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ResearchIn-Press PreviewEndocrinologyMetabolism Open Access | 10.1172/jci.insight.139946

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

1Department of Internal Medicine, Yale School of Medicine, New Haven, United States of America

2Department of Cellular and Molecular Physiology, Yale School of Medicine, New Haven, United States of America

Find articles by Lyu, K. in: JCI | PubMed | Google Scholar |

1Department of Internal Medicine, Yale School of Medicine, New Haven, United States of America

2Department of Cellular and Molecular Physiology, Yale School of Medicine, New Haven, United States of America

Find articles by Zhang, D. in: JCI | PubMed | Google Scholar

1Department of Internal Medicine, Yale School of Medicine, New Haven, United States of America

2Department of Cellular and Molecular Physiology, Yale School of Medicine, New Haven, United States of America

Find articles by Song, J. in: JCI | PubMed | Google Scholar |

1Department of Internal Medicine, Yale School of Medicine, New Haven, United States of America

2Department of Cellular and Molecular Physiology, Yale School of Medicine, New Haven, United States of America

Find articles by Li, X. in: JCI | PubMed | Google Scholar |

1Department of Internal Medicine, Yale School of Medicine, New Haven, United States of America

2Department of Cellular and Molecular Physiology, Yale School of Medicine, New Haven, United States of America

Find articles by Perry, R. in: JCI | PubMed | Google Scholar |

1Department of Internal Medicine, Yale School of Medicine, New Haven, United States of America

2Department of Cellular and Molecular Physiology, Yale School of Medicine, New Haven, United States of America

Find articles by Samuel, V. in: JCI | PubMed | Google Scholar |

1Department of Internal Medicine, Yale School of Medicine, New Haven, United States of America

2Department of Cellular and Molecular Physiology, Yale School of Medicine, New Haven, United States of America

Find articles by Shulman, G. in: JCI | PubMed | Google Scholar |

Published January 7, 2021 - More info

JCI Insight. https://doi.org/10.1172/jci.insight.139946.
Copyright © 2021, Lyu et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published January 7, 2021 - Version history
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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 InsrY1162 phosphorylation. In order to examine the role of InsrT1160 phosphorylation 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 - InsrT1160 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.

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