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Articles in PresS, published online ahead of print December 3, 2002
Am J Physiol Endocrinol Metab, 10.1152/ajpendo.00360.2002
Submitted on August 14, 2002
Accepted on November 25, 2002
1 Cardiovascular Research Group, University of Alberta, Faculty of Medicine, Edmonton, AB, Canada; Department of Pediatrics, University of Alberta, Faculty of Medicine, Edmonton, AB, Canada
2 Cardiovascular Research Group, University of Alberta, Faculty of Medicine, Edmonton, AB, Canada
3 Department of Surgery, University of Alberta, Faculty of Medicine, Edmonton, AB, Canada
* To whom correspondence should be addressed. E-mail: gary.lopaschuk{at}ualberta.ca.
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. Since 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) protein 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 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, CPT-1 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 reduced fatty acid oxidation. Furthermore, the accumulation of cardiac TG is associated with a reduction in insulin-stimulated glucose metabolism.
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