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

TLDR

Angiotensin type 1 receptor blockers lower type 2 diabetes risk, but the mechanism is unclear; the PPARγ nuclear receptor is the key regulator of insulin sensitivity. The study examined whether ARBs modulate PPARγ activity. Irbesartan and telmisartan strongly activated PPARγ, promoting adipocyte differentiation and aP2 expression even in AT1R‑deficient cells, while losartan required high doses and eprosartan had no effect, indicating that certain ARBs stimulate PPARγ independent of AT1R and may underlie their insulin‑sensitizing benefits.

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.