Angiotensin Type 1 Receptor Blockers Induce Peroxisome Proliferator–Activated Receptor-γ Activity

Abstract

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-γ (PPARγ) is the central regulator of insulin and glucose metabolism improving insulin sensitivity. We investigated the regulation of PPARγ function by ARBs. Methods and Results— The ARBs irbesartan and telmisartan (10 μmol/L) potently enhanced PPARγ-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 μmol/L: 3.6±0.3-fold induction; P <0.01), whereas eprosartan up to 100 μmol/L had no significant effects. In transcription reporter assays, irbesartan and telmisartan (10 μmol/L) markedly induced transcriptional activity of PPARγ 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 PPARγ ligand pioglitazone (10 μmol/L). Irbesartan and telmisartan also induced PPARγ activity in an AT 1 R-deficient cell model (PC12W), demonstrating that these ARBs stimulate PPARγ activity independent of their AT 1 R blocking actions. Conclusions— The present study demonstrates that a specific subset of ARBs induces PPARγ activity, thereby promoting PPARγ-dependent differentiation in adipocytes. The activation of PPARγ demonstrates new pleiotropic actions of certain ARBs, providing a potential mechanism for their insulin-sensitizing/antidiabetic effects.