Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Transgenic expression in the hypothalamus of syndecan-1, a cell surface heparan sulfate proteoglycan (HSPG) and modulator of ligand-receptor encounters, produces mice with hyperphagia and maturity-onset obesity resembling mice with reduced action of alpha melanocyte stimulating hormone (alphaMSH). Via their HS chains, syndecans potentiate the action of agouti-related protein and agouti signaling protein, endogenous inhibitors of alphaMSH. In wild-type mice, syndecan-3, the predominantly neural syndecan, is expressed in hypothalamic regions that control energy balance. Food deprivation increases hypothalamic syndecan-3 levels several-fold. Syndecan-3 null mice, otherwise apparently normal, respond to food deprivation with markedly reduced reflex hyperphagia. We propose that oscillation of hypothalamic syndecan-3 levels physiologically modulates feeding behavior.
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PMID:Transgenic expression of syndecan-1 uncovers a physiological control of feeding behavior by syndecan-3. 1146 6

Mutations in the melanocortin-4 receptor (MC4-R) cause obesity in both mice and humans, and the receptor is presumed to have an important role in the regulation of energy homeostasis. The MC4-R is expressed in discrete sets of neurons in the central nervous system, and thus it has been technically difficult to study the regulation of expression and the signaling mechanisms of this receptor. We report here a neuronal cell line that exhibits endogenous functional expression for the MC4-R. Initially, RT-PCR analysis showed the presence of MC4-R RNA in the hypothalamic GT1-1 and GT1-7 cells. In addition, GT1-7 cells expressed melanocortin-3 receptor while the GT1-1 subclone specifically expressed predominantly the MC4-R RNA. High-affinity binding sites were demonstrated in the GT1-1 and GT1-7 cells for NDP-alpha melanocyte-stimulating hormone (MSH; K(i) = 1.1 x 10(-10) and 1.8 x 10(-10) M) and agouti-related protein (AGRP; K(i) = 1.548 x 10(-9) and 1.663(-9) M). alpha-MSH-stimulated cAMP production in GT1-1 cells with an EC(50) of 2.2 x 10(-8) M, and cAMP production was inhibited in the presence of AGRP, an endogenous antagonist of the MC4-R. Stimulation of gonadotropin-releasing hormone (GnRH) secretion was achieved with 1 nM to 1 microM concentrations of NDP-alpha-MSH while no GnRH secretion was observed when the GT1-1 cells were treated with AGRP. The data presented here show that GT1-1 cells specifically express a functional MC4-R that couples to GnRH release.
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PMID:Expression of functional melanocortin-4 receptor in the hypothalamic GT1-1 cell line. 1152 21

The murine agouti related protein (mAGRP) is upregulated in obese and diabetic mice and stimulates hyperphagia when administered intracerebroventricularly (i.c.v.) or when overexpressed in transgenic mice. The human ortholog, hAGRP, has been isolated and has similar molecular and physiological properties. Here, we report the complete gene structure of the human AGRP gene and upstream regions with differential promoter activity. A polymorphism, A67T, in the third exon was identified but was not associated with obesity- or type 2 diabetes-related phenotypes. Putative binding sites for transcription factors were identified in the promoter of the gene including recognition sites for the signal transducers and activators of transcription (STATs) that may potentially mediate leptin's action in the hypothalamus. The upstream non-coding exon had significant promoter activity in a periphery- but not so in a hypothalamus-derived cell line, suggesting that it might contain the minimal promoter required for expression of the short transcript of hAGRP in the periphery.
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PMID:The gene structure and minimal promoter of the human agouti related protein. 1160 60

Animals with mutations in the leptin receptor (ObR) exhibit an obese phenotype that is indistinguishable from that of leptin deficient ob/ob mice. ObR is expressed in many tissues, including brain, and the relative importance of leptin's effects on central versus peripheral sites has not been resolved. To address this, we generated mice with neuron-specific (ObR(SynI)KO) and hepatocyte-specific (ObR(Alb)KO) disruption of ObR. Among the ObR(SynI)KO mice, the extent of obesity was negatively correlated with the level of ObR in hypothalamus and those animals with the lowest levels of ObR exhibited an obese phenotype. The obese mice with low levels of hypothalamic ObR also show elevated plasma levels of leptin, glucose, insulin, and corticosterone. The hypothalamic levels of agouti-related protein and neuropeptide Y RNA are increased in these mice. These data indicate that leptin has direct effects on neurons and that a significant proportion, or perhaps the majority, of its weight-reducing effects are the result of its actions on brain. To explore possible direct effects of leptin on a peripheral tissue, we also characterized ObR(Alb)KO mice. These mice weigh the same as controls and have no alterations in body composition. Moreover, while db/db mice and ObR(SynI)KO mice have enlarged fatty livers, ObR(Alb)KO mice do not. In summary, these data suggest that the brain is a direct target for the weight-reducing and neuroendocrine effects of leptin and that the liver abnormalities of db/db mice are secondary to defective leptin signaling in the brain.
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PMID:Selective deletion of leptin receptor in neurons leads to obesity. 1160 18

The identification of the genetic defect underlying the obese phenotype of the viable yellow mouse, ectopic overexpression of the agouti protein which acts as antagonist at the melanocortin-4 receptor, together with the demonstration that the brain melanocortin system was one major downstream effector pathway of leptin signaling has put forward melanocortin receptors as drug targets for obesity. The lack of compounds acting as melanocortin receptor antagonists was the reason why pharmacological studies had not recognized melanocortin receptors as important drug targets earlier. Blockade of brain melanocortin receptors results in increased food intake and body weight, whereas stimulation of the brain melanocortin system results in decreased food intake and activation of the hypothalamo-pituitary-adrenal axis. Anorexia nervosa is characterized by decreased body weight and food intake accompanied by changes in neuroendocrine systems such as strong activation of the hypothalamo-pituitary-adrenal axis. Since agouti-related protein suppresses the activity of the melanocortin system, the AgRP gene was investigated as candidate gene in anorexia nervosa. One variant of the AgRP gene was associated with anorexia nervosa, thus putting forward melanocortin receptor blockade as putative pharmacotherapy. Investigating variations in candidate genes in disease populations appears to be a fruitful approach towards the identification of drug targets.
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PMID:Drug target discovery by pharmacogenetics: mutations in the melanocortin system and eating disorders. 1170 25

The discovery of the adipose-derived hormone leptin has generated interest in the interaction between peripheral signals and brain targets involved in the regulation of feedings and energy balance. Potential anti-obesity drugs can be based on any intervention between the neuropeptide and its receptor that would alter the biological responses mediated by the neuronal network, in particular, food intake, metabolism and energy expenditure. Modulation of neurons in the arcuate nucleus by leptin results in reduced expression of neuropeptide Y and agouti-related protein, and increased expression of pro-opiomelanocortin (the precursor of a-melanocyte-stimulating hormone) and cocaine- and amphetamine- regulated transcript. Whether leptin finds its way into general usage as an anti-obesity drug, the use of modern methods to identify and target the components of leptin signaling pathway will form the basis for new pharmacological approaches to the treatment of obesity.
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PMID:[Potential molecular targets for anti-obesity drugs--after the discovery of leptin]. 1172 33

The fatty acid synthase inhibitor, C75, acts centrally to reduce food intake and body weight in mice. Here we report the effects of C75 on the expression of key orexigenic [neuropeptide Y (NPY), agouti-related protein (AgRP), and melanin-concentrating hormone] and anorexigenic [pro-opiomelanocortin (POMC) and cocaine-amphetamine-related transcript (CART)] neuropeptide messages in the hypothalami of lean and obese (ob/ob) mice. In lean mice, C75 rapidly and almost completely blocked food intake and prevented fasting-induced up-regulation of hypothalamic AgRP and NPY mRNAs, as well as down-regulation of CART and POMC mRNAs. Thus, in lean mice C75 seems to interrupt the fasting-induced signals that activate expression of NPY and AgRP and suppression of POMC and CART. In obese mice, C75 rapidly suppressed food intake, reduced body weight, and normalized obesity-associated hyperglycemia and hyperinsulinemia. Like its effect in lean mice, C75 prevented the fasting-induced increase of hypothalamic NPY and AgRP mRNAs in obese mice, but had no effect on the expression of POMC and CART mRNAs. The suppressive effect of C75 on food intake in lean mice seems to be mediated both by NPY/AgRP and POMC/CART neurons, whereas in obese mice the effect seems to be mediated primarily by NPY/AgRP neurons. In both lean and obese mice, C75 markedly increased expression of melanin-concentrating hormone and its receptor in the hypothalamus.
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PMID:Effect of a fatty acid synthase inhibitor on food intake and expression of hypothalamic neuropeptides. 1175 83

Animal studies have demonstrated the importance of orexigenic NPY and agouti-related protein (AGRP) hypothalamic neurons, which are inhibited by the adipocyte hormone leptin, in the regulation of body weight and neuroendocrine secretion. We have examined NPY and AGRP neurons in postmortem human hypothalami from controls, Prader-Willi syndrome and other obese subjects, using quantitative immunocytochemistry (ICC) and in situ hybridization, to identify causes of leptin resistance in human obesity. Using combined ICC and in situ hybridization, AGRP, but not POMC, was colocalized with NPY in infundibular nucleus neurons. Infundibular nucleus (including median eminence) NPY ICC staining or mRNA expression, and AGRP ICC staining, increased with premorbid illness duration. NPY ICC staining and mRNA expression were reduced in obese subjects, but AGRP ICC staining was unchanged, correcting for illness duration. This suggests normal responses of NPY and AGRP neurons to peripheral signals, such as leptin and insulin, in human illness and obesity. The pathophysiology of obesity and illness-associated anorexia appear to lie in downstream or separate neuronal circuits, but the infundibular neurons may mediate neuroendocrine responses to illness. The implications for pharmacological treatment of human obesity are discussed.
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PMID:Hypothalamic NPY and agouti-related protein are increased in human illness but not in Prader-Willi syndrome and other obese subjects. 1183 43

Significant progress in our understanding of the mechanisms of weight homeostasis has been made by studying the many genetic mouse models of obesity. Positional cloning in the obese mouse led to the discovery of leptin as a feedback messenger indicating the adequacy of peripheral energy stores. This was the first in a series of important advances in this field. Shortly after this discovery, two research laboratories presented evidence for the role of hypothalamic pro-opiomelanocortinergic (POMC) neurons as important mediators in the regulation of feeding behavior, insulin levels and, ultimately, body weight. One of these mouse obesity models, the lethal yellow mouse, constitutively overexpresses the agouti protein, an endogenous antagonist of both the melanocortin 1 (MC1) and melanocortin 4 (MC4) receptors. A second mouse obesity model was created by knocking out the MC4 receptor. Investigations using both the autosomal dominant lethal yellow mouse and MC4 receptor knockout mouse have provided clear evidence for the role of hypothalamic POMC neurons and the MC4 receptor in the regulation of weight homeostasis in the rodent. Furthermore, the recent discovery of agouti-related protein (AGRP), an agouti-like peptide naturally found in the hypothalamus, provides further evidence for the importance of POMC neurons in the regulation of weight. Although the significance of central POMC and AGRP in the rodent is apparent, the role of POMC neurons in the regulation of weight and feeding behavior in humans is only now being appreciated.
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PMID:Pro-opiomelanocortin and weight regulation: from mice to men. 1183 94

The effects of leptin on cocaine- and amphetamine-regulated transcript (CART) and agouti-related protein (AGRP) expression in the hypothalamic arcuate nucleus of obese A(y)/a mice were investigated. CART mRNA expression was upregulated by 41% and AGRP mRNA downregulated by 78% in hyperleptinemic A(y)/a mice relative to levels in lean a/a mice. The mRNA expression of these neuropeptides in either young nonobese A(y)/a mice or rats treated with SHU-9119, a synthetic melanocortin-4 receptor (MC4R) antagonist, did not differ significantly from that in the corresponding controls. After a 72-h fast, which decreased the concentration of serum leptin, CART and AGRP mRNA expression decreased and increased, respectively, in A(y)/a mice. The expression levels of these neuropeptides in leptin-deficient A(y)/a ob/ob double mutants were comparable to those in a/a ob/ob mice. Leptin thus modulates both CART and AGRP mRNA expression in obese A(y)/a mice, whereas leptin signals are blocked at the MCR4R level. Taken together, the present findings indicate that differential expression of these neuropeptides in A(y)/a and ob/ob mice results in dissimilar progression toward obesity.
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PMID:Hyperleptinemia in A(y)/a mice upregulates arcuate cocaine- and amphetamine-regulated transcript expression. 1188 20


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