A biochemical function for attractin in agouti-induced pigmentation and obesity

Agouti protein, a paracrine signaling molecule normally limited to skin, is ectopically expressed in lethal yellow (A^γ) mice, and causes obesity by mimicking agouti-related protein (Agrp), found primarily in the hypothalamus. Mouse attractin (Atrn) is a widely expressed transmembrane protein whose loss of function in mahogany (Atrn^mg-3J/Atrn^mg-3J) mutant mice blocks the pleiotropic effects of A^γ. Here we demonstrate in transgenic, biochemical and genetic-interaction experiments that attractin is a low-affinity receptor for agouti protein, but not Agrp, in vitro and in vivo. Additional histopathologic abnormalities in Atrn^mg-3J/Atrn^mg-3J mice and cross-species genomic comparisons indicate that Atrn has multiple functions distinct from both a physiologic and an evolutionary perspective.