Adipocyte XBP1s Promotes Adiponectin Multimerization and Systemic Glucose Homeostasis

  1. Ling Qi1,2
  1. 1Division of Nutritional Sciences, Cornell University, Ithaca, New York;
  2. 2Graduate Program in Biochemistry, Molecular and Cell Biology, Cornell University, Ithaca, New York;
  3. 3Department of Pharmacology, University of Texas Health Science Center at San Antonio, San Antonio, Texas;
  4. 4Laboratory of Metabolic Regulation and Metabolic Diseases, Institute of Nutritional Sciences, Shanghai, China;
  5. 5Nutrition, Metabolism, and Genomics group, Division of Human Nutrition, Wageningen University, Wageningen, The Netherlands.
  1. Corresponding author: Ling Qi, E-mail: lq35{at}cornell.edu
  • S.X. is currently affiliated with the Department of Immunology, School of Medical Science and Laboratory Medicine, Jiangsu University, Zhenjiang, China.

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. Here 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 HMW 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 Grp78, Pdia6, ERp44 and DsbA-L. 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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