PPARγ-Activating Angiotensin Type-1 Receptor Blockers Induce Adiponectin

Abstract

Abstract-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. (Hypertension. 2005;46:137-143.)

Potential impact of renin–angiotensin system inhibitors and calcium channel blockers on plasma high-molecular-weight adiponectin levels in hemodialysis patients

“…It has been reported that RAS inhibitors 25,26 and CCBs 27 increase adiponectin levels in non-hemodialysis patients. Previous studies have shown that angiotensin II receptor blocker inhibits obesity-induced hypoadiponectinemia through the inhibition of reactive oxygen species generation in mice 28 and that some angiotensin II receptor blockers have peroxisome proliferator-activated receptor g-activating properties, 29 thereby stimulating adiponectin production. Some CCBs have also been reported to have the ability to increase adiponectin levels through the inhibition of reactive oxygen species generation 30 and of monocyte and platelet activation.…”

Effects of phorbol ester‐sensitive PKC (c/nPKC) activation on the production of adiponectin in 3T3‐L1 adipocytes

“…However, contradictory data exist regarding the effects of AII and ARB on adipocyte gene expression. Clasen et al demonstrated that ARBinduced adiponectin protein expression was mediated via PPARc, whereas AII itself increased adiponectin production in 3T3-L1 adipocytes (32). Moriuch et al reported that neither AII nor candesartan had any effect on adiponectin promoter activity, and that another ARB, telmisartan, stimulated adiponectin transcription independent of PPARc (33).…”

Role of the renin-angiotensin system in autoimmune inflammation of the central nervous system

“…One such approach is the pharmacological blockade of the AT1R by losartan, which in contrast to other AT1R blockers, like telmisartan, does not display additional peroxisome proliferator-activating receptor (PPAR)␥ agonistic effects (9). Here we investigate the role of the RAS during autoimmune inflammation of the CNS in the model of myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis (MOG-EAE), which mimics many aspects of multiple sclerosis (10).…”