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; Huang-Ge Zhang

doi:10.1038/s41467-020-20500-w

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

Nat Commun. 2021 Jan 11;12(1):213. doi: 10.1038/s41467-020-20500-w.

Authors

Anil Kumar¹, Kumaran Sundaram¹, Jingyao Mu¹, Gerald W Dryden^{1

2}, Mukesh K Sriwastva¹, Chao Lei¹, Lifeng Zhang¹, Xiaolan Qiu¹, Fangyi Xu¹, Jun Yan¹, Xiang Zhang³, Juw Won Park^{4

5}, Michael L Merchant⁶, Henry C L Bohler⁷, Baomei Wang⁸, Shuangqin Zhang⁹, Chao Qin¹⁰, Ziying Xu¹⁰, Xianlin Han¹⁰, Craig J McClain², Yun Teng¹¹, Huang-Ge Zhang^{12

13}

Affiliations

¹ James Graham Brown Cancer Center, Department of Microbiology & Immunology, University of Louisville, Louisville, KY, 40202, USA.
² Department of Medicine, University of Louisville, Louisville, KY, 40202, USA.
³ Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY, 40202, USA.
⁴ Department of Computer Engineering and Computer Science, University of Louisville, Louisville, KY, 40202, USA.
⁵ KBRIN Bioinformatics Core, University of Louisville, Louisville, KY, 40202, USA.
⁶ Kidney Disease Program and Clinical Proteomics Center, University of Louisville, Louisville, KY, USA.
⁷ Department of Reproductive Endocrinology and Infertility, University of Louisville, Louisville, KY40202, USA.
⁸ Department of Dermatology, University of Pennsylvania, Philadelphia, 19104, USA.
⁹ Peeples Cancer Institute, 215 Memorial Drive, Dalton, GA, 30720, USA.
¹⁰ Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229, USA.
¹¹ James Graham Brown Cancer Center, Department of Microbiology & Immunology, University of Louisville, Louisville, KY, 40202, USA. [email protected].
¹² James Graham Brown Cancer Center, Department of Microbiology & Immunology, University of Louisville, Louisville, KY, 40202, USA. [email protected].
¹³ Robley Rex Veterans Affairs Medical Center, Louisville, KY, 40206, USA. [email protected].

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adipose Tissue / metabolism
Animals
Diabetes Mellitus, Type 2 / metabolism
Diabetes Mellitus, Type 2 / pathology
Diet, High-Fat*
Dyslipidemias / complications
Dyslipidemias / genetics
Dyslipidemias / pathology
Epithelial Cells / metabolism
Exosomes / metabolism*
Fatty Liver / complications
Fatty Liver / genetics
Fatty Liver / pathology
Feces
Gene Expression Regulation
Glucose Intolerance
Green Fluorescent Proteins / metabolism
Humans
Insulin / metabolism
Insulin Resistance / genetics*
Interleukin-6 / blood
Intestines / cytology
Lipids / chemistry
Liver / metabolism
Liver / pathology
Macrophage Activation
Mice
Mice, Inbred C57BL
Phosphatidylcholines / metabolism*
Receptors, Aryl Hydrocarbon / metabolism
Signal Transduction
Tetraspanin 30 / metabolism
Tumor Necrosis Factor-alpha / blood
Up-Regulation / genetics*

Substances

Insulin
Interleukin-6
Lipids
Phosphatidylcholines
Receptors, Aryl Hydrocarbon
Tetraspanin 30
Tumor Necrosis Factor-alpha
Green Fluorescent Proteins

Abstract

Publication types

MeSH terms

Substances

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