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)

Expression of Agouti protein is normally limited to the skin where it affects pigmentation, but ubiquitous expression causes obesity. An expressed sequence tag was identified that encodes Agouti-related protein, whose RNA is normally expressed in the hypothalamus and whose levels were increased eightfold in ob/ob mice. Recombinant Agouti-related protein was a potent, selective antagonist of Mc3r and Mc4r, melanocortin receptor subtypes implicated in weight regulation. Ubiquitous expression of human AGRP complementary DNA in transgenic mice caused obesity without altering pigmentation. Thus, Agouti-related protein is a neuropeptide implicated in the normal control of body weight downstream of leptin signaling.
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PMID:Antagonism of central melanocortin receptors in vitro and in vivo by agouti-related protein. 931 20

The agouti protein plays an important role in the development of diabetes and obesity in rodents and has been shown to be a potent antagonist of melanocortin receptors. For this reason alanine-scanning mutagenesis was performed on the agouti protein carboxyl terminus to locate residues important for melanocortin receptor binding inhibition. When agouti residues Arg116 and Phe118 are changed to alanine, very large decreases in agouti affinity for melanocortin receptor 1, 3, and 4 result. Mutation of Phe117 to alanine causes a similar increase in agouti KI app at melanocortin receptor 4. Substitution of agouti residue Asp108 with alanine results in large increases in KI app for all three melanocortin receptors examined. All of these residues are conserved in the agouti-related transcript, ART, whose expression is up-regulated in animal models of obesity. The three-dimensional structure of the agouti carboxyl terminus was modeled, and residues which decrease receptor binding by a factor of > or = 15 when mutated to alanine localize to one side of the structure. These agouti variants with altered receptor selectivity may be useful in determining the role of melanocortin receptors in diabetes and obesity.
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PMID:Melanocortin receptor binding determinants in the agouti protein. 945 89

Twin studies, adoption studies, and studies of familial aggregation indicate that obesity has a genetic component. Whereas, the genetic factors predisposing to obesity have been elucidated for several rare syndromes, the factors responsible for obesity in the general population have remained elusive. Genetic studies of complex traits are often accelerated by the use of candidate genes. To facilitate genetic studies of human obesity, seven multiplex panels of candidate genes for obesity that are suitable for fluorescent genotyping have been assembled. The multiplex panels are composed of 66 microsatellite markers linked tightly to 16 human gene products that are of potential importance in the control of body weight or linked to syndromic forms of obesity. As part of these efforts 12 previously cloned genes have been placed on the human physical map. In addition the chromosomal location of three of these genes, ART, NYP Y6R, and PPARgamma, are reported for the first time. These resources will be of use in studies to identify the genetic factors responsible for human obesity. [Figures are available at http://www.genome.org]
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PMID:Microsatellite marker content mapping of 12 candidate genes for obesity: assembly of seven obesity screening panels for automated genotyping. 975 Jan 97

Agouti-related protein (Agrp) is present in rat and human hypothalamus and is structurally related to agouti protein. Overexpression of either of these proteins results in obesity. However the effect of exogenous Agrp and its in vivo interaction with alpha-melanocyte stimulating hormone (alphaMSH), the likely endogenous melanocortin 3 and 4 receptor (MC3-R and MC4-R) agonist, have not been demonstrated. We report that 1 nmol of Agrp(83-132), a C-terminal fragment of Agrp, when administered intracerebroventricularly (ICV) into rats, increased food intake over a 24-h period (23.0+/-1.4 g saline vs 32.9+/-2.3 g Agrp, p<0.05). The hyperphagia was similar to that seen when 1 nmol of the synthetic MC3-R and MC4-R antagonist SHU9119 was given i.c.v. (19.6+/-1.8 g saline vs 32.5+/-1.7 g SHU9119, p<0.001). Both Agrp(83-132) and SHU9119 blocked the reduction in 1-h food intake of i.c.v. alphaMSH at the beginning of the dark phase. This effect occurred independently of whether the antagonists were administered simultaneously, or nine hours prior, to the alphaMSH. We have also shown Agrp(83-132) is an antagonist at the MC3-R and MC4-R, with similar inhibition of cAMP activation to that previously reported for the full length peptide. In conclusion, Agrp(83-132) administered i.c.v. increases feeding with long lasting effects and is able to inhibit the action of alphaMSH. This interaction may be mediated by the MC3-R and/or MC4-R.
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PMID:A C-terminal fragment of Agouti-related protein increases feeding and antagonizes the effect of alpha-melanocyte stimulating hormone in vivo. 975 29

Brown adipose tissue-deficient [uncoupling protein (UCP)-promoter-driven diphtheria toxin A (DTA)] mice develop obesity as a result of both decreased energy expenditure and hyperphagia. The hyperphagia occurs despite high serum leptin levels. Hence, this is a model of leptin-resistant obesity in which the mechanism driving hyperphagia is unknown. Leptin is a regulator of a number of hypothalamic neuropeptides involved in energy homeostasis. In ob/ob mice, leptin deficiency results in increased expression of neuropeptide Y (NPY), agouti-related protein (AGRP), and melanin-concentrating hormone (MCH), and decreased expression of POMC. We have previously shown that NPY is reduced in the UCP-DTA mouse, suggesting a normal NPY response to leptin. To define other potential sites of leptin resistance, we used in situ hybridization to evaluate the expression of messenger RNAs (mRNAs) encoding a number of peptides, including NPY, AGRP, MCH, and POMC. We confirmed that the decrease in NPY expression previously detected by Northern blots reflects a decrease in NPY expression in the arcuate nucleus. AGRP mRNA was also decreased, whereas POMC mRNA levels in the arcuate nucleus were the same as control. MCH mRNA levels in the lateral hypothalamic area were also decreased. In contrast, there was induction of NPY expression in the dorsomedial hypothalamic nucleus in the UCP-DTA animals but not in the controls. The results indicate that these neuropeptides generally respond to leptin and that the hyperphagia seen in the UCP-DTA mice is likely the result of dysregulated expression of other, as yet unexamined, hypothalamic peptides, or lies at sites distal to the hypothalamus.
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PMID:Characterization of expression of hypothalamic appetite-regulating peptides in obese hyperleptinemic brown adipose tissue-deficient (uncoupling protein-promoter-driven diphtheria toxin A) mice. 979 75

The agouti-related protein gene (Agrp) is a novel gene implicated in the control of feeding behavior. The hypothalamic expression of Agrp is regulated by leptin, and overexpression of Agrp in transgenic animals results in obesity and diabetes. By analogy with the known actions of agouti, these data suggest a role for the Agrp gene product in the regulation of melanocortin receptors expressed in the central nervous system. The availability of recombinant, highly purified protein is required to fully address this potential interaction. A nearly full-length form of AGRP (MKd5-AGRP) was expressed in the cytosolic or soluble fraction of Escherichia coli and appeared as large intermolecular disulfide-bonded aggregates. Following oxidation, refolding, and purification, this protein was soluble, and eluted as a single symmetric peak on RP-HPLC. Circular dichroism studies indicated that the purified protein contains primarily random coil and beta-sheet secondary structure. Sedimentation velocity studies at neutral pH demonstrated that MKd5-AGRP is monomeric at low micromolar concentrations. Mobility shifts observed using SDS-PAGE under reducing and nonreducing conditions for bacterially expressed and mammalian expressed AGRP were identical, an indication of a similar disulfide structure. The purification to homogeneity of a second, truncated form of AGRP (Md65-AGRP) which was expressed in the insoluble or inclusion body fraction is also described. Both forms act as competitive antagonists of alpha-melanocyte stimulating hormone (alpha-MSH) at melanocortin-3 (MC-3) and melanocortin-4 receptors (MC-4). The demonstration that AGRP is an endogenous antagonist with respect to these receptors is a unique mechanism within the central nervous system, and has important implications in the control of feeding.
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PMID:Biochemical, biophysical, and pharmacological characterization of bacterially expressed human agouti-related protein. 981 97

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

Mutations reducing the functional activity of leptin, the leptin receptor, alpha-melanocyte stimulating hormones (alpha-MSH) and the melanocortin-4 receptor (Mc4r) all lead to obesity in mammals. Moreover, mutant mice that ectopically express either agouti (Ay/a mice) or agouti-related protein (Agrp), antagonists of melanocortin signalling, become obese. These data suggest that alpha-MSH signalling transduced by Mc4r tonically inhibits feeding; however, it is not known to what extent this pathway mediates leptin signalling. We show here that Mc4r-deficient (Mc4r-/-) mice do not respond to the anorectic actions of MTII, an MSH-like agonist, suggesting that alpha-MSH inhibits feeding primarily by activating Mc4r. Obese Mc4r-/-mice do not respond significantly to the inhibitory effects of leptin on feeding, whereas non-obese Mc4r-/- mice do. These data demonstrate that melanocortin signalling transduced by Mc4r is not an exclusive target of leptin action and that factors resulting from obesity contribute to leptin resistance. Leptin resistance of obese Mc4r-/- mice does not prevent their response to the anorectic actions of ciliary neurotrophic factor (CNTF), corticotropin releasing factor (CRF), or urocortin; or the orexigenic actions of neuropeptide Y (NPY) or peptide YY (PYY), indicating that these neuromodulators act independently or downstream of Mc4r signalling.
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PMID:Response of melanocortin-4 receptor-deficient mice to anorectic and orexigenic peptides. 991 4

Agouti-related protein (AGRP) is a homologue of the agouti gene product and, when overexpressed, promotes obesity. Like neuropeptide Y (NPY) messenger RNA (mRNA), AGRP mRNA is produced in the hypothalamic arcuate nucleus and is elevated in leptin-deficient ob/ob and leptin-resistant db/db mice. These data suggest that AGRP mRNA might be affected by leptin and nutritional status in parallel with NPY mRNA. To test this hypothesis, we examined if AGRP mRNA would be, like NPY mRNA, inhibited by leptin injections and stimulated by fasting. AGRP mRNA was elevated in ob/ob mice about 5-fold compared with wild-type controls and was significantly inhibited by leptin treatment, as assessed by Northern blot analysis. In wild-type mice, AGRP mRNA was increased at least 13-fold by a 2-day fast, as assessed both by Northern blot analysis and in situ hybridization. In ad lib fed db/db mice, AGRP mRNA was elevated about 8-fold compared with ad lib fed wild-type controls, and was further increased by fasting in db/db mice. These data suggest that AGRP mRNA and NPY mRNA respond similarly to leptin and fasting.
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PMID:Hypothalamic agouti-related protein messenger ribonucleic acid is inhibited by leptin and stimulated by fasting. 992 10

Agouti protein and agouti-related protein are homologous paracrine signalling molecules that normally regulate hair colour and body weight, respectively, by antagonizing signalling through melanocortin receptors. Expression of Agouti is normally limited to the skin, but rare alleles from which Agouti is expressed ubiquitously, such as lethal yellow, have pleiotropic effects that include a yellow coat, obesity, increased linear growth, and immune defects. The mahogany (mg) mutation suppresses the effects of lethal yellow on pigmentation and body weight, and results of our previous genetic studies place mg downstream of transcription of Agouti but upstream of melanocortin receptors. Here we use positional cloning to identify a candidate gene for mahogany, Mgca. The predicted protein encoded by Mgca is a 1,428-amino-acid, single-transmembrane-domain protein that is expressed in many tissues, including pigment cells and the hypothalamus. The extracellular domain of the Mgca protein is the orthologue of human attractin, a circulating molecule produced by activated T cells that has been implicated in immune-cell interactions. These observations provide new insight into the regulation of energy metabolism and indicate a molecular basis for crosstalk between melanocortin-receptor signalling and immune function.
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PMID:The mouse mahogany locus encodes a transmembrane form of human attractin. 1008 56


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