Insulin inhibition of 5' adenosine monophosphate-activated protein kinase in the heart results in activation of acetyl coenzyme A carboxylase and inhibition of fatty acid oxidation.
Acetyl coenzyme A (CoA) carboxylase (ACC) is an important regulator of fatty acid oxidation in the heart, since it produces malonyl CoA, a potent inhibitor of mitochondrial fatty acid uptake. Under conditions of metabolic stress, 5'adenosine monophosphate-activated protein kinase (AMPK), which is highly expressed in cardiac muscle, can phosphorylate and decrease ACC activity. In this study, we determined if fatty acid oxidation in the heart could be regulated by insulin, due to alterations in AMPK regulation of ACC activity. Isolated working rat hearts were perfused with Krebs-Henseleit solution containing 11 mmol/L glucose, 0.4 mmol/L [9,10(-3)H]palmitate, and either 100 microU/mL insulin or 1,000 microU/mL insulin. Increasing insulin concentration resulted in a decrease in fatty acid oxidation rates (P < .05), a decrease in AMPK activity (P < .05), and an increase in ACC activity (P < .05) compared with the low-insulin group. A negative correlation was observed between AMPK and ACC activity (r = -.76). We conclude that insulin, acting through inhibition of AMPK and stimulation of ACC, is capable of inhibiting myocardial fatty acid oxidation.
Gamble
J
J
Department of Pediatrics, University of Alberta, Edmonton, Canada.
Lopaschuk
G D
GD
D055372:AMP-Activated Protein Kinases; D000103:Acetyl-CoA Carboxylase / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D004789:Enzyme Activation / Q000187:drug effects; D007328:Insulin / Q000494:pharmacology*; D008297:Male; D009097:Multienzyme Complexes / Q000187:drug effects / Q000378:metabolism*; D009206:Myocardium / Q000166:cytology / Q000201:enzymology* / Q000378:metabolism; D009924:Organ Culture Techniques; D010084:Oxidation-Reduction; D010168:Palmitates / Q000378:metabolism*; D010477:Perfusion; D011494:Protein Kinases / Q000187:drug effects / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases; D051381:Rats; D017207:Rats, Sprague-Dawley
D007328:Insulin; D009097:Multienzyme Complexes; D010168:Palmitates; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D000103:Acetyl-CoA Carboxylase