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. McClainYun Teng, Huang Ge Zhang

Research output: Contribution to journalArticlepeer-review

98 Scopus citations


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.

Original languageEnglish (US)
Article number213
JournalNature communications
Issue number1
StatePublished - Dec 1 2021

ASJC Scopus subject areas

  • Physics and Astronomy(all)
  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)


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