat, glucocorticoids increased, while FFA, IGF-I and insulin decreased GH release in baboon pituitary cell cultures, where changes in GH release were reflected by comparable changes in GH mRNA levels. In addition, glucocorticoids increased, while FFA, IGF-I and insulin decreased the expression of the GH stimulatory receptors, GHRH-R and GHS-R, without significantly altering cyclophilin A mRNA levels. A role of insulin/INSR pathway, independent of IGF-I, in regulating pituitary function is supported by the fact that (1) IGF-I and insulin significantly suppressed somatotrope function at doses (0.5 and 5 nM respectively) not anticipated to activate their respective receptors, and (2) the baboon pituitary expresses INSR mRNA at levels comparable to or greater than that of tissues commonly considered as insulin sensitive (i.e. liver, skeletal muscle, and fat). Taken together, these results demonstrate that metabolic factors can directly modulate primate somatotrope function through regulating GH synthesis and release, as well as mediating the expression of receptors important in central (GHRH) and systemic (ghrelin) regulation of GH secretion.
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PMID:Examination of the direct effects of metabolic factors on somatotrope function in a non-human primate model, Papio anubis. 1690 21

Leptin-deficient obese mice (ob/ob) have decreased circulating growth hormone (GH) and pituitary GH and ghrelin receptor (GHS-R) mRNA levels, whereas hypothalamic GH-releasing hormone (GHRH) and somatostatin (SST) expression do not differ from lean controls. Given the fact that GH is suppressed in diet-induced obesity (a state of hyperleptinemia), it remains to be determined whether the absence of leptin contributes to changes in the GH axis of ob/ob mice. Therefore, to study the impact of leptin replacement on the hypothalamic-pituitary GH axis of ob/ob mice, leptin was infused for 7 days (sc), resulting in circulating leptin levels that were similar to wild-type controls (approximately 1 ng/ml). Leptin treatment reduced food intake, body weight, and circulating insulin while elevating circulating n-octanoyl ghrelin concentrations. Leptin treatment did not alter hypothalamic GHRH, SST, or GHS-R mRNA levels compared with vehicle-treated controls. However, leptin significantly increased pituitary GH and GHRH-R expression and tended to enhance circulating GH levels, but this latter effect did not reach statistical significance. In vitro, leptin (1 ng/ml, 24 h) did not affect pituitary GH, GHRH-R, or GHS-R mRNA but did enhance GH release. The in vivo effects of leptin on circulating hormone and pituitary mRNA levels were not replicated by pair feeding ob/ob mice to match the food intake of leptin-treated mice. However, leptin did prevent the fall in hypothalamic GHRH mRNA and circulating IGF-I levels observed in pair-fed mice. These results demonstrate that leptin replacement has positive effects on multiple levels of GH axis function in ob/ob mice.
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PMID:Effects of leptin replacement on hypothalamic-pituitary growth hormone axis function and circulating ghrelin levels in ob/ob mice. 1712 91

The gastric hormone ghrelin and its receptor, growth hormone secretagogue receptor (GHSR), are expressed in pancreas. Here, we report that ghrelin is released from pancreatic islets to regulate glucose-induced insulin release. Plasma concentrations of ghrelin, as well as insulin, were higher in pancreatic veins than in arteries. GHSR antagonist and immunoneutralization of endogenous ghrelin enhanced glucose-induced insulin release from perfused pancreas, whereas exogenous ghrelin suppressed it. GHSR antagonist increased plasma insulin levels in gastrectomized and normal rats to a similar extent. Ghrelin knockout mice displayed enhanced glucose-induced insulin release from isolated islets, whereas islet density, size, insulin content, and insulin mRNA levels were unaltered. Glucose tolerance tests (GTTs) in ghrelin knockout mice showed increased insulin and decreased glucose responses. Treatment with high-fat diet produced glucose intolerance in GTTs in wild-type mice. In ghrelin knockout mice, the high-fat diet-induced glucose intolerance was largely prevented, whereas insulin responses to GTTs were markedly enhanced. These findings demonstrate that ghrelin originating from pancreatic islets is a physiological regulator of glucose-induced insulin release. Antagonism of the ghrelin function can enhance insulin release to meet increased demand for insulin in high-fat diet-induced obesity and thereby normalize glycemic control, which may provide a potential therapeutic application to counteract the progression of type 2 diabetes.
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PMID:Blockade of pancreatic islet-derived ghrelin enhances insulin secretion to prevent high-fat diet-induced glucose intolerance. 1713 Apr 96

Ghrelin, a 28-amino acid hormone that is acylated post-translation, is the endogenous ligand for the growth hormone (GH) secretagogue (GHS) receptor (GHS-R). The highest concentrations of ghrelin are found in the stomach; however ghrelin peptide is also present in hypothalamic nuclei known to be important in the control of GH and feeding behavior. Exogenous ghrelin potently stimulates pituitary GH release through a mechanism that is dependent, in part, on endogenous GH-releasing hormone. Whether endogenous ghrelin plays a role in the control of GH secretion and growth is not clear and ghrelin deficient animals appear to grow normally. In contrast, experimental animal and clinical data suggest that abnormalities in GHS-R signaling could impact growth. Ghrelin or other GHS are clinically useful for GH-testing and limited data suggest that they might be useful in the treatment of some patients with GH deficiency. Substantial data have implicated ghrelin as an important regulator of feeding behavior and energy equilibrium. Ghrelin has a potent orexigenic effect in both animals and humans and this effect is mediated through hypothalamic neuropeptide Y (NPY) and Agouti-related peptide (AgRP). Appetite simulation coupled with other metabolic effects promotes weight gain during chronic treatment with ghrelin. These metabolic effects are in part mediated through an increase in respiratory quotient (VQ). Presence of ghrelin appears to be necessary for the development of obesity in some animal models. Whether abnormalities in ghrelin signaling are involved in human obesity is not yet known.
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PMID:Role of endogenous ghrelin in growth hormone secretion, appetite regulation and metabolism. 1719 43


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