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

The melanocortin system plays an important role in the regulation of energy homeostasis. The Agouti-related protein (AGRP) is a natural antagonist of the action of alpha-melanocyte stimulating hormone (alpha-MSH) at the melanocortin receptors (MCR). AGRP is upregulated by fasting while intracerebroventricular injections of synthetic AGRP lead to increased appetite and food intake. Transgenic mice overexpressing AGRP are also hyperphagic and eventually become obese. AGRP is, therefore, a significant regulator of energy balance and a candidate gene for human fatness. Indeed, humans with common single nucleotide polymorphisms (SNPs) in the promoter or the coding region are leaner and resistant to late-onset obesity than wild-type individuals. AGRP is also expressed in the periphery. Recent studies show that AGRP in the adrenal gland is upregulated by fasting as much as it is in the hypothalamus. These data open up the possibility for a wider role by AGRP not only in food intake but also in the regulation of energy balance through its actions on peripheral tissues. This review summarizes recent advances in the biochemical and physiological properties of AGRP in an effort to enhance our understanding of the role this powerful neuropeptide plays in mammalian energy homeostasis.
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PMID:The agouti-related protein and its role in energy homeostasis. 1596 Nov 86

It is well established that agouti-related protein (AGRP) can act as a competitive antagonist to proopiomelanocortin (POMC)-derived peptides at the melanocortin-4 receptor (MC4R), and that this homeostatic mechanism is important as a means of coordinating appetite with perceived metabolic requirement. However, there are clearly additional facets to the physiological role of AGRP, given that it is active in MC4R knockout mice and it has strikingly long-lasting effects on food intake, compared with MC4R agonists. In this review we focus on: (i) evidence that AGRP is more sensitive to perturbations in energy balance than POMC and is therefore the primary basis of melanocortinergic regulation. (ii) Evidence that the bioactive peptide AGRP83-132, acts by alternate mechanism(s) to elicit its long-term effects on food intake. (iii) Evidence that AGRP is post-translationally cleaved to generate AGRP83-132 and one or more N terminal peptides, which may have an important physiological role(s) that are independent of the melanocortin system. A clear understanding of how proAGRP processing is regulated, and the role of resultant peptides, may define additional therapeutic targets in the treatment of obesity.
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PMID:Agouti-related protein: more than a melanocortin-4 receptor antagonist? 1599 91

Congenital lack of proopiomelanocortin (POMC) causes obesity and glucocorticoid deficiency. The responses of Pomc-/- and wild-type mice to the administration of corticosterone were compared. In study 1, mice were given corticosterone-supplemented water (CORT) for 10 days, resulting in plasma CORT levels within the physiological range, with partial suppression of hypothalamic corticotropin-releasing hormone expression to a similar degree between genotypes. Body weight, fat mass, and food intake increased in CORT-treated Pomc-/- but not wild-type mice. CORT increased plasma insulin levels 50-fold in Pomc-/- versus 14-fold in wild-type mice (P < 0.01) and increased hypothalamic agouti-related protein (AgRP) expression by more than 200% in Pomc-/- versus 40% in wild type (P < 0.05). In study 2, mice were given CORT from weaning, and Pomc-/- but not wild-type mice developed hyperglycemia, ketonuria, and hepatic steatosis by 8-12 weeks. Thus, Pomc-/- mice are hypersensitive to the adverse metabolic effects of glucocorticoids. Additionally, as the levels of plasma CORT achieved, especially in study 1, were not grossly supraphysiological, we conclude that glucocorticoid deficiency may afford Pomc-/- mice some protection from the full adverse consequences of melanocortin deficiency. This may occur through a mechanism involving the suppression of AgRP by the hypoadrenal state.
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PMID:Proopiomelanocortin-deficient mice are hypersensitive to the adverse metabolic effects of glucocorticoids. 1604 91

The blood concentration of agouti-related protein (AgRP), a protein related to hyperphagia and obesity, is increased in obese human and fasted lean subjects. Because there is no saturable transport system at the blood-brain barrier for circulating AgRP to reach its central nervous system target, uptake of AgRP by peripheral organs might be physiologically meaningful. Using the biologically active fragment AgRP(82-131), we determined the pharmacokinetics of its radioactively labeled tracer after iv bolus injection and compared it with that of the vascular marker albumin. AgRP enters peripheral organs at different influx rates, all of which were higher than into brain and spinal cord. At 10 min after iv injection, the radioactivity recovered in the liver, which had the fastest influx rate for AgRP, represented intact (125)I-AgRP. The adrenal gland had a moderately fast uptake (but the highest initial volume of distribution), followed by the heart, lungs, and skeletal muscle. By comparison, epididymal fat, testis, and pancreas had low permeability to AgRP. Saturation of influx was determined by coadministration of excess unlabeled AgRP and was shown to be present in the liver and adrenal gland. The influx rate and initial volume of distribution did not show a linear correlation with vascular permeability or regional blood flow. AgRP uptake by the liver and epididymal fat was significantly increased by overnight fasting, whereas that by the adrenal gland was significantly decreased in fasted mice. Thus, the differential uptake of AgRP by peripheral organs could be a regulated process that is modulated by food deprivation.
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PMID:Selective tissue uptake of agouti-related protein(82-131) and its modulation by fasting. 1614 94

We have previously shown that growth hormone (GH) overexpression in the brain increased food intake, accompanied with increased hypothalamic agouti-related protein (AgRP) expression. Ghrelin, which stimulates both appetite and GH secretion, was injected intracerebroventricularly to GHR-/- and littermate control (+/+) mice to determine whether ghrelin's acute effects on appetite are dependent on GHR signaling. GHR-/- mice were also analyzed with respect to serum levels of lipoproteins, apolipoprotein (apo)B, leptin, glucose, and insulin as well as body composition. Central injection of ghrelin into the third dorsal ventricle increased food consumption in +/+ mice, whereas no change was observed in GHR-/- mice. After ghrelin injection, AgRP mRNA expression in the hypothalamus was higher in +/+ littermates than in GHR-/- mice, indicating a possible importance of AgRP in the GHR-mediated effect of ghrelin. Compared with controls, GHR-/- mice had increased food intake, leptin levels, and total and intra-abdominal fat mass per body weight and deceased lean mass. Moreover, serum levels of triglycerides, LDL and HDL cholesterol, and apoB, as well as glucose and insulin levels were lower in the GHR-/- mice. In summary, ghrelin's acute central action to increase food intake requires functionally intact GHR signaling. Long-term GHR deficiency in mice is associated with high plasma leptin levels, obesity, and increased food intake but a marked decrease in all lipoprotein fractions.
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PMID:Growth hormone receptor deficiency results in blunted ghrelin feeding response, obesity, and hypolipidemia in mice. 1617 55

Normal aging in humans and rodents is accompanied by a progressive increase in adiposity. To investigate the role of hypothalamic neuronal circuits in this process, we used a Cre-lox strategy to create mice with specific and progressive degeneration of hypothalamic neurons that express agouti-related protein (Agrp) or proopiomelanocortin (Pomc), neuropeptides that promote positive or negative energy balance, respectively, through their opposing effects on melanocortin receptor signaling. In previous studies, Pomc mutant mice became obese, but Agrp mutant mice were surprisingly normal, suggesting potential compensation by neuronal circuits or genetic redundancy. Here we find that Pomc-ablation mice develop obesity similar to that described for Pomc knockout mice, but also exhibit defects in compensatory hyperphagia similar to what occurs during normal aging. Agrp-ablation female mice exhibit reduced adiposity with normal compensatory hyperphagia, while animals ablated for both Pomc and Agrp neurons exhibit an additive interaction phenotype. These findings provide new insight into the roles of hypothalamic neurons in energy balance regulation, and provide a model for understanding defects in human energy balance associated with neurodegeneration and aging.
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PMID:Effects of hypothalamic neurodegeneration on energy balance. 1629 93

The Melanocortin-4 Receptor is a G-protein coupled receptor that has been physiologically linked to participate in the regulation of energy homeostasis. The Melanocortin-4 Receptor is stimulated by endogenous melanocortin agonists derived from the pro-opiomelanocortin gene transcript and antagonized by the endogenous antagonist agouti-related protein. Central administration of melanocortin agonists has been demonstrated to decrease food intake and conversely, treatment with antagonists resulted in increased food intake. Deletion of the Melanocortin-4 Receptor gene from the mouse genome results in an obese and hyperphagic phenotype. Polymorphisms of the human Melanocortin-4-Receptor have been found in severely obese individuals, suggesting that Melanocortin-4 Receptor malfunction might be involved in human obesity and obesity-associated diabetes. Herein, we have performed experiments to understand the molecular mechanisms associated with the L250Q human Melanocortin-4-Receptor polymorphism discovered in an extremely obese woman. This L250Q human Melanocortin-4-Receptor has been pharmacologically characterized to result in a constitutively active receptor. The fact that a constitutively active human Melanocortin-4-Receptor mutation was found in an obese person is a physiologic contradiction, as chronic activation of the human Melanocortin-4-Receptor and subsequently high cyclic adenosine monophosphate levels should theoretically result in a normal or lean phenotype. In this study, we demonstrated that agouti-related protein acts as an inverse agonist at this constitutively active receptor, and we propose a mechanism by which agouti-related protein might contribute to the obese phenotype in the L250Q patient. In addition, using receptor mutagenesis, pharmacology, and computer modeling approaches, we investigated the molecular mechanism by which modification of the L250 residue results in constitutive activation of the human Melanocortin-4-Receptor.
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PMID:Molecular mechanism of the constitutive activation of the L250Q human melanocortin-4 receptor polymorphism. 1661 Dec 15

The transcription factor carbohydrate response element-binding protein (ChREBP) mediates insulin-independent, glucose-stimulated gene expression of multiple liver enzymes responsible for converting excess carbohydrate to fatty acids for long-term storage. To investigate ChREBP's role in the development of obesity and obesity-associated metabolic dysregulation, ChREBP-deficient mice were intercrossed with ob/ob mice. As a result of deficient leptin expression, ob/ob mice overeat, become obese and resistant to insulin, and display marked elevations in hepatic lipogenesis, gluconeogenesis, and plasma glucose and triglycerides. mRNA expression of all hepatic lipogenic enzymes was significantly lower in ob/ob-ChREBP-/- than in ob/ob mice, resulting in decreased hepatic fatty acid synthesis and normalization of plasma free fatty acid and triglyceride levels. Overall weight gain in addition to adiposity was reduced in the doubly deficient mice. The former was largely attributable to decreased food intake and may result from decreased hypothalamic expression of the appetite-stimulating neuropeptide agouti-related protein. mRNA expression and activity of gluconeogenic enzymes also was lower in the doubly deficient mice, contributing to significantly lower blood glucose levels. The results of this study suggest that inactivation of ChREBP expression not only reduces fat synthesis and obesity in ob/ob mice but also results in improved glucose tolerance and appetite control.
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PMID:Deficiency of carbohydrate-activated transcription factor ChREBP prevents obesity and improves plasma glucose control in leptin-deficient (ob/ob) mice. 1670 63

The melanocortin-4 receptor (MC4R) is a G-protein coupled receptor (GPCR) that is expressed in the central nervous system and has a role in regulating energy homeostasis and obesity. Up to a remarkable 6% of morbidly obese adults and children studied possess single nucleotide polymorphisms (SNPs) of the MC4R. Upon stimulation by agonist, the MC4R signals through the intracellular adenylate cyclase signal transduction pathway. Posttranslational modification of the pro-opiomelanocortin (POMC) gene transcript results in the generation of several endogenous melanocortin receptor agonists including alpha-, beta-, gamma-melanocyte stimulating hormones (MSH) and adrenocorticotropin (ACTH) ligands. The endogenous MC4R antagonist, agouti-related protein (AGRP), is expressed in the brain and is only one of two naturally occurring antagonists of GPCRs identified to date. Herein, we have generated 40 hMC4 polymorphic receptors and evaluated their cell surface expression by flow cytometry as well as pharmacologically characterized their functionality using the endogenous agonists alpha-MSH, beta-MSH, gamma2-MSH, ACTH(1-24), the antagonist hAGRP(87-132), and the synthetic agonists NDP-MSH and MTII. This is the first study in which polymorphic hMC4Rs have been pharmacologically characterized simultaneously with multiple endogenous ligands. Interestingly, at the N97D, L106P, and C271Y hMC4Rs beta-MSH was more potent than the other endogenous agonists alpha-MSH, gamma2-MSH, ACTH(1-24). The S58C and R165Q/W hMC4Rs possessed significantly reduced endogenous agonist potency (15- to 90-fold), but the synthetic ligands NDP-MSH and MTII possessed only 2-9-fold reduced potency as compared to the wild-type receptor, suggesting their potential as therapeutic ligands to treat individuals with these polymorphisms.
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PMID:Pharmacological characterization of 40 human melanocortin-4 receptor polymorphisms with the endogenous proopiomelanocortin-derived agonists and the agouti-related protein (AGRP) antagonist. 1675 16

Obesity is a major global epidemic, with over 300 million obese people worldwide, and nearly 1 billion overweight adults. Being overweight carries significant health risks, reduced quality of life, and impaired socioeconomic success, with profound consequences for health expenditure. The most successful treatment for obesity is gastric bypass surgery, which acts in part by reducing appetite through alterations in gut hormones. Circulating gut hormones, secreted or suppressed after eating food, act in the brain, particularly the hypothalamus, to alter hunger and fullness. Stomach-derived ghrelin increases food intake even in those with anorexia from chronic illness, while pancreatic polypeptide (PP), intestinal peptide YY 3-36 (PYY), oxyntomodulin, and other hormones reduce food intake and appetite. While obese subjects have appropriate reductions in orexigenic ghrelin, other gut-hormone disturbances may contribute to obesity such as reduced anorexigenic PYY and PP. Prader-Willi syndrome (PWS) arises from the loss of paternally inherited genes on chromosome 15q11-13, leading to life-threatening insatiable hunger and obesity from early childhood, through developmental brain, particularly hypothalamic defects. The study of genetically homogenous causes of abnormal-feeding behavior helps our understanding of appetite regulation. PWS subjects have inappropriately elevated plasma ghrelin for their obesity, at least partly explained by preserved insulin sensitivity. It remains unproven if their hyperghrelinemia or other gut-hormone abnormalities contribute to the hyperphagia in PWS, in addition to brain defects. Postmortem human hypothalamic studies and generation of animal models of PWS can also provide insight into the pathophysiology of abnormal-feeding behavior. Changes in orexigenic NPY and AGRP hypothalamic neurons, or anorexigenic oxytocin neurons have been found in illness and PWS. Functional neuroimaging studies, using PET and fMRI, will also allow us to tease apart the hormonal and brain pathways responsible for controlling human appetite, and their defects in obesity.
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PMID:The hypothalamus, hormones, and hunger: alterations in human obesity and illness. 1687 68


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