Short-term overnutrition induces white adipose tissue insulin resistance through <i>sn</i>-1,2-diacylglycerol – PKCε – insulin receptor<sup>T1160</sup> phosphorylation

Kun Lyu; Dongyan Zhang; Joongyu D. Song; Xiruo Li; Rachel J. Perry; Varman T. Samuel; Gerald I. Shulman

doi:10.1172/jci.insight.139946

Short-term overnutrition induces white adipose tissue insulin resistance through sn-1,2-diacylglycerol – PKCε – insulin receptor^T1160 phosphorylation

Kun Lyu,¹ Dongyan Zhang,¹ Joongyu D. Song,¹ Xiruo Li,² Rachel J. Perry,¹ Varman T. Samuel,¹ and Gerald I. Shulman¹

Published January 7, 2021 - More info

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Abstract

Insulin-mediated suppression of white adipose tissue (WAT) lipolysis is an important anabolic function that is dysregulated in states of overnutrition. However, the mechanism of short-term high-fat diet (HFD)-induced WAT insulin resistance is poorly understood. Based on our recent studies we hypothesize that a short-term HFD causes WAT insulin resistance through increases in plasma membrane (PM) sn-1,2-diacylglycerols (DAG), which promotes protein kinase C-ε (PKCε) 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 insulin resistance, reflected by reductions in both insulin-mediated WAT glucose uptake and suppression of WAT lipolysis. These changes were specifically associated with increased PM sn-1,2-diacylglycerol (DAG) content, increased PKCε activation and impaired insulin-stimulated Insr^Y1162 phosphorylation. In order to examine the role of Insr^T1160phosphorylation in mediating lipid-induced WAT insulin resistance, we examined these same parameters in short-term HFD-fed InsrT1150A knockin mice (mouse homolog for human Thr¹¹⁶⁰). Similar to the rat study HFD feeding induced WAT insulin resistance in WT control mice but failed to induce WAT insulin resistance in InsrT1150A mice. Taken together these data demonstrate that the PM sn-1,2-DAG - PKCε - Insr^T1160 phosphorylation pathway plays an important role in mediating lipid-induced WAT insulin resistance and represents a potential therapeutic target to improve insulin sensitivity in WAT.

Short-term overnutrition induces white adipose tissue insulin resistance through sn-1,2-diacylglycerol – PKCε – insulin receptor^T1160 phosphorylation

Kun Lyu,¹ Dongyan Zhang,¹ Joongyu D. Song,¹ Xiruo Li,² Rachel J. Perry,¹ Varman T. Samuel,¹ and Gerald I. Shulman¹

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Short-term overnutrition induces white adipose tissue insulin resistance through sn-1,2-diacylglycerol – PKCε – insulin receptorT1160 phosphorylation

Kun Lyu,1 Dongyan Zhang,1 Joongyu D. Song,1 Xiruo Li,2 Rachel J. Perry,1 Varman T. Samuel,1 and Gerald I. Shulman1

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Short-term overnutrition induces white adipose tissue insulin resistance through sn-1,2-diacylglycerol – PKCε – insulin receptor^T1160 phosphorylation

Kun Lyu,¹ Dongyan Zhang,¹ Joongyu D. Song,¹ Xiruo Li,² Rachel J. Perry,¹ Varman T. Samuel,¹ and Gerald I. Shulman¹