Valsartan ameliorates the constitutive adipokine expression pattern in mature adipocytes: a role for inverse agonism of the angiotensin II type 1 receptor in obesity

Angiotensin (Ang) II receptor blockers (ARBs) alleviate obesity-related insulin resistance, which suggests an important role for the Ang II type 1 receptor (AT1R) in the regulation of adipocytokines. Therefore, we treated mature 3T3-L1 adipocytes with 50 mu mol l(-1) of valsartan, a selective AT1R blocker without direct agonism to peroxisome proliferator-activated receptor (PPAR)-gamma. In the absence of effective concentrations of Ang II, unstimulated mature adipocytes expressed and secreted high levels of interleukin (IL)-6. This constitutive proinflammatory activity was attenuated by the suppression of extracellular signal-regulated kinase phosphorylation by valsartan but was unaffected by the Ang II type 2 receptor blocker PD123319. COS7 cells co-transfected with AT1R and IL-6, which expressed NF-kappa B but lacked PPAR-gamma, showed no constitutive but substantial ligand-dependent IL-6 reporter activity, which was counteracted by valsartan. Valsartan preserved cytosolic I kappa B-alpha and subsequently reduced nuclear NF-kappa B1 protein expression in mature adipocytes. Interestingly, valsartan did not increase PPAR-gamma messenger RNA expression per se but enhanced the transcriptional activity of PPAR-gamma in mature adipocytes; this enhancement was accompanied by upregulation of the PPAR coactivator (PGC)-1 alpha. Moreover, T0090907, a PPAR-gamma inhibitor, increased IL-6 expression, and this increase was attenuated by valsartan. Indeed, addition of valsartan without direct PPAR-gamma agonism increased adiponectin production in mature adipocytes. Together, the findings indicate that valsartan blocks the constitutive AT1R activity involving the NF-kappa B pathway that limits PPAR-gamma activity in mature adipocytes. Thus, inverse agonism of AT1R attenuates the spontaneous proinflammatory response and enhances the constitutive insulin-sensitizing activities of mature adipocytes, which may underlie the beneficial metabolic impacts of ARBs.