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This Article Full Text Full Text (PDF) All Versions of this Article: 291/3/E611    most recent 00034.2006v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Web of Science (2) Citing Articles via Google Scholar Google Scholar Articles by Phan, L. K. Articles by Leibel, R. L. Search for Related Content PubMed PubMed Citation Articles by Phan, L. K. Articles by Leibel, R. L.

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