Fat-Specific DsbA-L Overexpression Promotes Adiponectin Multimerization and Protects Mice From Diet-Induced Obesity and Insulin Resistance

  1. Feng Liu1,3,4
  1. 1Department of Pharmacology, University of Texas Health Science Center at San Antonio (UTHSCSA), San Antonio, Texas
  2. 2Department of Cellular and Structural Biology, UTHSCSA, San Antonio, Texas
  3. 3Diabetes Division, UTHSCSA, San Antonio, Texas
  4. 4Department of Biochemistry, UTHSCSA, San Antonio, Texas
  5. 5Cancer Therapy and Research Center, UTHSCSA, San Antonio, Texas
  6. 6Barshop Institute for Longevity and Aging Studies, UTHSCSA, San Antonio, Texas
  7. 7South Texas Veterans Health Care System, San Antonio, Texas
  8. 8Touchstone Diabetes Center, Department of Internal Medicine, and Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas
  1. Corresponding author: Feng Liu, liuf{at}uthscsa.edu.

Abstract

The antidiabetic and antiatherosclerotic effects of adiponectin make it a desirable drug target for the treatment of metabolic and cardiovascular diseases. However, the adiponectin-based drug development approach turns out to be difficult due to extremely high serum levels of this adipokine. On the other hand, a significant correlation between adiponectin multimerization and its insulin-sensitizing effects has been demonstrated, suggesting a promising alternative therapeutic strategy. Here we show that transgenic mice overexpressing disulfide bond A oxidoreductase-like protein in fat (fDsbA-L) exhibited increased levels of total and the high-molecular-weight form of adiponectin compared with wild-type (WT) littermates. The fDsbA-L mice also displayed resistance to diet-induced obesity, insulin resistance, and hepatic steatosis compared with WT control mice. The protective effects of DsbA-L overexpression on diet-induced insulin resistance, but not increased body weight and fat cell size, were significantly decreased in adiponectin-deficient fDsbA-L mice (fDsbA-L/Ad−/−). In addition, the fDsbA-L/Ad−/− mice displayed greater activity and energy expenditure compared with adiponectin knockout mice under a high-fat diet. Taken together, our results demonstrate that DsbA-L protects mice from diet-induced obesity and insulin resistance through adiponectin-dependent and independent mechanisms. In addition, upregulation of DsbA-L could be an effective therapeutic approach for the treatment of obesity and its associated metabolic disorders.

Footnotes

  • Received February 14, 2012.
  • Accepted April 21, 2012.

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  1. Diabetes vol. 61 no. 11 2776-2786
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