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Endothelin-1 Regulates Adiponectin Gene Expression and Secretion in 3T3-L1 Adipocytes via Distinct Signaling Pathways

Departments of Physiology (C.-C.J., T.-Y.C., C.-L.C., L.-T.H.) and Surgery (S.-W.H.), School of Medicine, National Yang-Ming University, and Department of Medical Research and Education (C.-C.J., S.-W.H., L.-T.H.), Taipei Veterans General Hospital, Taipei, Taiwan

Address all correspondence and requests for reprints to: Chi-Chang Juan, Ph.D., Department of Physiology, National Yang-Ming University, No. 155, Section 2, Li-Nong Street, Taipei, Taiwan. E-mail: ccjuan{at}ym.edu.tw.

Adiponectin, which is specifically and highly expressed in adipose tissue, has pleiotropic insulin-sensitizing effects. Endothelin-1 (ET-1) is a potent vasoconstrictive peptide mainly produced by endothelial cells. We previously showed that ET-1 can induce insulin resistance in vitro and in vivo and proposed that it might regulate adiponectin expression and secretion, thus affecting the homeostasis of whole-body energy metabolism. In the present study, we explored the regulatory effects of ET-1 on adiponectin expression and secretion and the underlying mechanisms in 3T3-L1 adipocytes using Northern blotting and ELISA. ET-1 was found to cause a significant time- and dose-dependent decrease in adiponectin expression, and this effect was inhibited by the ET type A receptor (ET_AR) antagonist BQ-610 but not by the ET_BR antagonist BQ-788. To explore the underlying mechanism, we examined the involvement of the cAMP-dependent protein kinase A-, phospholipase A2-, protein kinase C-, and MAPK-mediated pathways using inhibitors and found that only PD98059 and U0126, inhibitors that blocked MAPK/ERK kinase’s ability to activate the ERKs, prevented ET-1-induced down-regulation of adiponectin. Furthermore, acute ET-1 treatment significantly stimulated adiponectin secretion by 3T3-L1 adipocytes, and this effect was inhibited by the ET_AR antagonist BQ-610, the inositol-1,4,5-triphosphate receptor blocker 2-APB, and phospholipase C inhibitor U73122, showing that the release of adiponectin stimulated by ET-1 was mediated through the ET_AR and the inositol-1,4,5-triphosphate pathway. In conclusion, ET-1 regulates adiponectin expression and secretion by two different signaling pathways in 3T3-L1 adipocytes. These findings suggested that the cardiovascular system affects adipocyte physiology by regulating the expression of adipocytokines and, consequently, energy homeostasis via vasoactive factors, such as ET-1.