期刊
CARDIOVASCULAR DIABETOLOGY
卷 11, 期 -, 页码 -出版社
BIOMED CENTRAL LTD
DOI: 10.1186/1475-2840-11-139
关键词
Adiponectin; AMP-activated protein kinase; Obesity; Peroxisome proliferator-activated receptor-gamma; SIRT1
资金
- Ministry of Education, Culture, Sports, Science, and Technology
- Ministry of Health, Labor, and Welfare (MHLW)
- Joint Research Association for Japanese Diabetes
- Grants-in-Aid for Scientific Research [22390159, 24659392, 23591314, 22590979] Funding Source: KAKEN
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) gamma, 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 PPAR gamma, 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 PGC1 alpha, FATP1, ACO, and GLUT4. Conclusions: Our results indicate that telmisartan acts through a PPAR gamma-independent pathway, but at least partially exerts its effects by acting directly on skeletal muscle AMPK/SIRT1 pathways.
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