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(Hypertension. 2005;46:137.)
© 2005 American Heart Association, Inc.

Original Articles

PPAR-Activating Angiotensin Type-1 Receptor Blockers Induce Adiponectin

Ronald Clasen; Michael Schupp; Anna Foryst-Ludwig; Christiane Sprang; Markus Clemenz; Maxim Krikov; Christa Thöne-Reineke; Thomas Unger; Ulrich Kintscher

From the Center for Cardiovascular Research (CCR) (R.C., M.S., A.F.-L., C.S., M.C., M.K., C.T.-R., T.U., U.K.), Institut für Pharmakologie und Toxikologie, Charité Campus Mitte, Charité-Universitätsmedizin Berlin; and the Institut für Pharmazie (R.C.), Freie Universität Berlin, Berlin, Germany.

Correspondence to Ulrich Kintscher, MD, Center for Cardiovascular Research (CCR), Institut für Pharmakologie und Toxikologie, Charité Campus Mitte, Universitätsmedizin Berlin, Hessische Str. 3/4, 10115 Berlin, Germany. E-mail ulrich.kintscher{at}charite.de

The adipose-specific protein adiponectin has been recently discovered to improve insulin sensitivity. Angiotensin type-1 receptor (AT1R) blockers (ARBs) reduce the incidence of type 2 diabetes mellitus by mostly unknown molecular mechanisms. To identify new antidiabetic mechanisms of ARBs, we studied the regulation of adiponectin by angiotensin II (Ang II) and different ARBs in murine 3T3-L1 adipocytes and obese Zucker rats. Adiponectin protein expression was markedly stimulated by Ang II (5 nmol/L), which was inhibited by blockade of the AT2R, and further enhanced by the ARB irbesartan. Irbesartan-mediated adiponectin upregulation started beyond the concentrations needed for AT1R blockade and was also present in the absence of Ang II, implicating an AT1R-independent mechanism of action. Recently, certain ARBs (irbesartan, telmisartan) were identified as ligands of the peroxisome proliferator-activated receptor (PPAR). Telmisartan also stimulated adiponectin protein expression, whereas the non-PPAR-activating ARB eprosartan had no effect. Blockade of PPAR activation by the PPAR antagonist GW9662 markedly inhibited irbesartan-induced adiponectin expression. Cognate mRNA levels of adiponectin were not affected by ARBs. Kinetic studies using the protein synthesis inhibitor cycloheximide showed that irbesartan prevented the cellular depletion of adiponectin protein. Finally, administration of irbesartan to obese Zucker rats improved insulin sensitivity and attenuated adiponectin serum depletion. The present study demonstrates that AT2R activation and certain ARBs induce adiponectin in adipocytes, which was associated with an improvement of parameters of insulin sensitivity in vivo. ARB-induced adiponectin stimulation is likely to be mediated via PPAR activation involving a post-transcriptional mechanism.

Key Words: angiotensin antagonist • diabetes mellitus • insulin resistance • adipose tissue

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