Molecular activation of PPARγ by angiotensin II type 1-receptor antagonists

Objective and design: Elevated blood pressure and insulin resistance are strongly associated in patients. We explored the potential for the antihypertensive angiotensin II type 1-receptor (ATR(1)) antagonists to improve insulin sensitivity through modulation of the nuclear receptor PPAR gamma, in vitro and in vivo compared to the potent insulin sensitizer, rosiglitazone. Methods: PPAR gamma modulation by ATR1 antagonists was measured first by direct recruitment of PGC-1, followed by trans-activation reporter assays in cells, and promotion of adipogenesis in fibroblast and pre-adipocyte cell lines. Improvement of insulin sensitivity was measured as changes in levels of glucose, insulin, and adiponectin in ob/ob mice. Results: Telmisartan, candesartan, irbesartan, and losartan (but not valsartan or olmesartan) each served as bona fide PPAR gamma ligands in vitro, with EC50 values between 3 and 5 mu mol/l. However, only telmisartan, and to a lesser extent candesartan, resulted in significant PPAR gamma agonism in cells. In vivo, although rosiglitazone significantly lowered both glucose (33%, p < 0.01) and insulin (61%, p < 0.01) levels and increased expression of adiponectin (74%, p < 0.001), sartan treatment had no effect. Conclusions: Many members of the sartan family of ATR(1) antagonists are PPAR gamma ligands in cell-free assays but their modulation of PPAR gamma in cells is relatively weak. Furthermore, none appear to improve insulin sensitivity in a rodent model under conditions where other insulin sensitizers, including rosiglitazone, do. These results question whether reported effects of sartans on insulin sensitivity may be through other means, and should guide further efforts to develop dual agents to treat hypertension and insulin resistance. (c) 2006 Elsevier Inc. All rights reserved.