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

• DOI: 10.2337/db08-1001
• Publication Date: 2009-03-17T00:34:38Z
• Authors: Jane J. Kim; Pingping Li; Jessica Huntley; Jeffrey P. Chang; Karen C. Arden; Jerrold M. Olefsky
• Keywords: Male; 0301 basic medicine; 2. Zero hunger; Forkhead Box Protein O1; Reverse Transcriptase Polymerase Chain Reaction; Forkhead Transcription Factors; Dietary Fats; PPAR gamma; Mice; 03 medical and health sciences; Phenotype; Adipose Tissue; Reference Values; Glucose Clamp Technique; Animals; Hypoglycemic Agents; Original Article; Thiazolidinediones; RNA, Messenger; Insulin Resistance; Gene Deletion

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 in 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)γ gene expression in adipose tissue, with enhanced expression of PPARγ target genes known to influence metabolism. Moreover, treatment of mice with the PPARγ 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 PPARγ function.