Fat-specific DsbA-L overexpression promotes adiponectin multimerization and protects mice from diet-induced obesity and insulin resistance

Meilian Liu, Ruihua Xiang, Sarah Ann Wilk, Ning Zhang, Lauren B. Sloane, Kian Azarnoush, Lijun Zhou, Hongzhi Chen, Guangda Xiang, Christi A. Walter, Steven N Austad, Nicolas Musi, Ralph A. DeFronzo, Reto H Asmis, Philipp E. Scherer, Lily Q. Dong, Feng Liu

Research output: Contribution to journalArticlepeer-review

59 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)2776-2786
Number of pages11
JournalDiabetes
Volume61
Issue number11
DOIs
StatePublished - Nov 2012

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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