Angiotensin type 1 receptor antagonists induce human in-vitro adipogenesis through peroxisome proliferator-activated receptor-γ activation

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Abstract
In clonal animal cells, certain angiotensin receptor blockers (ARB) activate the peroxisome proliferator-activated receptor-γ (PPARγ). The aim of this work was to validate that observation in human cells and humans. We investigated the induction of in-vitro adipogenesis and the activation of PPARγ-target genes, adiponectin and lipoprotein lipase, by ARB in human preadipocytes. We also studied PPARγ response-element-driven luciferase reporter gene activation in human adipocytes. Finally, we treated 14 obese men for 10 days with placebo crossed over with 150 mg/day irbesartan. Subcutaneous fat was analyzed for mRNA expression of adiponectin and lipoprotein lipase. Telmisartan and irbesartan, and to a lesser degree losartan, induced adipogenesis and activated PPARγ-target genes. This stimulation of PPARγ-target genes was prevented by the PPARγ antagonist GW9662. Eprosartan had no effect. Paradoxically, all ARB activated the luciferase reporter gene. PPARγ activity increased approximately two-fold with pioglitazone and 1.5-fold with the ARB in all assays. In the cross-over clinical study, irbesartan lowered blood pressure but had no effect on adiponectin or lipoprotein lipase mRNA expression. Our data are the first to show that ARB induce adipogenesis and PPARγ-target gene expression in human adipocytes. Pharmacokinetic differences may contribute to the heterogeneous effects on metabolism and preadipocyte differentiation. In humans, larger doses of ARB, longer treatments, or both may be required to activate PPARγ in adipose cells.