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Short-term overnutrition induces white adipose tissue insulin resistance through sn-1,2-diacylglycerol/PKCε/insulin receptor Thr1160 phosphorylation.

Citation
Lyu, K., et al. “Short-Term Overnutrition Induces White Adipose Tissue Insulin Resistance Through Sn-1,2-Diacylglycerol/Pkcε/Insulin Receptor Thr1160 Phosphorylation.”. Jci Insight.
Center Yale University
Author Kun Lyu, Dongyan Zhang, Joongyu Song, Xiruo Li, Rachel J Perry, Varman T Samuel, Gerald I Shulman
Keywords Adipose tissue, Endocrinology, glucose metabolism, Insulin Signaling, Metabolism
Abstract

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) 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 PKCε activation, and impaired insulin-stimulated Insr Tyr1162 phosphorylation. In order to examine the role of Insr Thr1160 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/PKCε/Insr Thr1160 phosphorylation pathway in mediating lipid-induced WAT IR and represent a potential therapeutic target to improve WAT insulin sensitivity.

Year of Publication
2021
Journal
JCI insight
Volume
6
Issue
4
Date Published
02/2021
ISSN Number
2379-3708
DOI
10.1172/jci.insight.139946
Alternate Journal
JCI Insight
PMID
33411692
PMCID
PMC7934919
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