gms | German Medical Science

The adipose-specific protein adiponectin has been recently discovered to improve insulin sensitivity exerting beneficial effects in type 2 diabetic patients. Angiotensin type 1 receptor (AT1R) blockers (ARBs) reduce the incidence of type 2 diabetes mellitus by mostly unknown molecular mechanisms. To identify new anti-diabetic mechanisms of ARBs, we studied the regulation of adiponectin by different ARBs in murine 3T3-L1 adipocytes and obese Zucker rats.

Adiponectin protein expression was potently induced by the ARB irbesartan (2.7±0.2-fold induction vs. vehicle-treated cells, p<0.01). Irbesartan-mediated adiponectin upregulation started beyond the concentrations needed for AT1R blockade and was also present in the absence of AngII implicating an AT1R-independent mechanism of action. Recently, certain ARBs (irbesartan, telmisartan) were identified as partial agonists of the nuclear hormone receptor peroxisome proliferator-activated receptor gamma (PPARg). Telmisartan also stimulated adiponectin protein expression, whereas the non PPARg-activating ARB eprosartan had no effect. Blockade of PPARg activation by the PPARg antagonist GW9662 markedly inhibited irbesartan-induced adiponectin expression underscoring that adiponectin regulation results from PPARg activation. 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 prevented adiponectin serum depletion.

The present study demonstrates that PPARg-activating ARBs induce adiponectin protein expression at a posttranscriptional level, independently of their AT1R-blocking properties. Accordingly, the PPARg-activating ARB irbesartan improved parameters of insulin sensitivity in obese Zucker rats which was associated with the prevention of adiponectin serum depletion.