| 1. CLONING |
| CLONING The agouti gene in mice (see 600201) encodes a cell-signaling protein that acts as an antagonist at the melanocortin-1 receptor (MC1R; 155555). Shutter et al. (1997) cloned a gene, which they designated ART for 'agouti-related transcript,' whose sequence predicted a 132-amino acid protein with 25% identity to human agouti. Northern blot analysis of human tissues showed that ART is expressed most abundantly in the adrenal gland, hypothalamus, and subthalamic nucleus, with weaker expression in the testis, lung, and kidney. The ART gene is alternatively spliced; Northern blot analysis revealed a 0.7-kb mRNA with a noncoding 5-prime exon in brain and a 0.5-kb mRNA in peripheral tissues. |
| 2. GENE FUNCTION |
| GENE FUNCTION Since Shutter et al. (1997) observed hypothalamic ART expression to be elevated 10-fold in the mouse models of obesity ob/ob (164160) and db/db (601007), they suggested that ART is a participant in the hypothalamic control of feeding. From an expressed sequence tag database, Ollmann et al. (1997) isolated a protein that they named Agrp for 'Agouti-related protein' and showed that Agrp expression is reduced 5-fold in the hypothalamus of agouti mutant mice. Ollmann et al. (1997) demonstrated that, in vitro, AGRP was a potent, selective antagonist of MC3R (155540) and MC4R (155541). Ubiquitous expression of human AGRP in transgenic mice led to obesity, but had no effect on pigmentation. Therefore, Ollmann et al. (1997) concluded that AGRP normally regulates body weight via central melanocortin receptors, analogous to the relation between agouti and MC1R for regulation of pigmentation. Graham et al. (1997) found that overexpression of Agrt recapitulated many unique features of obese yellow and MC4R-deficient mice, including obesity, increased body length, hyperinsulinemia, late-onset hyperglycemia, pancreatic islet hyperplasia, and lack of elevated corticosterone. The fact that Agrt is expressed in the arcuate nucleus, is regulated by leptin (164160), and is a potent antagonist of MC3R and MC4R, suggested that Agrt is an endogenous regulator of melanocortinergic neurons in the brain. Graham et al. (1997) stated that the ectopic expression of agouti produces obesity by mimicking the normal action of Agrt in the hypothalamus. To investigate the relationship between peripheral blood levels of AGRP and various parameters of obesity, Katsuki et al. (2001) measured the plasma level of AGRP in 15 obese and 15 nonobese men and evaluated its relationship with body mass index (BMI); body fat weight; visceral, subcutaneous, and total fat areas; fasting insulin (176730) levels; glucose infusion rate; serum leptin; and plasma alpha-MSH (see 176830). Obese men had significantly higher plasma concentrations of AGRP than nonobese men. Univariate analysis showed that plasma levels of AGRP are proportionally correlated with BMI, body fat weight, and subcutaneous fat area in obese men. In all men, the plasma levels of AGRP were significantly correlated with the visceral fat area, total fat area, fasting insulin level, glucose infusion rate, serum level of leptin, and the plasma level of alpha-MSH. The authors concluded that the circulating levels of AGRP are increased in obese men and that they are correlated with various parameters of obesity. |
| 3. MAPPING |
| MAPPING Shutter et al. (1997) mapped the ART gene to 16q22 by fluorescence in situ hybridization. |
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