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High-fat diet-induced upregulation of exosomal phosphatidylcholine contributes to insulin resistance

Author

Listed:
  • Anil Kumar

    (University of Louisville)

  • Kumaran Sundaram

    (University of Louisville)

  • Jingyao Mu

    (University of Louisville)

  • Gerald W. Dryden

    (University of Louisville
    University of Louisville)

  • Mukesh K. Sriwastva

    (University of Louisville)

  • Chao Lei

    (University of Louisville)

  • Lifeng Zhang

    (University of Louisville)

  • Xiaolan Qiu

    (University of Louisville)

  • Fangyi Xu

    (University of Louisville)

  • Jun Yan

    (University of Louisville)

  • Xiang Zhang

    (University of Louisville)

  • Juw Won Park

    (University of Louisville
    University of Louisville)

  • Michael L. Merchant

    (University of Louisville)

  • Henry C. L. Bohler

    (University of Louisville)

  • Baomei Wang

    (University of Pennsylvania)

  • Shuangqin Zhang

    (Peeples Cancer Institute)

  • Chao Qin

    (University of Texas Health Science Center at San Antonio)

  • Ziying Xu

    (University of Texas Health Science Center at San Antonio)

  • Xianlin Han

    (University of Texas Health Science Center at San Antonio)

  • Craig J. McClain

    (University of Louisville)

  • Yun Teng

    (University of Louisville)

  • Huang-Ge Zhang

    (University of Louisville
    Robley Rex Veterans Affairs Medical Center)

Abstract

High-fat diet (HFD) decreases insulin sensitivity. How high-fat diet causes insulin resistance is largely unknown. Here, we show that lean mice become insulin resistant after being administered exosomes isolated from the feces of obese mice fed a HFD or from patients with type II diabetes. HFD altered the lipid composition of exosomes from predominantly phosphatidylethanolamine (PE) in exosomes from lean animals (L-Exo) to phosphatidylcholine (PC) in exosomes from obese animals (H-Exo). Mechanistically, we show that intestinal H-Exo is taken up by macrophages and hepatocytes, leading to inhibition of the insulin signaling pathway. Moreover, exosome-derived PC binds to and activates AhR, leading to inhibition of the expression of genes essential for activation of the insulin signaling pathway, including IRS-2, and its downstream genes PI3K and Akt. Together, our results reveal HFD-induced exosomes as potential contributors to the development of insulin resistance. Intestinal exosomes thus have potential as broad therapeutic targets.

Suggested Citation

  • Anil Kumar & Kumaran Sundaram & Jingyao Mu & Gerald W. Dryden & Mukesh K. Sriwastva & Chao Lei & Lifeng Zhang & Xiaolan Qiu & Fangyi Xu & Jun Yan & Xiang Zhang & Juw Won Park & Michael L. Merchant & H, 2021. "High-fat diet-induced upregulation of exosomal phosphatidylcholine contributes to insulin resistance," Nature Communications, Nature, vol. 12(1), pages 1-21, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-020-20500-w
    DOI: 10.1038/s41467-020-20500-w
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    Cited by:

    1. Daewon Lee & Eunju Yoon & Su Jin Ham & Kunwoo Lee & Hansaem Jang & Daihn Woo & Da Hyun Lee & Sehyeon Kim & Sekyu Choi & Jongkyeong Chung, 2024. "Diabetic sensory neuropathy and insulin resistance are induced by loss of UCHL1 in Drosophila," Nature Communications, Nature, vol. 15(1), pages 1-22, December.

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