Adipocyte Spliced Form of X-Box–Binding Protein 1 Promotes Adiponectin Multimerization and Systemic Glucose Homeostasis
- Haibo Sha1,
- Liu Yang2,
- Meilian Liu3,
- Sheng Xia1,
- Yong Liu4,
- Feng Liu3,
- Sander Kersten1,5 and
- Ling Qi1,2⇑
- 1Division of Nutritional Sciences, Cornell University, Ithaca, NY
- 2Graduate Program in Biochemistry, Molecular and Cell Biology, Cornell University, Ithaca, NY
- 3Department of Pharmacology, University of Texas Health Science Center at San Antonio, San Antonio, TX
- 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
- 5Nutrition, Metabolism, and Genomics Group, Division of Human Nutrition, Wageningen University, Wageningen, the Netherlands
- Corresponding author: Ling Qi, .
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.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db13-1067/-/DC1.
S.X. is currently affiliated with the Department of Immunology, School of Medical Science and Laboratory Medicine, Jiangsu University, Zhenjiang, China.
- Received July 9, 2013.
- Accepted November 13, 2013.
- © 2014 by the American Diabetes Association.
Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.