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Open Access Highly Accessed Original investigation

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

Asuka Shiota12, Michio Shimabukuro12*, Daiju Fukuda12, Takeshi Soeki2, Hiromi Sato3, Etsuko Uematsu2, Yoichiro Hirata2, Hirotsugu Kurobe4, Norikazu Maeda5, Hiroshi Sakaue3, Hiroaki Masuzaki6, Iichiro Shimomura5 and Masataka Sata2

Author Affiliations

1 Department of Cardio-Diabetes Medicine, University of Tokushima Graduate School of Health Biosciences, 3-18-15 Kuramoto, Tokushima, 770-8503, Japan

2 Department of Cardiovascular Medicine, University of Tokushima Graduate School of Health Biosciences, Tokushima, Japan

3 Department of Nutrition and Metabolism, University of Tokushima Graduate School of Health Biosciences, Tokushima, Japan

4 Department of Cardiovascular Surgery, University of Tokushima Graduate School of Health Biosciences, Tokushima, Japan

5 Department of Metabolic Medicine, Osaka University Graduate School of Medicine, Osaka, Japan

6 Division of Endocrinology, Diabetes and Metabolism, Hematology, Rheumatology, Second Department of Internal Medicine, University of the Ryukyus, Graduate School of Medicine, Okinawa, Japan

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Cardiovascular Diabetology 2012, 11:139  doi:10.1186/1475-2840-11-139

Published: 8 November 2012

Abstract

Background

Telmisartan 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.

Methods

Nine-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 discussion

Telmisartan 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.

Conclusions

Our 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.

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