Attractin more interest in weight regulation

Abstract

Mutant mice continue to expand our understanding of appetite and energy metabolism. The latest entry to the web of hypothalamic weight regulatory proteins is the product of the mahogany gene. “Mahogany” refers to the color of the first mice identified with mutations in this gene, mutations that reverse the coat discoloration and obesity conferred by the agouti (yellow) mutation on otherwise dark-haired mice. Endogenous agouti protein blocks pigment synthesis by interfering with activation of the melanocortin type 1 receptor (MC-1R) in hair follicles by α-melanocyte-stimulating hormone (α-MSH). A similar αM-MSH receptor (MC-4R) present in the hypothalamus is critical to normal regulation of food intake and energy expenditure. In mice, deletion of the MC-4R gene is associated with obesity, and recent studies have revealed MC-4R mutations in selected severely obese humans. In the agouti mice, excess agouti production in the hypothalamus blocks signaling of the MC-4R and renders the animals obese. Through a mechanism that remains obscure, mutations in the mahogany gene reverse this effect, correcting the obesity and the yellow coat discoloration.