Institute of Vascular Medicine, Chinese University of Hong Kong, Hong Kong, China; Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Hong Kong, China.
Cell Metab. 2011 Jul 6;14(1):104-15. doi: 10.1016/j.cmet.2011.05.009.
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.
罗格列酮是一种常用于治疗糖尿病的 PPARγ 激动剂。除了改善胰岛素敏感性外，罗格列酮还通过一种机制恢复正常的血管功能，但该机制仍不清楚。在这里，我们表明脂联素是介导 PPARγ 对糖尿病小鼠血管内皮作用所必需的。在 db/db 和饮食诱导肥胖的小鼠中，罗格列酮激活 PPARγ 可恢复主动脉的内皮依赖性松弛，而缺乏脂联素的糖尿病小鼠或用抗脂联素抗体治疗的小鼠则没有反应。罗格列酮刺激脂肪外植体释放脂联素，并且来自罗格列酮处理的小鼠的皮下脂肪移植再现未处理的 db/db 受者中的血管舒张作用。从机制上讲，脂联素激活主动脉中的 AMPK/eNOS 和 cAMP/PKA 信号通路，从而增加 NO 生物利用度并减少氧化应激。总之，这些结果表明脂肪细胞衍生的脂联素是 PPARγ 介导的糖尿病内皮功能改善所必需的。因此，脂肪组织代表了治疗糖尿病血管病变的有希望的靶标。
