TY - JOUR
T1 - Adipocyte spliced form of x-box-binding protein 1 promotes adiponectin multimerization and systemic glucose homeostasis
AU - Sha, Haibo
AU - Yang, Liu
AU - Liu, Meilian
AU - Xia, Sheng
AU - Liu, Yong
AU - Liu, Feng
AU - Kersten, Sander
AU - Qi, Ling
PY - 2014/3/1
Y1 - 2014/3/1
N2 - 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 highmolecular- 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.
AB - 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 highmolecular- 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.
UR - http://www.scopus.com/inward/record.url?scp=84894429746&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84894429746&partnerID=8YFLogxK
U2 - 10.2337/db13-1067
DO - 10.2337/db13-1067
M3 - Article
C2 - 24241534
AN - SCOPUS:84894429746
VL - 63
SP - 867
EP - 879
JO - Diabetes
JF - Diabetes
SN - 0012-1797
IS - 3
ER -