Metformin promotes irisin release from murine skeletal muscle independently of AMP-activated protein kinase activation.
OBJECTIVE
Irisin, a novel myocyte-secreted hormone mediating beneficial effects of exercise on metabolism, is supposed to be an ideal therapeutic target for metabolic disorders such as obesity and diabetes. Here, we investigated the potential effects of metformin and glibenclamide, two antidiabetic medicines, on irisin release in mouse.


METHODS
Wild-type and diabetic obese db/db mice were administrated with metformin and glibenclamide for 2 weeks, and cultured C2C12 myotubes were treated by metformin. Expression of irisin precursor FNDC5 was measured and blood irisin concentration was detected. AMP-activated protein kinase (AMPK) was blocked by chemical inhibitor compound C or knocking down with specific siRNA.


RESULTS
The mRNA and protein expression of FNDC5 in skeletal muscle and blood irisin concentrations were lower in diabetic db/db mice than those in wild-type mice. Metformin and glibenclamide decreased blood glucose in db/db mice. Metformin, but not glibenclamide, increased intramuscular FNDC5 mRNA/protein expression and blood irisin levels. Additionally, the reductions of blood glucose and body weight in metformin-treated db/db mice were positively associated with blood irisin concentrations. In C2C12 myotubes, metformin upregulated intracellular FDNC5 mRNA/protein expression and promoted irisin release. Although metformin activated AMPK signalling in skeletal muscle cells, disrupting of AMPK signalling by chemical inhibitor or siRNA-mediated knockdown did not abolish the promoting effect of metformin on irisin release.


CONCLUSIONS
Metformin promotes irisin release from murine skeletal muscle into blood, independently of AMPK pathway activation. Our results suggest that stimulation of irisin may be a novel molecular mechanism of metformin which is widely used for treatment of metabolic disorders.
Department of Pharmacy, Shanghai Tenth People's Hospital, Tongji University, Shanghai, China.
D-J
DJ
Li
F
F
Huang
W-J
WJ
Lu
G-J
GJ
Jiang
Y-P
YP
Deng
F-M
FM
Shen
D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D015415:Biomarkers / Q000097:blood; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000201:enzymology; D004195:Disease Models, Animal; D004789:Enzyme Activation; D005353:Fibronectins / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D005905:Glyburide / Q000494:pharmacology; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D008297:Male; D008687:Metformin / Q000494:pharmacology*; D051379:Mice; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000201:enzymology; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000201:enzymology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014162:Transfection; D015854:Up-Regulation
D015415:Biomarkers; D001786:Blood Glucose; C571428:FNDC5 protein, mouse; D005353:Fibronectins; D007004:Hypoglycemic Agents; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D008687:Metformin; D055372:AMP-Activated Protein Kinases; D005905:Glyburide
AMP-activated protein kinase; body weight; diabetes; irisin; metformin; skeletal muscle