Potential mechanisms and consequences of cardiac triacylglycerol accumulation in insulin-resistant rats.
The accumulation of intracellular triacylglycerol (TG) is highly correlated with muscle insulin resistance. However, it is controversial whether the accumulation of TG is the result of increased fatty acid supply, decreased fatty acid oxidation, or both. Because abnormal fatty acid metabolism is a key contributor to the pathogenesis of diabetes-related cardiovascular dysfunction, we examined fatty acid and glucose metabolism in hearts of insulin-resistant JCR:LA-cp rats. Isolated working hearts from insulin-resistant rats had glycolytic rates that were reduced to 50% of lean control levels (P < 0.05). Cardiac TG content was increased by 50% (P < 0.05) in the insulin-resistant rats, but palmitate oxidation rates remained similar between the insulin-resistant and lean control rats. However, plasma fatty acids and TG levels, as well as cardiac fatty acid-binding protein (FABP) expression, were significantly increased in the insulin-resistant rats. AMP-activated protein kinase (AMPK) plays a major role in the regulation of cardiac fatty acid and glucose metabolism. When activated, AMPK increases fatty acid oxidation by inhibiting acetyl-CoA carboxylase (ACC) and reducing malonyl-CoA levels, and it decreases TG content by inhibiting glycerol-3-phosphate acyltransferase (GPAT), the rate-limiting step in TG synthesis. The activation of AMPK also stimulates cardiac glucose uptake and glycolysis. We thus investigated whether a decrease in AMPK activity was responsible for the reduced cardiac glycolysis and increased TG content in the insulin-resistant rats. However, we found no significant difference in AMPK activity. We also found no significant difference in various established downstream targets of AMPK: ACC activity, malonyl-CoA levels, carnitine palmitoyltransferase I activity, or GPAT activity. We conclude that hearts from insulin-resistant JCR:LA-cp rats accumulate substantial TG as a result of increased fatty acid supply rather than from reduced fatty acid oxidation. Furthermore, the accumulation of cardiac TG is associated with a reduction in insulin-stimulated glucose metabolism.
Atkinson
Laura L
LL
Cardiovascular Research Group, Department of Pediatrics, Faculty of Medicine, The University of Alberta, Edmonton, Alberta, Canada T6G 2S2.
Kozak
Ray
R
Kelly
Sandra E
SE
Onay Besikci
Arzu
A
Russell
James C
JC
Lopaschuk
Gary D
GD
D055372:AMP-Activated Protein Kinases; D000818:Animals; D005227:Fatty Acids / Q000378:metabolism; D006019:Glycolysis; D006321:Heart / Q000502:physiology; D066298:In Vitro Techniques; D007333:Insulin Resistance / Q000502:physiology*; D008297:Male; D009097:Multienzyme Complexes / Q000502:physiology; D009206:Myocardium / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D051381:Rats; D014280:Triglycerides / Q000378:metabolism*
D005227:Fatty Acids; D009097:Multienzyme Complexes; D014280:Triglycerides; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases