Agouti protein, a paracrine signaling molecule normally limited to skin, is
ectopically expressed in lethal yellow (A(y)) mice, and causes obesity by
mimicking agouti-related protein (Agrp), found primarily in the hypothalamu
s. 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(y). Here we demonstrate in transgenic, biochem
ical and genetic-interaction experiments that attractin is a low-affinity r
eceptor for agouti protein, but not Agrp, in vitro and in vivo. Additional
histopathologic abnormalities in Atrn(mg-3J)/Atrn(mg-3J) mice and cross-spe
cies genomic comparisons indicate that Atrn has multiple functions distinct
from both a physiologic and an evolutionary perspective.