Mahoganoid (Mgrn1(md)) is a mutation of the mahogunin (Mgrn1) gene. The hypomorphic allele suppresses the yellow pigmentation and
obesity of the A(y) mouse that ubiquitously overexpresses
agouti signaling protein (ASP). To assess the physiological effects of MGRN1 on energy and
glucose homeostasis, we generated animals doubly mutant for Mgrn1(md) and A(y), Lep(ob), or a null allele of Mc4r, and diet-induced
obesity (DIO) mice segregating for Mgrn1(md). Mgrn1(md) suppressed the
obesity,
hyperglycemia, and
hyperinsulinemia of A(y) mice. Mgrn1(md) suppressed A(y)-induced
obesity by reducing food intake, and reduced adiposity in Lep(ob)/Lep(ob) females, but did not alter the
body weight or body composition of mice fed a high-fat diet. There was no effect of Mgrn1(md) on
weight gain, body composition, energy intake, or energy expenditure in Mc4r-null animals. Mgrn1(md) reduced circulating
insulin concentrations in DIO, A(y), and Mc4r-null but not Lep(ob)/Lep(ob) mice. The effect of Mgrn1(md) on circulating
insulin concentrations was not due primarily to reductions in fat mass, since the plasma
insulin concentrations of Mgrn1(md) mice segregating for either A(y) or Mc4r-null alleles, adjusted for fat mass and plasma
glucose, were reduced compared with A(y) and Mc4r mice, respectively. The effect of Mgrn1(md) on
insulin sensitivity of Mc4r-null mice suggests that Mgrn1(md) may be increasing
insulin sensitivity via the hypothalamic
melanocortin-3 receptor pathway.