Fat-Specific DsbA-L Overexpression Promotes Adiponectin Multimerization and Protects Mice From Diet-Induced Obesity and Insulin Resistance
- Meilian Liu1,
- Ruihua Xiang2,
- Sarah Ann Wilk2,
- Ning Zhang3,
- Lauren B. Sloane2,
- Kian Azarnoush2,
- Lijun Zhou2,
- Hongzhi Chen4,
- Guangda Xiang2,
- Christi A. Walter2,5,6,7,
- Steven N. Austad2,6,
- Nicolas Musi3,
- Ralph A. DeFronzo3,
- Reto Asmis4,
- Philipp E. Scherer8,
- Lily Q. Dong2 and
- Feng Liu1,3,4⇓
- 1Department of Pharmacology, University of Texas Health Science Center at San Antonio (UTHSCSA), San Antonio, Texas
- 2Department of Cellular and Structural Biology, UTHSCSA, San Antonio, Texas
- 3Diabetes Division, UTHSCSA, San Antonio, Texas
- 4Department of Biochemistry, UTHSCSA, San Antonio, Texas
- 5Cancer Therapy and Research Center, UTHSCSA, San Antonio, Texas
- 6Barshop Institute for Longevity and Aging Studies, UTHSCSA, San Antonio, Texas
- 7South Texas Veterans Health Care System, San Antonio, Texas
- 8Touchstone Diabetes Center, Department of Internal Medicine, and Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas
- Corresponding author: Feng Liu, .
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.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db12-0169/-/DC1.
- Received February 14, 2012.
- Accepted April 21, 2012.
- © 2012 by the American Diabetes Association.
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