The role of Foxo1 on the mechanism by which insulin signaling regulates food intake

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We investigated the role of Foxo1 in mediating the hypothalamic actions of insulin on food intake and leptin sensitivity. In situ hybridization revealed that Foxo1 mRNA is expressed in hypothalamus, mainly in the arcuate nucleus. We next analyzed mice with a heterozygous Foxo1 mutation. Although body weight and amount of food intake in Foxo1+/-mice are the same as in wild type mice, BMI(bw/naso-anal lenght2) and leptin concentration level are lower significantly than in wild type controls. Intraperitoneal leptin administration decreased food intake and body weight in Foxo1+/-significantly, but had no effects in wild type mice. Although Agrp and Npy mRNA expression in hypothalamus increased by 4-and 1.5-fold, respectively, in wild type mice fasted for 72 hours, no significant differences of Agrp and Npy expression levels but increased expression of pomc were detected in Foxo1+/-in the same condition. These data suggest that haploinsufficiency for Foxo1 increases leptin sensitivity by downregulating Agrp and Npy gene expression and upregulating Pomc gene expression in hypothalamus and that Foxo1 may have an important role inn insulin regulation of food intake. We further investigated the role of Foxo1 in the fatty tissue on actions of insulin. We generated fatty tissue-specific dominant-negative type Foxo1 overexpressed transgenic mice. These mice showed decreased high-fat induced insulin sensitivity and decreased glucose intolerance by inhibiting formation of hypertrophied fatty cells, increased expression of adiponectin gene, normalized expression of Glut4 and decreased expression of TNFα. From these data it is suggested that Foxo1 plays also an important role in fatty tissue for the pathogenesis of diabetes