Telmisartan ameliorates insulin sensitivity by activating the AMPK/SIRT1 pathway in skeletal muscle of obese db/db mice

Cardiovascular Diabetology

Original Investigation

Michio Shimabukuro¹  Asuka Shiota¹  Daiju Fukuda¹  Yoichiro Hirata²  Masataka Sata²  Etsuko Uematsu²  Takeshi Soeki²  Hirotsugu Kurobe³  Norikazu Maeda⁴  Iichiro Shimomura⁴  Hiroshi Sakaue⁵  Hiromi Sato⁵  Hiroaki Masuzaki⁶ 

[1] Department of Cardio-Diabetes Medicine, University of Tokushima Graduate School of Health Biosciences, 3-18-15 Kuramoto, 770-8503, Tokushima, Japan;Department of Cardiovascular Medicine, University of Tokushima Graduate School of Health Biosciences, Tokushima, Japan;Department of Cardiovascular Medicine, University of Tokushima Graduate School of Health Biosciences, Tokushima, Japan;Department of Cardiovascular Surgery, University of Tokushima Graduate School of Health Biosciences, Tokushima, Japan;Department of Metabolic Medicine, Osaka University Graduate School of Medicine, Osaka, Japan;Department of Nutrition and Metabolism, University of Tokushima Graduate School of Health Biosciences, Tokushima, Japan;Division of Endocrinology, Diabetes and Metabolism, Hematology, Rheumatology, Second Department of Internal Medicine, University of the Ryukyus, Graduate School of Medicine, Okinawa, Japan;

关键词: Adiponectin;    AMP-activated protein kinase;    Obesity;    Peroxisome proliferator-activated receptor-γ;    SIRT1;   

DOI  :  10.1186/1475-2840-11-139

 received in 2012-08-29, accepted in 2012-10-18,  发布年份 2012

来源: Springer

【 摘 要 】

BackgroundTelmisartan is a well-established angiotensin II type 1 receptor blocker that improves insulin sensitivity in animal models of obesity and insulin resistance, as well as in humans. Telmisartan has been reported to function as a partial agonist of the peroxisome proliferator-activated receptor (PPAR) γ, which is also targeted by the nicotinamide adenine dinucleotide (NAD)-dependent deacetylase (SIRT1). Here, we investigated the pathways through which telmisartan acts on skeletal muscle, in vitro as well as in vivo.MethodsNine-week-old male db/db mice were fed a 60% high-fat diet, with orally administrated either vehicle (carboxymethyl-cellulose, CMC), 5 mg/kg telmisartan, or 5 mg/kg telmisartan and 1 mg/kg GW9662, a selective irreversible antagonist of PPARγ, for 5 weeks. Effects of telmisartan on Sirt1 mRNA, AMPK phosphorylation, and NAD+/NADH ratio were determined in C2C12 cultured myocytes.Results and discussionTelmisartan treatment improved insulin sensitivity in obese db/db mice fed a high-fat diet and led to reduction in the size of hypertrophic pancreatic islets in these mice. Moreover, in vitro treatment with telmisartan led to increased expression of Sirt1 mRNA in C2C12 skeletal muscle cells; the increase in Sirt1 mRNA in telmisartan-treated C2C12 myoblasts occurred concomitantly with an increase in AMPK phosphorylation, an increase in NAD+/NADH ratio, and increases in the mRNA levels of PGC1α, FATP1, ACO, and GLUT4.ConclusionsOur results indicate that telmisartan acts through a PPARγ-independent pathway, but at least partially exerts its effects by acting directly on skeletal muscle AMPK/SIRT1 pathways.

【 授权许可】

Unknown   
© Shiota et al.; licensee BioMed Central Ltd. 2012. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.