Agouti protein, a paracrine signaling molecule normally limited to skin, is ectopically expressed in lethal yellow (Aγ) 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 (Atrnmg-3J/Atrnmg-3J) mutant mice blocks the pleiotropic effects of Aγ. 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 Atrnmg-3J/Atrnmg-3J mice and cross-species genomic comparisons indicate that Atrn has multiple functions distinct from both a physiologic and an evolutionary perspective.
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