Adipocyte-Specific Overexpression of FOXC2 Prevents Diet-Induced Increases in Intramuscular Fatty Acyl CoA and Insulin Resistance

  1. Jason K. Kim1,
  2. Hyo-Jeong Kim1,
  3. So-Young Park1,
  4. Anna Cederberg2,
  5. Rickard Westergren2,
  6. Daniel Nilsson2,
  7. Takamasa Higashimori1,
  8. You-Ree Cho1,
  9. Zhen-Xiang Liu1,
  10. Jianying Dong1,
  11. Gary W. Cline1,
  12. Sven Enerback2 and
  13. Gerald I. Shulman134
  1. 1Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut
  2. 2Department of Medical Biochemistry, Medical Genetics, Goteborg University, Goteborg, Sweden
  3. 3Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut
  4. 4Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut
  1. Address correspondencereprint requests to Prof. Jason K. Kim, Yale University School of Medicine, Department of Internal Medicine, Section of EndocrinologyMetabolism, The Anlyan Center, S269C, 300 Cedar St., P.O. Box 208020, New Haven, CT 06520-8020. E-mail:{at}


Insulin resistance plays a major role in the development of type 2 diabetes and may be causally associated with increased intracellular fat content. Transgenic mice with adipocyte-specific overexpression of FOXC2 (forkhead transcription factor) have been generated and shown to be protected against diet-induced obesity and glucose intolerance. To understand the underlying mechanism, we examined the effects of chronic high-fat feeding on tissue-specific insulin action and glucose metabolism in the FOXC2 transgenic (Tg) mice. Whole-body fat mass were significantly reduced in the FOXC2 Tg mice fed normal diet or high-fat diet compared with the wild-type mice. Diet-induced insulin resistance in skeletal muscle of the wild-type mice was associated with defects in insulin signaling and significant increases in intramuscular fatty acyl CoA levels. In contrast, FOXC2 Tg mice were completely protected from diet-induced insulin resistance and intramuscular accumulation of fatty acyl CoA. High-fat feeding also blunted insulin-mediated suppression of hepatic glucose production in the wild-type mice, whereas FOXC2 Tg mice were protected from diet-induced hepatic insulin resistance. These findings demonstrate an important role of adipocyte-expressed FOXC2 on whole-body glucose metabolism and further suggest FOXC2 as a novel therapeutic target for the treatment of insulin resistance and type 2 diabetes.


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    • Accepted March 16, 2005.
    • Received May 20, 2004.
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