Short-term overnutrition induces white adipose tissue insulin resistance through sn-1,2-diacylglycerol/PKCε/insulin receptor Thr(1160) phosphorylation

White adipose tissue (WAT) insulin action has critical anabolic function and is dysregulated in overnutrition. However, the mechanism of short-term high-fat diet–induced (HFD-induced) WAT insulin resistance (IR) is poorly understood. Based on recent evidences, we hypothesize that a short-term HFD causes WAT IR through plasma membrane (PM) sn-1,2-diacylglycerol (sn-1,2-DAG) accumulation, which promotes protein kinase C-ε (PKCε) activation to impair insulin signaling by phosphorylating insulin receptor (Insr) Thr(1160). To test this hypothesis, we assessed WAT insulin action in 7-day HFD–fed versus regular chow diet–fed rats during a hyperinsulinemic-euglycemic clamp. HFD feeding caused WAT IR, reflected by impaired insulin-mediated WAT glucose uptake and lipolysis suppression. These changes were specifically associated with PM sn-1,2-DAG accumulation, higher PKCε activation, and impaired insulin-stimulated Insr Tyr(1162) phosphorylation. In order to examine the role of Insr Thr(1160) phosphorylation in mediating lipid-induced WAT IR, we examined these same parameters in Insr(T1150A) mice (mouse homolog for human Thr(1160)) and found that HFD feeding induced WAT IR in WT control mice but not in Insr(T1150A) mice. Taken together, these data demonstrate the importance of the PM sn-1,2-DAG/PKCε/Insr Thr(1160) phosphorylation pathway in mediating lipid-induced WAT IR and represent a potential therapeutic target to improve WAT insulin sensitivity.