FoxO1 Haploinsufficiency Protects Against High-Fat Diet–Induced Insulin Resistance With Enhanced Peroxisome Proliferator–Activated Receptor γ Activation in Adipose Tissue
- Jane J. Kim1,2,
- Pingping Li3,
- Jessica Huntley1,
- Jeffrey P. Chang1,
- Karen C. Arden3,4 and
- Jerrold M. Olefsky3
- 1Department of Pediatrics, University of California at San Diego, La Jolla, California;
- 2Rady Children's Hospital of San Diego, San Diego, California;
- 3Department of Medicine, University of California at San Diego, La Jolla, California;
- 4Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, California.
- Corresponding author: Jane J. Kim, janekim{at}ucsd.edu.
Abstract
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.
Footnotes
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The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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- Received July 23, 2008.
- Accepted March 3, 2009.
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- © 2009 by the American Diabetes Association.
