The mahoganoid mutation (Mgrn1) improves insulin sensitivity in mice with mutations in the melanocortin signaling pathway independently of effects on adiposity

Phan, Loan K., Wendy K. Chung, and Rudolph L. Leibel. The mahoganoid mutation (Mgrn1) improves insulin sensitivity in mice with mutations in the melanocortin signaling pathway independently of effects on adiposity. Am J Physiol Endocrinol Metab 291: E611–E620, 2006. First published April 25, 2006; doi:10.1152/ajpendo.00034.2006.—Mahoganoid (Mgrn1) is a mutation of the mahogunin (Mgrn1) gene. The hypomorphic allele suppresses the yellow pigmentation and obesity of the A 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 and A, Lep, or a null allele of Mc4r, and diet-induced obesity (DIO) mice segregating for Mgrn1. Mgrn1 suppressed the obesity, hyperglycemia, and hyperinsulinemia of A mice. Mgrn1 suppressed A-induced obesity by reducing food intake, and reduced adiposity in Lep/Lep females, but did not alter the body weight or body composition of mice fed a high-fat diet. There was no effect of Mgrn1 on weight gain, body composition, energy intake, or energy expenditure in Mc4r-null animals. Mgrn1 reduced circulating insulin concentrations in DIO, A, and Mc4r-null but not Lep/Lep mice. The effect of Mgrn1 on circulating insulin concentrations was not due primarily to reductions in fat mass, since the plasma insulin concentrations of Mgrn1 mice segregating for either A or Mc4r-null alleles, adjusted for fat mass and plasma glucose, were reduced compared with A and Mc4r mice, respectively. The effect of Mgrn1 on insulin sensitivity of Mc4r-null mice suggests that Mgrn1 may be increasing insulin sensitivity via the hypothalamic melanocortin-3 receptor pathway.