Submitted on January 25, 2006
Accepted on April 23, 2006
The Mahoganoid mutation Mgrn1md improves insulin sensitivity in mice with mutations in the melanocortin signaling pathway independent of effects on adiposity
Loan K Phan1, Wendy K Chung2, and Rudolph L. Leibel3*
1 Division of Molecular Genetics, Department of Pediatrics, Columbia University, New York, New York, United States; Institute of Human Nutrition, Columbia University, New York, New York, United States
2 Division of Molecular Genetics, Department of Pediatrics, Columbia University, New York, New York, United States; Naomi Berrie Diabetes Center, Columbia University, New York, New York, United States
3 Division of Molecular Genetics, Department of Pediatrics, Columbia University, New York, New York, United States; Institute of Human Nutrition, Columbia University, New York, New York, United States; Naomi Berrie Diabetes Center, Columbia University, New York, New York, United States
* To whom correspondence should be addressed. E-mail: rl232{at}columbia.edu.
Mahoganoid (Mgrn1md) is a mutation of the mahogunin (Mgrn1) gene. The hypomorphic allele suppresses the yellow pigmentation and obesity of the Ay 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 Mgrn1md and Ay, Lepob, or a null allele of Mc4r, and diet-induced obesity (DIO) mice segregating for Mgrn1md. Mgrn1md suppressed the obesity, hyperglycemia and hyperinsulinemia of Ay mice. Mgrn1md suppressed Ay-induced obesity by reducing food intake, and reduced adiposity in Lep ob/Lepob females, but did not alter the body weight or body composition of mice fed a high fat diet. There was no effect of Mgrn1md on weight gain, body composition, energy intake or energy expenditure in Mc4r-null animals. Mgrn1md reduced circulating insulin concentrations in DIO, Ay and Mc4r-null, but not Lepob/Lepob mice. The effect of Mgrn1md on circulating insulin concentrations was not due primarily to reductions in fat mass, since the plasma insulin concentrations of Mgrn1md mice segregating for either Ay or Mc4r-null alleles - adjusted for fat mass and plasma glucose - were reduced in comparison to Ay and Mc4r mice, respectively. The effect of Mgrn1md on insulin sensitivity of Mc4r-null mice suggests that Mgrn1md may be increasing insulin sensitivity via the hypothalamic MC3R pathway.
