The yellow mouse obesity syndrome and mechanisms of Agouti-induced obesity

The yellow mouse obesity syndrome is due to dominant mutations at the Agout i locus, which is characterized by obesity, hyperinsulinemia, insulin resis tance, hyperglycemia, hyperleptinemia, increased linear growth, and yellow coat color. This syndrome is caused by ectopic expression of Agouti in mult iple tissues. Mechanisms of Agouti action in obesity seem to involve, at le ast in part, competitive melanocortin antagonism. Both central and peripher al effects have been implicated in Agouti-induced obesity. An Agouti-Relate d Protein (AGRP) has been described recently. It has been shown to be expre ssed in mice hypothalamus and to act similarly to agouti as a potent antago nist to central melanocortin receptor MC4-R, suggesting that AGRP is an end ogenous MC4-R ligand. Mice lacking MC4-R become hyperphagic and develop obe sity, implying that agouti may lead to obesity by interfering with MC4-R si gnaling in the brain and consequently regulating food intake. Furthermore, food intake is inhibited by intracerebroventricular injection of a potent m elanocortin agonist and was reversed by administration of an MC4-R antagoni st. The direct cellular actions of Agouti include stimulation of fatty acid and triglyceride synthesis via a Ca2+-dependent mechanism. Agouti and insu lin act in an additive manner to increase lipogenesis. This additive effect of agouti and insulin is demonstrated by the necessity of insulin in elici ting weight gain in transgenic mice expressing agouti specifically in adipo se tissue. This suggests that agouti expression in adipose tissue combined with hyperinsulinemia may lead to increased adiposity. The roles of melanoc ortin receptors or agouti-specific receptor(s) in agouti regulation of adip ocyte metabolism and other peripheral effects remain to be determined. In c onclusion, bath central and peripheral actions of agouti contribute to the yellow mouse obesity syndrome and this action is mediated at least in part by antagonism with melanocortin receptors and/or regulation of intracellula r calcium.