FoxO1 Haploinsufficiency Protects Against High-Fat Diet-Induced Insulin Resistance With Enhanced Peroxisome Proliferator-Activated Receptor γ Activation in Adipose Tissue

OBJECTIVE-Forkhead box O (FoxO) transcription factors represent evolutionarily conserved targets of insulin signaling regulating metabolism and cellular differentiation in response to changes in nutrient availability. Although the FoxO1 isoform is known to play a key role in adipogenesis, its physiological role ill differentiated adipose tissue remains unclear. RESEARCH DESIGN AND METHODS-In this study, we analyzed the phenotype of FoxO1. haploinsufficient mice to investigate the role of FoxO1 in high-fat, diet-induced obesity and adipose tissue metabolism. RESULTS-We showed that reduced FoxO1 expression protects mice against, obesity-related insulin resistance with marked improvement not, only in hepatic insulin sensitivity but, also in skeletal muscle insulin action. FoxO1 haploinsufficiency also resulted in increased peroxisome proliferator-activated receptor (PPAR)gamma gene expression in adipose tissue, with enhanced expression of PPAR gamma target, genes known to influence metabolism Moreover, treatment of mice with the PPAR gamma agonist, rosiglitazone caused a greater improvement in in vivo insulin sensitivity in FoxO1 haploinsufficient animals, including reductions in circulating proinflammatory cytokines. CONCLUSIONS-These findings indicate that FoxO1 proteins negatively regulate insulin action and that their effect may be explained, at least in part, by inhibition of PPAR gamma function. Diabetes 58:1275-1282, 2009