TY - JOUR
T1 - High-fat diet-induced upregulation of exosomal phosphatidylcholine contributes to insulin resistance
AU - Kumar, Anil
AU - Sundaram, Kumaran
AU - Mu, Jingyao
AU - Dryden, Gerald W.
AU - Sriwastva, Mukesh K.
AU - Lei, Chao
AU - Zhang, Lifeng
AU - Qiu, Xiaolan
AU - Xu, Fangyi
AU - Yan, Jun
AU - Zhang, Xiang
AU - Park, Juw Won
AU - Merchant, Michael L.
AU - Bohler, Henry C.L.
AU - Wang, Baomei
AU - Zhang, Shuangqin
AU - Qin, Chao
AU - Xu, Ziying
AU - Han, Xianlin
AU - McClain, Craig J.
AU - Teng, Yun
AU - Zhang, Huang Ge
N1 - Funding Information:
We thank Dr. D. Wilkey for mass spectrometry analysis, Dr. Xandra O. Breakefield (Department of Neurology, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA) for providing lentivirus vectors expressing GFP, Dr. Jongsook Kim Kemper (University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA) for providing pGL3B-PEMT-Luc, and Dr. J. Ainsworth for editorial assistance. We thank Penn Diabetes Research Center (Rodent Metabolic Phenotyping Core, University of Pennsylvania, PA 19104) for the CLAM assay. Funding: This work was supported by a grant from the National Institutes of Health (NIH) (R01AT008617). Huang-Ge Zhang is supported by a Research Career Scientist (RCS) Award and P20GM125504. M.M. and J.M are supported by P50 AA024337 and P20 GM113226. J.P. was supported by the National Institute of General Medical Sciences of the National Institutes of Health (NIH) grant P20GM103436.
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12/1
Y1 - 2021/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-020-20500-w
DO - 10.1038/s41467-020-20500-w
M3 - Article
C2 - 33431899
AN - SCOPUS:85099194832
SN - 2041-1723
VL - 12
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 213
ER -