title: Activation of AMPK-Sirt1 pathway by telmisartan in white adipose tissue: A possible link to anti-metabolic effects.
abstract: 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-γ (PPAR-γ)-dependent and PPAR-γ-independent mechanisms underlying the anti-metabolic effects of telmisartan in white adipose tissue. Nine-week-old male C57BL/6 mice were fed with a 60% high-fat diet for 6 weeks, with 1mg/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-γ, 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 O staining. The activation of transcription factor PPAR-γ2 was evaluated by using a luciferase reporter assay for mPPAR-γ2 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-γ2-independent mechanism. Precise understanding of this molecular mechanism will require further investigation.
authors: Department of Cardio-Diabetes Medicine, The University of Tokushima Graduate School of Health Biosciences, 3-18-15 Kuramoto, Tokushima 770-8503, Japan.
authors: Asuka
authors: A
authors: Shiota
authors: Michio
authors: M
authors: Shimabukuro
authors: Daiju
authors: D
authors: Fukuda
authors: Takeshi
authors: T
authors: Soeki
authors: Hiromi
authors: H
authors: Sato
authors: Etsuko
authors: E
authors: Uematsu
authors: Yoichiro
authors: Y
authors: Hirata
authors: Hirotsugu
authors: H
authors: Kurobe
authors: Hiroshi
authors: H
authors: Sakaue
authors: Yutaka
authors: Y
authors: Nakaya
authors: Hiroaki
authors: H
authors: Masuzaki
authors: Masataka
authors: M
authors: Sata
mesh_terms: D041721:3T3-L1 Cells; D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D052242:Adiponectin / Q000097:blood / Q000235:genetics; D052436:Adipose Tissue, White / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology*; D001565:Benzoates / Q000494:pharmacology*; D017930:Genes, Reporter / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D050152:Intra-Abdominal Fat / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D050356:Lipid Metabolism / Q000187:drug effects; D008156:Luciferases / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D047495:PPAR gamma / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D056564:Sirtuin 1 / Q000378:metabolism*; D000077333:Telmisartan; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D052242:Adiponectin; D001562:Benzimidazoles; D001565:Benzoates; D047495:PPAR gamma; D008156:Luciferases; D055372:AMP-Activated Protein Kinases; D056564:Sirtuin 1; D000077333:Telmisartan