Lands cycle and skeletal muscle insulin action

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Project Summary Skeletal muscle insulin resistance is an early and fundamental defect in the development of type 2 diabetes. Molecular mechanisms by which obesity promotes muscle insulin resistance remain incompletely understood, but multiple lines of evidence suggest aberrant lipid metabolism as a likely contributor. Recently, our laboratory published findings that accelerated lyso-phospholipid metabolism (Lands cycle) desensitizes skeletal muscle insulin receptor to promote diabetes. In humans, obesity increased skeletal muscle lyso-phosphatidylcholine (lyso-PC) acyltransferase-3 (LPCAT3) and decreased lyso-PC concomitant to a decrease in insulin sensitivity. In mice, genetic or pharmacologic inhibition of LPCAT3 increased lyso-PC and enhanced skeletal muscle and systemic insulin sensitivity. In this proposal, we will further exploit skeletal muscle Lands cycle to understand its role in modulating insulin action. We hypothesize that: 1) Lands cycle modulates plasma membrane microdomain clustering to amplify insulin signaling, 2) pharmacological inhibition of Lands cycle can ameliorate hyperglycemia in the Zucker Diabetic Fatty rats, and 3) exercise training enhances skeletal muscle insulin responsiveness by deceleration of Lands cycle.