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

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, Henry C. L. Bohler, Baomei Wang, Shuangqin Zhang, Chao Qin, Ziying Xu, Xianlin Han, Craig J. McClain, Yun Teng () and Huang-Ge Zhang ()
Additional contact information
Anil Kumar: University of Louisville
Kumaran Sundaram: University of Louisville
Jingyao Mu: University of Louisville
Gerald W. Dryden: 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
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

Nature Communications, 2021, vol. 12, issue 1, 1-21

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-020-20500-w

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