The mahogany protein is a receptor involved in suppression of obesity

Genetic studies have shown that mutations within the mahogany locus(1) supp ress the pleiotropic phenotypes, including obesity, of the agouti-lethal-ye llow mutant(2,3). Here we identify the mahogany gene and its product; this study, to our knowledge, represents the first positional cloning of a suppr essor gene in the mouse. Expression of the mahogany gene is broad; however, in situ hybridization analysis emphasizes the importance of its expression in the ventromedial hypothalamic nucleus, a region that is intimately invo lved in the regulation of body weight and feeding. We present new genetic s tudies that indicate that the mahogany locus does not suppress the obese ph enotype of the melanocortin-4-receptor null allele(4) or those of the monog enic obese models (Lep(db), tub and Cpe(fat)). However, mahogany can suppre ss diet-induced obesity, the mechanism of which is likely to have implicati ons for therapeutic intervention in common human obesity. The amino-acid se quence of the mahogany protein suggests that it is a large, single-transmem brane-domain receptor-like molecule, with a short cytoplasmic tail containi ng a site that is conserved between Caenorhabditis elegans and mammals. We propose two potential, alternative modes of action for mahogany: one draws parallels with the mechanism of action of low-affinity proteoglycan recepto rs such as fibroblast growth factor and transforming growth factor-beta, an d the other suggests that mahogany itself is a signalling receptor.