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

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.

• Authors: Asuka Shiota, Michio Shimabukuro, Daiju Fukuda, Takeshi Soeki, Hiromi Sato, Etsuko Uematsu, Yoichiro Hirata, Hirotsugu Kurobe, Norikazu Maeda, Hiroshi Sakaue, Hiroaki Masuzaki, Iichiro Shimomura, Masataka Sata
• Journal: Cardiovascular diabetology (Cardiovasc Diabetol) Vol. 11 Pg. 139 (Nov 08 2012) ISSN: 1475-2840 [Electronic] England
• PMID: 23137106 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 2-chloro-5-nitrobenzanilide
• Angiotensin II Type 1 Receptor Blockers
• Anilides
• Benzimidazoles
• Benzoates
• Fatty Acid Transport Proteins
• Glucose Transporter Type 4
• Insulin
• PPAR gamma
• Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
• Ppargc1a protein, mouse
• RNA, Messenger
• Slc27a1 protein, mouse
• Slc2a4 protein, mouse
• Trans-Activators
• Transcription Factors
• NAD
• AMP-Activated Protein Kinases
• Sirt1 protein, mouse
• Sirtuin 1
• Telmisartan

Topics

• AMP-Activated Protein Kinases (metabolism)
• Adipocytes (drug effects, metabolism, pathology)
• Administration, Oral
• Angiotensin II Type 1 Receptor Blockers (administration & dosage, pharmacology)
• Anilides (pharmacology)
• Animals
• Benzimidazoles (administration & dosage, pharmacology)
• Benzoates (administration & dosage, pharmacology)
• Cell Line
• Diabetes Mellitus (drug therapy, enzymology, genetics, pathology)
• Diet, High-Fat
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Enzyme Activation
• Fatty Acid Transport Proteins (genetics, metabolism)
• Glucose Transporter Type 4 (genetics, metabolism)
• Hypertrophy
• Insulin (metabolism)
• Islets of Langerhans (drug effects, metabolism, pathology)
• Male
• Mice
• Muscle Fibers, Skeletal (drug effects, enzymology)
• Muscle, Skeletal (drug effects, enzymology)
• NAD (metabolism)
• Obesity (drug therapy, enzymology, genetics, pathology)
• PPAR gamma (antagonists & inhibitors, metabolism)
• Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
• Phosphorylation
• RNA, Messenger (metabolism)
• Signal Transduction (drug effects)
• Sirtuin 1 (genetics, metabolism)
• Telmisartan
• Time Factors
• Trans-Activators (genetics, metabolism)
• Transcription Factors