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

The hypothalamic disorders of obesity include hyperphagia, a low central orthosympathetic tone (with reduced thermogenesis), vagal hyperinsulinism, low serotonin efficacy, a hyperactive hypothalamo-hypophyseal-adrenal axis, a hypoactive GHRH-GH-IGF axis and hypogonadism of central origin. Hyperlipogenesis, glucose intolerance and excessive gluconeogenesis are secondary features. Most frequently the hypothalamic ARC reacts poorly to the leptin hypersecreted by adipose tissue, so that the local synthesis of NPY is unchecked. Fortunately, two prostaglandins derived from dietary arachidonic acid bind fat cell PPAR gamma and hepatic PPAR alpha. Both nuclear proteins are phosphorylated through an insulin pathway, thereby inhibiting the expression of genes favoring obesity and stimulating that of genes accelerating fatty acid oxidation. The array of dietetic and pharmacologic tools considered today is analyzed.
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PMID:[Molecular endocrinology of hereditary obesity]. 949 39

Leptin, a product of the obese (ob) gene, is secreted by adipocytes and appears to act as a hormone to regulate food intake, metabolism and body weight. Subcutaneous administration of leptin causes reductions in food intake and body and fat-depot weights in both lean and genetically obese (ob/ob) mice, and leptin infusion into the lateral cerebral ventricles decreases feeding with short latency, suggesting a central site of action. A gene defect in the Zucker obese rat causes an amino acid substitution in the leptin receptor and reduced leptin binding at the cell surface. An antiserum to a portion of the mouse leptin receptor (AA 877-894) located within the intracellular domain was used to label Zucker lean (Fa/?) and obese (fa/fa) rat brain sections. At optimal dilution (1:8000), only cells in the basal forebrain, preoptic area, hypothalamus and brainstem were moderately or intensely labeled. The most intensely-labeled nuclei, the anterior commissural, magnocellular paraventricular, supraoptic, circularis in the anterior hypothalamus and fornical in the lateral hypothalamus contain large neurons that synthesize and secrete vasopressin or oxytocin and their respective neurophysins. Diminished leptin transport into the central nervous system or defective signal transduction in Zucker obese rats may sufficiently compromise leptin regulation of the HPA axis, NPY-immunoreactive neurons or other hypothalamic elements to cause obesity.
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PMID:Localization of leptin receptor immunoreactivity in the lean and obese Zucker rat brain. 952 52

Recent studies using melanocortin-4 receptor (MC4R) knockout mice and MC4R antagonists have shown that weakening of MC4R-ergic tone increases food intake and causes obesity. In this study, we used the newly discovered selective MC4R antagonist HS014 for increasing food intake in free-feeding rats and evaluated the effects of the NPY Y1 receptor antagonist 1229U91 and the selective serotonin uptake inhibitor fluoxetine on this increased feeding behavior. 1229U91 (12 nmol, i.c.v.), which alone does not affect food intake, significantly attenuated the orexigenic effects of HS014, whereas 1 and 3 nmol doses of 1229U91 were ineffective. Fluoxetine, which has been shown to inhibit NPY release, inhibited spontaneous food intake and completely blocked the stimulation of food intake by HS014. These data suggest that feeding induced by weakening of the MC4R-ergic tone may be mediated through activation of the NPY-ergic system. This is the first report showing that physiological feeding response evoked by MC4R blockage is influenced by NPY signalling.
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PMID:Evidence that orexigenic effects of melanocortin 4 receptor antagonist HS014 are mediated by neuropeptide Y. 967 21

Obese Zucker rats are characterized by a reduced hypothalamic NPY receptor density. We tested the effects of intracerebroventricular injections of human NPY (hNPY) and [D-Trp32]NPY, a weak but selective NPY Y5 receptor agonist, on food intake in lean and obese Zucker rats. The effect of a maximal dose of hNPY (10 microg) on feeding was more pronounced in lean than in obese rats. [D-Trp32]NPY (10 microg) stimulated feeding in lean but not in obese Zucker rats. It did not affect the feeding response to hNPY, excluding the activation of an inhibitory receptor. These results are in favor of a down-regulation of the NPY 'feeding' receptor in the obese rat, which is suggested to be the Y5 subtype.
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PMID:Stimulation of feeding in lean but not in obese Zucker rats by a selective neuropeptide Y Y5 receptor agonist. 972 54

The regulation of body fat stores is a problem of energy and nutrient balance that can be most readily viewed as a feedback system. Several elements are involved in any feedback system, including afferent signals, a controller that senses the afferent signals and transduces their information and then activates efferent controls that regulate the controlled system. The recent discovery of leptin has provided a major missing link in the feedback control system. This afferent signal is produced exclusively in fat cells of nonpregnant mammals but can be produced in the placenta as well. This circulating peptide has a very strong relationship to the level of body fat and its absence experimentally and clinically produces massive obesity. In the controller, or brain, several anatomic regions play a central role in regulating fat stores. Damage to the ventromedial nucleus (VMH) or the paraventricular nucleus (PVN) in the hypothalamus produces massive obesity in mammals and birds. Injury to the central nucleus of the amygala will also produce obesity. In contrast, damage to the lateral hypothalamus reduces body fat. The syndrome of leptin deficiency or defects in the leptin receptors produce a massive obesity that is metabolically similar to the VMH or PVN lesion syndromes of obesity, suggesting that leptin may have its metabolic effects through these medial hypothalamic centers. Support for this idea has come from studies showing that damage to the PVN or VMH will block the effects of leptin. A number of neuropeptides and monoamines are involved with modulating of food intake and fat stores. Both serotonin, acting through 5-HT2C receptors, and norepinephrine, acting through beta 2 and/or beta 3 receptors, reduce food intake. A variety of peptides also influence food intake and body fat. Neuropeptide Y, dynorphin, galanin, and melanocyte-stimulating hormone all increase food intake. In contrast, a large number of peptides--including cholecystokinin, corticotrophin-releasing hormone/urocortin, enterostatin, insulin, leptin, alpha-MSH, and TRH--reduce food intake. Chronic administration of neuropeptide Y, acting through Y-5 receptors, can produce chronically increased food intake and obesity. This syndrome is similar to the VMH syndrome and suggests that NPY must be acting as an inhibitor of a feeding system. The melanocortin receptor system may be particularly important because a mouse that does not express MC4 receptors is massively overweight. These central systems modulate food intake and fat stores by the controlled system. Glucocorticoids from the adrenal gland are important in obesity, since adrenalectomy will reverse or prevent the development of all forms of obesity. The sympathetic nervous system is also important because low sympathetic activity is associated with experimental and clinical obesity. The reciprocal relationship between food intake and sympathetic activity has been a robust relationship, suggesting that beta receptors in the periphery or brain may be involved in feeding control. In one model of dietary obesity resulting when animals eat a high-fat diet, the syndrome is blocked by inhibitory adrenal steroid activity. These animals show a lower level of sympathetic activity and a low level of brain serotonin. Finally, they show an enhanced sensitivity to essential fatty acids when these are applied to the tongue or given into the gut. In this chapter, the control of energy stores as fat is viewed as a feedback system. Leptin is perceived as a key afferent signal and glucocorticoids and the sympathetic nervous system through beta receptors as essential elements of this control system.
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PMID:The MONA LISA hypothesis in the time of leptin. 976 5

NPY is a 36-amino acid peptide which exerts its physiological effects through the activation of a family of G-protein coupled receptors. In vivo and in vitro characterization of the recently cloned rat Y5 receptor suggests that it is a primary mediator of NPY-induced feeding (Gerald et al., Nature 1996;382:168-171). We now report the molecular cloning and pharmacological characterization of the human, dog and mouse homologs of the Y5 receptor. With the exception of a 21 amino acid repeat in the amino terminus of the mouse Y5 receptor, the sequence of the four species homologs appear to be highly conserved, with 88% to 97% amino acid identities between any two species. Similarly, the pharmacological profiles of the four species homologs as determined in porcine 125I-PYY binding assays show a great deal of conservation, with the following rank order of affinity: human or porcine NPY, PYY, [Leu31,Pro34]NPY, NPY(2-36), human PP > human [D-Trp32]NPY > rat PP, C2-NPY. Northern blot analysis reveals that the Y5 receptor is widely distributed in the human brain, with the strongest signals detected in the cortex, putamen and caudate nucleus. The chromosomal localization of the human Y5 receptor, previously shown to be overlapping and in the opposite orientation to the Y1 receptor, is determined to be 4q31, the same locus as previously demonstrated for the human Y1 receptor (Herzog et al., J Biol Chem 1993;268:6703-6707), suggesting that these receptors may be coregulated. These Y5 species homologs along with corresponding animal models may be useful in the search for novel therapeutics in the treatment of obesity and related feeding disorders.
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PMID:Molecular biology and pharmacology of multiple NPY Y5 receptor species homologs. 980 93

Alterations of hypothalamic neuropeptide Y(NPY) and melanocortinergic functions in diet-induced obese (DIO) C57BL/6J mice were investigated by in situ hybridization. Compared with controls, the DIO mice displayed a profound induction (approximately 40-fold) of NPY expression in the dorsomedial (DMH) and ventromedial (VMH) hypothalamic nuclei, whereas the level of NPY mRNA in the arcuate nucleus (ARC) was reduced by 44%. The expression of pro-opiomelanocortin (POMC) and agouti-related protein was not significantly altered in the ARC of obese mice. Both excess body weight gain and altered hypothalamic NPY expression were reversible. We propose that the highly induced NPY expression in DMH and/or VMH may be a contributing etiological factor for the development of obesity and leptin resistance in the DIO mice.
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PMID:Induction of neuropeptide Y expression in dorsomedial hypothalamus of diet-induced obese mice. 985 91

Melanocortinergic neurons are believed to play a role in the control of food intake. Melanocortin receptor agonists and antagonists modulate feeding in several mouse models of chemically and genetically induced hyperphagia. To date, little information is available describing the role of this neurological system in the control of the natural feeding cycle in genetically intact rats. To evaluate the involvement of melanocortins in spontaneous nocturnal feeding, the synthetic melanocortin receptor agonist, MTII and the antagonist, SHU9119 were administered ICV (third ventricle) alone and in combination. Dose-dependent inhibition or stimulation of food intake was observed with MTII or SHU9119, respectively. Co-injections containing equal concentrations of MTII and SHU9119 resulted in food intake that was indistinguishable from controls. Food intake patterns observed in studies in which various dose combinations of MTII and SHU9119 were co-injected are consistent with the concept that both affect feeding by acting on similar melanocortin receptors. The hypothesis that effects of melanocortins on feeding may be mediated via an NPY related pathway was tested by co-injecting MTII and NPY in a 2-h satiated food intake paradigm. MTII inhibited food intake induced by 5.0 microg hNPY in a dose dependent manner with the highest dose tested abolishing the NPY feeding response. The studies suggest that melanocortins act via specific receptors to control food intake in rats, possibly via an NPY related pathway. If similar neurochemical processes operate in humans, selectively modulating specific melanocortin receptor signaling may be an approach to the treatment of human obesity.
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PMID:Melanocortin mediated inhibition of feeding behavior in rats. 992 Apr 46

Anitobesity drugs must increase the sensitivity of the hypothalamic satiety center towards leptin and antagonize the synthesis and action of NPY. The array of pharmacologic tools available is vast and presently ineffective. Among peptide analogs considered for evaluation [NPY-5 antagonists and CCK-A, bombesin, amylin and melanocyte-stimulating hormone-4 (or melanin-concentrating hormone?) agonists], is there a place for GLP-1 and PACAP? GLP-1 receptors present in ARC, PVN, VMN, and SON are the target for both central and blood-borne GLP-1 in those hypothalamic neurons endowed with GLUT-2 and glucokinase. GLP-1, hypersecreted by L-cells after a meal, is a potent insulinotropic agent and, together with glucose, reduces food intake and induces c-fos in the ARC. PACAP is present in the ARC, PVN, and SCH, and its hypothalamic type I receptor elevates cAMP and inositol triphosphate in the PVN, where it may perhaps antagonize NPY-induced food intake and hyperinsulinemia. However, irrelevant neuroendocrine, autonomic, and circadian functions are also activated by this peptide, making it a less than ideal base on which to build an obesity treatment.
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PMID:Is there appetite after GLP-1 and PACAP? 992 26

Obesity is a serious health problem in the Western societies, therefore its treatment has become the subject of intense interest in the scientific community. A significant number of recent publications enlist different central and peripheral factors which play important roles in the regulation of food intake, body weight and energy expenditure. Neuropeptide Y, a 36 amino acid peptide, which is quite abundant in the brain, seems to be one of the more important players in these regulations. Recently five NPY receptors have been cloned and pharmacological evidence strongly supports the existence of a sixth receptor. There are many contradictory findings regarding which NPY receptor mediates the effect of NPY on food intake. This article will review the effects of NPY on the regulation of food intake and energy expenditure and will discuss the pharmacological and molecular evidence as to which NPY receptor(s) mediate this effect. The review will also summarize the progress which has been made in the design of novel NPY-ergic ligands, especially NPY receptor antagonists, for potential use in the treatment of obesity.
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PMID:Central control of feeding behavior by neuropeptide Y. 1019 48


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