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

¹Division of Molecular Genetics, Department of Pediatrics; ²Institute of Human Nutrition; and ³Naomi Berrie Diabetes Center, Columbia University, New York, NY

Submitted 7 April 2006 ; accepted in final form 23 April 2006

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.

agouti; insulin resistance; melanocortin-4 receptor; obesity; mahogany