Short-term overnutrition induces white adipose tissue insulin resistance through sn-1,2-diacylglycerol/PKC epsilon/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-e (PKCe) activation to impair insulin signaling by phosphorylating insulin receptor (Insr) Thr1160. 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 PKCe activation, and impaired insulin-stimulated Insr Tyr1(162) phosphorylation. In order to examine the role of Insr Thr1(160) phosphorylation in mediating lipid-induced WAT IR, we examined these same parameters in InsrT1150A mice (mouse homolog for human Thr1160) and found that HFD feeding induced WAT IR in WT control mice but not in InsrT1150A mice. Taken together, these data demonstrate the importance of the PM sn-1,2-DAG/PKCe/Insr Thr1160 phosphorylation pathway in mediating lipid-induced WAT IR and represent a potential therapeutic target to improve WAT insulin sensitivity.

Automated summary

Short-term high-fat diet may cause WAT insulin resistance by promoting PM sn-1,2-DAG accumulation and activating PKCe, impairing insulin signaling. Experiments showed that HFD feeding led to WAT IR, and Insr Thr1160 phosphorylation plays a crucial role in mediating lipid-induced WAT IR.