HYPOTHALAMIC EXPRESSION OF ART, A NOVEL GENE-RELATED TO AGOUTI, IS UP-REGULATED IN OBESE AND DIABETIC MUTANT MICE

We have isolated cDNA clones that encode a novel human gene related to agouti. Sequence analysis of this gene, named ART, for agouti-related transcript, predicts a 132-amino-acid protein that is 25% identical t o human agouti. The highest degree of identity is within the carboxyl terminus of both proteins. Like agouti, ART contains a putative signal sequence and a cysteine rich carboxyl terminus, but lacks the region of basic residues and polyproline residues found in the middle of the agouti protein. Both agouti and ART contain 11 cysteines, and 9 of the se are conserved spatially. ART is expressed primarily in the adrenal gland, subthalamic nucleus, and hypothalamus, with a lower level of ex pression occurring in testis, lung, and kidney. The murine homolog of ART was also isolated and is predicted to encode a 131-amino-acid prot ein that shares 81% amino acid identity to humans. The mouse was found to have the same expression pattern as human when assessed by RT-PCR. Examination by in situ hybridization using mouse tissues showed local ized expression in the arcuate nucleus of the hypothalamus, the median eminence, and the adrenal medulla. In addition, the hypothalamic expr ession of ART was elevated similar to 10-fold in ob/ob and db/db mice. ART was mapped to human chromosome 16q22 and to mouse chromosome 8D1- D2. The expression pattern and transcriptional regulation of ART, coup led with the known actions of agouti, suggests a role for ART in the r egulation of melanocortin receptors within the hypothalamus and adrena l gland, and implicates this novel gene in the central control of feed ing.