Angiotensin type 1 receptor blockers induce peroxisome proliferator-activated receptor-α activity

Background - Angiotensin type 1 receptor (AT(1)R) blockers (ARB) have been shown to reduce the incidence of type 2 diabetes mellitus by an unknown molecular mechanism. The peroxisome proliferator - activated receptor-gamma (PPARgamma) is the central regulator of insulin and glucose metabolism improving insulin sensitivity. We investigated the regulation of PPARgamma function by ARBs. Methods and Results - The ARBs irbesartan and telmisartan (10 mumol/L) potently enhanced PPARgamma-dependent 3T3-L1 adipocyte differentiation associated with a significant increase in mRNA expression of the adipogenic marker gene adipose protein 2 (aP2), as measured by quantitative real-time polymerase chain reaction ( irbesartan: 3.3 +/- 0.1-fold induction; telmisartan: 3.1 +/- 0.3-fold induction; both P < 0.01). Telmisartan showed a more pronounced induction of aP2 expression in lower, pharmacologically relevant concentrations compared with the other ARBs. The ARB losartan enhanced aP2 expression only at high concentrations (losartan 100 mu mol/L: 3.6 +/- 0.3-fold induction; P < 0.01), whereas eprosartan up to 100 mumol/L had no significant effects. In transcription reporter assays, irbesartan and telmisartan (10 mumol/L) markedly induced transcriptional activity of PPARgamma by 3.4 +/- 0.9-fold and 2.6 +/- 0.6-fold (P < 0.05), respectively, compared with 5.2 +/- 1.1-fold stimulation by the PPAR gamma ligand pioglitazone (10 mu mol/L). Irbesartan and telmisartan also induced PPAR gamma activity in an AT(1)R-deficient cell model (PC12W), demonstrating that these ARBs stimulate PPAR gamma activity independent of their AT1R blocking actions. Conclusions - The present study demonstrates that a specific subset of ARBs induces PPAR gamma activity, thereby promoting PPAR gamma-dependent differentiation in adipocytes. The activation of PPAR gamma demonstrates new pleiotropic actions of certain ARBs, providing a potential mechanism for their insulin-sensitizing/ antidiabetic effects.