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1 Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA
2 Ste-Justine Hospital, University of Montreal, Montreal, Canada
3 CHUM, University of Montreal, Montreal, Canada
4 Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA; Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT, USA; Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT, USA
* To whom correspondence should be addressed. E-mail: jason.k.kim{at}yale.edu.
Insulin resistance in skeletal muscle and heart plays a major role in the development of type 2 diabetes and diabetic heart failure and may be causally associated with altered lipid metabolism. Hormone sensitive lipase (HSL) is a rate-determining enzyme in the hydrolysis of triacylglycerol in adipocytes, and HSL-deficient mice have reduced circulating fatty acids and are resistant to diet-induced obesity. In order to determine the metabolic role of HSL, we examined the changes in tissue-specific insulin action and glucose metabolism in vivo during hyperinsulinemic-euglycemic clamps following 3 weeks of high fat or normal chow diet in awake HSL-deficient (HSL KO) mice. On normal diet, HSL KO mice showed a 2-fold increase in hepatic insulin action but a 40% decrease in insulin-stimulated cardiac glucose uptake as compared to the wild-type littermates. High fat feeding caused a similar increase in whole body fat mass in both groups of mice. Insulin-stimulated glucose uptake was reduced by 50~80% in skeletal muscle and heart of wild-type mice following high fat feeding. In contrast, HSL KO mice were protected from diet-induced insulin resistance in skeletal muscle and heart, and these effects were associated with reduced intramuscular triglyceride and fatty acyl CoAs levels in the fat-fed HSL KO mice. Overall, these findings demonstrate the important role of HSL on skeletal muscle, heart, and liver glucose metabolism.
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