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Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In previous studies we reported that the abnormality of the gamma-GTP level was found not only in hepatobiliary diseases but also in obesity and ingestion of alcohol in healthy individuals. In relation to this results, the present study deals with the relationship between abnormal gamma-GTP level in serum on the one hand and obesity and ingestion of alcohol on the other hand on the basis of test data for 1493 cases (1256 male cases, 237 female cases) who were examined in the short-term human dry dock managed by the Fukuoka University Hospital. To observe how results of various measurements including the degree of obesity and the amount of alcohol ingested exert effects on one another, principle component analysis was done by means of SAS statistic package for computer analysis. In men, as the first principle main components, obesity rate, Hb, Ht, RBC, GPT, gamma-GTP, LAP, GOT, triglyceride and total protein were extracted. As the second main principle components, alcohol, gamma-GTP, MCH, MCV, and HDL were extracted. Theses result demonstrate that the obesity is accompanied by variations in Hb, Ht, RBC and triglyceride and that digestion of alcohol is accompanied by variations in MCH, MCV and HDL in male. In women, components related to erythrocyte and transaminase along with the degree of obesity were extracted as the first main principle components, and principle components related to erythrocyte and alcohol were extracted as the second main components. In either case, alcohol and gamma-GTP were not included.
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PMID:[Studies on background of gamma-GTP abnormality in human multiphasic screening. (Part 2): Principle component analysis by SAS statistic package for computer analysis]. 790 15

A subset of Sprague-Dawley rats developed persistent obesity when maintained on a high-fat diet for 6 months followed by a low-fat diet for 1 month, while another subset from the same cohort of rats remained lean on the same diet regimens. The diet-induced obese (DIO) rats had higher energy intake than expenditure, while diet-resistant (DR) rats maintained energy balance. DIO rats also had an increased respiratory quotient and higher levels of plasma leptin, insulin and cholesterol. In the hypothalamic areas, DIO rats had elevated NPY and AGRP mRNA, but not MCH mRNA. Our data suggest that the increase in hypothalamic expression of NPY and AGRP may contribute to the development of persistent obesity in DIO rats.
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PMID:Characterization of diet-induced obese rats that develop persistent obesity after 6 months of high-fat followed by 1 month of low-fat diet. 1198 34

A chronic minor imbalance between energy intake and energy expenditure may lead to obesity. Both lean and obese subjects eventually reach energy balance and their body weight regulation implies that the adipose tissue mass is "sensed", leading to appropriate responses of energy intake and energy expenditure. The cloning of the ob gene and the identification of its encoded protein, leptin, have provided a system signaling the amount of adipose energy stores to the brain. Leptin, a hormone secreted by fat cells, acts in rodents via hypothalamic receptors to inhibit feeding and increase thermogenesis. A feedback regulatory loop with three distinct steps has been identified: (1) a sensor (leptin production by adipose cells) monitors the size of the adipose tissue mass; (2) hypothalamic centers receive and integrate the intensity of the leptin signal through leptin receptors (LRb); (3) effector systems, including the sympathetic nervous system, control the two main determinants of energy balance-energy intake and energy expenditure. While this feedback regulatory loop is well established in rodents, there are many unsolved questions about its applicability to body weight regulation in humans. The rate of leptin production is related to adiposity, but a large portion of the interindividual variability in plasma leptin concentration is independent of body fatness. Gender is an important factor determining plasma leptin, with women having markedly higher leptin concentrations than men for any given degree of fat mass. The ob mRNA expression is also upregulated by glucocorticoids, whereas stimulation of the sympathetic nervous system results in its inhibition. Furthermore, leptin is not a satiety factor in humans because changes in food intake do not induce short-term increases in plasma leptin levels. After its binding to LRb in the hypothalamus, leptin stimulates a specific signaling cascade that results in the inhibition of several orexigenic neuropeptides, while stimulating several anorexigenic peptides. The orexigenic neuropeptides that are downregulated by leptin are NPY (neuropeptide Y), MCH (melanin-concentrating hormone), orexins, and AGRP (agouti-related peptide). The anorexigenic neuropeptides that are upregulated by leptin are alpha-MSH (alpha-melanocyte-stimulating hormone), which acts on MC4R (melanocortin-4 receptor); CART (cocaine and amphetamine-regulated transcript); and CRH (corticotropin-releasing-hormone). Obese humans have high plasma leptin concentrations related to the size of adipose tissue, but this elevated leptin signal does not induce the expected responses (i.e., a reduction in food intake and an increase in energy expenditure). This suggests that obese humans are resistant to the effects of endogenous leptin. This resistance is also shown by the lack of effect of exogenous leptin administration to induce weight loss in obese patients. The mechanisms that may account for leptin resistance in human obesity include a limitation of the blood-brain-barrier transport system for leptin and an inhibition of the leptin signaling pathways in leptin-responsive hypothalamic neurons. During periods of energy deficit, the fall in leptin plasma levels exceeds the rate at which fat stores are decreased. Reduction of the leptin signal induces several neuroendocrine responses that tend to limit weight loss, such as hunger, food-seeking behavior, and suppression of plasma thyroid hormone levels. Conversely, it is unlikely that leptin has evolved to prevent obesity when plenty of palatable foods are available because the elevated plasma leptin levels resulting from the increased adipose tissue mass do not prevent the development of obesity. In conclusion, in humans, the leptin signaling system appears to be mainly involved in maintenance of adequate energy stores for survival during periods of energy deficit. Its role in the etiology of human obesity is only demonstrated in the very rare situations of absence of the leptin signal (mutations of the leptin gene or of the leptin receptor gene), which produces an internal perception of starvation and results in a chronic stimulation of excessive food intake.
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PMID:Leptin signaling, adiposity, and energy balance. 1207 65

Leptin, the long-sought satiety factor of adipocytes origin, has emerged as one of the major signals that relay the status of fat stores to the hypothalamus and plays a significant role in energy homeostasis. Understanding the mechanisms of leptin signaling in the hypothalamus during normal and pathological conditions, such as obesity, has been the subject of intensive research during the last decade. It is now established that leptin action in the hypothalamus in regulation of food intake and body weight is mediated by a neural circuitry comprising of orexigenic and anorectic signals, including NPY, MCH, galanin, orexin, GALP, alpha-MSH, NT, and CRH. In addition to the conventional JAK2-STAT3 pathway, it has become evident that PI3K-PDE3B-cAMP pathway plays a critical role in leptin signaling in the hypothalamus. It is now established that central leptin resistance contributes to the development of diet-induced obesity and ageing associated obesity. Central leptin resistance also occurs due to hyperleptinimia produced by exogenous leptin infusion. A defective nutritional regulation of leptin receptor gene expression and reduced STAT3 signaling may be involved in the development of leptin resistance in DIO. However, leptin resistance in the hypothalamic neurons may occur despite an intact JAK2-STAT3 pathway of leptin signaling. Thus, in addition to defective JAK2-STAT3 pathway, defects in other leptin signaling pathways may be involved in leptin resistance. We hypothesize that defective regulation of PI3K-PDE3B-cAMP pathway may be one of the mechanisms behind the development of central leptin resistance seen in obesity.
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PMID:Leptin signaling in the hypothalamus: emphasis on energy homeostasis and leptin resistance. 1472 56

Removal of glucocorticoids by adrenalectomy (ADX) reduces food intake and body weight in rodents and prevents excessive weight gain in many genetic and dietary models of obesity. Glucocorticoids play a key role to promote positive energy balance in normal and pathological conditions, at least in part, by altering the sensitivity to hypothalamic peptides. The hyperphagia after central neuropeptide Y administration, for example, is attenuated by ADX, and there is evidence that glucocorticoids influence both MCH and orexin A activity. In the present study, feeding responses to third ventricular MCH and orexin A were measured in rats after bilateral ADX or sham surgery. ADX rats were significantly less sensitive to the orexigenic action of third ventricular MCH, whereas orexin A-induced hyperphagia was unaffected. Replacement of corticosterone in the drinking water of ADX rats reversed the effects of ADX on MCH sensitivity. Although we found significant populations of glucocorticoid receptors in the lateral hypothalamus, none were colocalized with either MCH or orexin A-containing cell bodies. Furthermore, whereas ADX significantly reduced hypothalamic MCH and orexin gene expression, this could not be restored by glucocorticoids in the drinking water. Collectively, the present data suggest that glucocorticoids may promote food intake in part by potentiating the orexigenic actions of MCH without affecting the actions of orexin A and that glucocorticoids act indirectly to influence the effects of MCH on food intake.
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PMID:Differential effects of adrenalectomy on melanin-concentrating hormone and orexin A. 1504 62

Mch1r-deficient (Mch1r(-/-)) mice are hyperphagic, hyperactive, lean, and resistant to diet-induced obesity. To examine whether the MCH1R is involved in regulating activity-based energy expenditure, we investigated voluntary wheel running (WR) activity of wild-type (WT) and Mch1r(-/-) mice basally, in response to diets with different caloric density and with different feeding schedules. We also evaluated WR activity of mice with ablation of the prepro-MCH gene (Pmch(-/-) mice). Dark cycle WR activity of Mch1r(-/-) mice fed low fat (LF) chow was increased significantly relative to WT mice. Transition to moderate high-fat (MHF) diet was associated with an increase in nocturnal WR activity in both genotypes. Both Mch1r(-/-) and WT mice exhibited food anticipatory activity (FAA) before the daily scheduled feeding time, indicating that MCH1R is not required for FAA. Naloxone (3 mg/kg, i.p.) suppressed WR activity of both genotypes, suggesting opioid regulation of locomotor activity. WR increased nocturnal dynorphin mRNA levels in Mch1r(-/-) brain. Importantly, Pmch-deficient mice had significantly enhanced WR activity relative to WT controls. These results suggest that endogenous MCH plays an inhibitory role in regulating locomotor activity. In summary, we demonstrated enhanced WR activities in mice lacking either MCH or its cognate receptor.
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PMID:Enhanced running wheel activity of both Mch1r- and Pmch-deficient mice. 1554 41

One subset of the G-protein coupled receptor (GPCR) superfamily is that which is activated by a peptide carrying an obligatory positively charged residue (GPCR-PA(+)). This subclass is exemplified by receptors for melanocortins, GnRH, galanin, MCH, orexin, and some chemokine receptors variously involved in eating disorders, reproductive disorders, pain, narcolepsy, obesity, and inflammation. Using the methods described in this study, a region of chemical property space enriched in GPCR ligands was identified. This information was used to design and synthesize a "test" library of 2025 single, pure compounds to sample portions of this property space associated with GPCR-PA(+) ligands. The library was evaluated by high-throughput screening against three different receptors, rMCH, hMC4, and hGnRH, and found to be highly enriched in active ligands (4.5-61-fold) compared to a control set of 2024 randomly selected compounds. In addition, the analysis suggested that about 7000 compounds will be necessary to complete the sampling of this GPCR-PA(+) ligand-rich region and to better define its borders.
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PMID:A screening library for peptide activated G-protein coupled receptors. 1. The test set. 1561 35

The Society for Medicines Research organized a one-day meeting on antiobesity drugs on March 26, 1998, in London. Current environmental risks for obesity include an increase in the proportion of fat consumption--especially an increase in the fat-to-carbohydrate ratio--and an increase in a sedentary life-style without an appropriate lowering in food intake. Energy balance plays a pivotal role of in the control of body stores. Knowing the mechanisms of the control of energy intake and energy expenditure provides explanations for the incidence of obesity and also possible sites for drug intervention. The genetic basis for obesity is complex, with the probability of a number of interacting genes being involved (polygenic inheritance). Each of the main components of the energy balance relationship has a distinct genetic basis. The ob gene was first identified in 1994 by Friedman, and its product is leptin, which may well be a potential target for obesity treatment. Speakers at the meeting highlighted various targets that hold promise in developing pharmacological treatments for obesity: increasing the activity of satiety factors (CCK-8, GPL-1, ACTH, alphaMSH and 5-HT acting on 5-HT(2C) receptors); inhibiting orexigenic agents (NPY, MCH, galanin); targeting thermogenesis (beta(3)-adrenergic agonists and uncoupling proteins); targeting fat absorption; and targeting neuropeptides. Some of the compounds developed to act on these sites are now becoming available.
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PMID:Update on antiobesity drugs. 1561 66

Biaryl urea lead compound 1 was discovered earlier in our MCH antagonist program. Novel benzimidazole analogues with increased chemical stability, devoid of the potential carcinogenic liability associated with a biarylamine moiety, were synthesized and evaluated to be potent MCH R1 antagonists. Two compounds in this series have demonstrated in vivo efficacy in a rodent obesity model.
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PMID:Design and synthesis of orally efficacious benzimidazoles as melanin-concentrating hormone receptor 1 antagonists. 1669 Mar 15

Amylin is a pancreatic B-cell hormone that plays an important role in the regulation of nutrient fluxes. As such, amylin reduces food intake in laboratory animals and man, slows gastric emptying and it reduces postprandial glucagon secretion. Amylin deficiency which occurs concomitantly to insulin deficiency in diabetes mellitus, may therefore contribute to some of the major derangements associated with this disorder (hyperphagia, excessive glucagon secretion, accelerated rate of gastric emptying). The described actions of amylin all seem to depend on a direct effect of amylin on the area postrema (AP). As to amylin's satiating effect, the physiological relevance of this action is underlined by studies involving specific amylin antagonists and amylin-deficient mice. In the AP, amylin seems to modulate the anorectic signal elicited by CCK. Subsequent to AP activation, the amylin signal is conveyed to the forebrain via distinct relay stations. Within the lateral hypothalamic area, amylin diminishes the expression of orexigenic neuropeptides such as orexin and MCH. Whether these effects contribute to amylin's short term satiating action remains to be determined. Recent studies suggest that amylin may also play a role as a long-term, lipostatic signal, especially when other feedback systems to the brain are deficient. Obese, leptin-resistant Zucker rats which are hyperinsulinemic and hyperamylinemic, were chronically infused with the amylin antagonist AC 187. AC 187 significantly elevated food intake in obese Zucker rats while having no effect in lean controls. This indicates that at least under certain conditions, chronic blockade of endogenous amylin action may lead to an increase in food intake and/or body weight. As mentioned, the site and mechanism of action for peripheral amylin to reduce food intake seems to be well established. It is less clear how centrally administered amylin reduces food intake although it is well known that 3rd ventricular administration of amylin produces a very strong and long-lasting anorectic action. Amylin receptors have been described in various hypothalamic nuclei but the endogenous ligand of these receptors remains to be investigated. The same holds true as to the physiological relevance of the anorectic effect seen after central amylin administration.
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PMID:Amylinergic control of food intake. 1669 20


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