Adiponectin Is Required for PPARγ-Mediated Improvement of Endothelial Function in Diabetic Mice

• DOI: 10.1016/j.cmet.2011.05.009
• Publication Date: 2011-07-07T00:45:33Z
• Authors: Wing Tak Wong; Xiao Yu Tian; Aimin Xu; Jun Yu; Chi Wai Lau; Ruby L.C. Hoo; Yu Wang; Vivian W.Y. Lee; Karen S.L. Lam; Paul M. Vanhoutte; Yu Huang
• Keywords: Male; 0301 basic medicine; Nitric Oxide Synthase Type III; Adiponectin - metabolism; Physiology; Mice, Obese; AMP-Activated Protein Kinases; Endothelium, Vascular - drug effects - metabolism - physiology; Nitric Oxide; Diabetes Mellitus, Experimental; PPAR gamma - agonists - metabolism; Rosiglitazone; Mice; 03 medical and health sciences; Diabetes Mellitus; Cyclic AMP; Animals; Hypoglycemic Agents; Endothelium; Molecular Biology; Aorta; 0303 health sciences; Diabetes Mellitus, Experimental - drug therapy - metabolism; Experimental - drug therapy - metabolism; Cell Biology; Cyclic AMP-Dependent Protein Kinases; 3. Good health; PPAR gamma; Vascular - drug effects - metabolism - physiology; Thiazolidinediones; Adiponectin; Endothelium, Vascular; AMP-Activated Protein Kinases - metabolism; Signal Transduction

Rosiglitazone is a PPARγ agonist commonly used to treat diabetes. In addition to improving insulin sensitivity, rosiglitazone restores normal vascular function by a mechanism that remains poorly understood. Here we show that adiponectin is required to mediate the PPARγ effect on vascular endothelium of diabetic mice. In db/db and diet-induced obese mice, PPARγ activation by rosiglitazone restores endothelium-dependent relaxation of aortae, whereas diabetic mice lacking adiponectin or treated with an anti-adiponectin antibody do not respond. Rosiglitazone stimulates adiponectin release from fat explants, and subcutaneous fat transplantation from rosiglitazone-treated mice recapitulates vasodilatation in untreated db/db recipients. Mechanistically, adiponectin activates AMPK/eNOS and cAMP/PKA signaling pathways in aortae, which increase NO bioavailability and reduce oxidative stress. Taken together, these results demonstrate that adipocyte-derived adiponectin is required for PPARγ-mediated improvement of endothelial function in diabetes. Thus, the adipose tissue represents a promising target for treating diabetic vasculopathy.