Adipocyte Spliced Form of X-Box–Binding Protein 1 Promotes Adiponectin Multimerization and Systemic Glucose Homeostasis

  1. Ling Qi1,2
  1. 1Division of Nutritional Sciences, Cornell University, Ithaca, NY
  2. 2Graduate Program in Biochemistry, Molecular and Cell Biology, Cornell University, Ithaca, NY
  3. 3Department of Pharmacology, University of Texas Health Science Center at San Antonio, San Antonio, TX
  4. 4Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Graduate School of the Chinese Academy of Sciences, Shanghai, China
  5. 5Nutrition, Metabolism, and Genomics Group, Division of Human Nutrition, Wageningen University, Wageningen, the Netherlands
  1. Corresponding author: Ling Qi, lq35{at}cornell.edu.

Abstract

The physiological role of the spliced form of X-box–binding protein 1 (XBP1s), a key transcription factor of the endoplasmic reticulum (ER) stress response, in adipose tissue remains largely unknown. In this study, we show that overexpression of XBP1s promotes adiponectin multimerization in adipocytes, thereby regulating systemic glucose homeostasis. Ectopic expression of XBP1s in adipocytes improves glucose tolerance and insulin sensitivity in both lean and obese (ob/ob) mice. The beneficial effect of adipocyte XBP1s on glucose homeostasis is associated with elevated serum levels of high-molecular-weight adiponectin and, indeed, is adiponectin-dependent. Mechanistically, XBP1s promotes adiponectin multimerization rather than activating its transcription, likely through a direct regulation of the expression of several ER chaperones involved in adiponectin maturation, including glucose-regulated protein 78 kDa, protein disulfide isomerase family A, member 6, ER protein 44, and disulfide bond oxidoreductase A–like protein. Thus, we conclude that XBP1s is an important regulator of adiponectin multimerization, which may lead to a new therapeutic approach for the treatment of type 2 diabetes and hypoadiponectinemia.

Footnotes

  • Received July 9, 2013.
  • Accepted November 13, 2013.

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  1. Diabetes vol. 63 no. 3 867-879
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