Activation of AMPK-Sirt1 pathway by telmisartan in white adipose tissue: A possible link to anti-metabolic effects

Telmisartan exerts anti-metabolic effects beyond its angiotensin receptor blockade activities, but the mechanisms have hitherto remained elusive. We sought to elucidate the peroxisome proliferator-activated receptor-gamma (PPAR-gamma)-dependent and PPAR-gamma-independent mechanisms underlying the anti-metabolic effects of telmisartan in white adipose tissue. Nine-week-old male C57BL16 mice were fed with a 60% high-fat diet for 6 weeks, with 1 mg/kg telmisartan or vehicle administrated orally during the last 3 weeks. 3T3-L1 adipocytes were cultured with telmisartan either with 2-chloro-5-nitro-N-phenylbenzamide (GW9662), a selective irreversible antagonist of PPAR-gamma, or compound C, an ATP-competitive inhibitor of AMPK. Western blotting and semiquantitative RT-PCR analysis were used to assess adiponectin, Sirt1, and AMPK levels. Lipid accumulation was assessed by Oil red 0 staining. The activation of transcription factor PPAR-gamma 2 was evaluated by using a luciferase reporter assay for mPPAR-gamma 2 expression plasmid vector. Treatment with telmisartan increased serum adiponectin levels in high-fat diet-fed mice concomitantly with an upregulation of adiponectin mRNA in visceral adipose tissue. In vitro telmisartan treatment dose-dependently increased adiponectin mRNA in 3T3-L1 cells; the increase was inhibited by compound C, but not by GW9662. Telmisartan increased expression of Sirt1 mRNA and Sirt1 protein as well as the phosphorylation of AMPK in 3T3-L1 cells. Telmisartan can increase adiponectin production in white adipose tissue partly via a PPAR-gamma 2-independent mechanism. Precise understanding of this molecular mechanism will require further investigation. (C) 2012 Elsevier B.V All rights reserved.