Journal Article

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

Park, Juw Won, Zhang, Shuangqin, Teng, Yun, Zhang, Huang-Ge, Mu, Jingyao, Zhang, Lifeng, Bohler, Henry C. L., McClain, Craig J., Xu, Fangyi, Zhang, Xiang, Dryden, Gerald W., Qiu, Xiaolan, Qin, Chao, Lei, Chao, Sriwastva, Mukesh K., Han, Xianlin, Kumar, Anil, Yan, Jun, Wang, Baomei, Xu, Ziying, Sundaram, Kumaran, Merchant, Michael L.

2021

Overview

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. High-fat diet plays a role in development of insulin resistance. Here, the authors report a mechanism that underlies the development of diet induced insulin resistance through the activation of an aryl hydrocarbon receptor mediated signalling pathway in the liver by faecal exosomes derived from intestinal cells.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 1-Phosphatidylinositol 3-kinase / 38/39 / 38/61 / 38/91 / 692/4017 / 692/4020/4021 / 692/699/2743/2037 / 96 / 96/21 / Adipose Tissue - metabolism / AKT protein / Animals / Aromatic compounds / Diabetes mellitus / Diabetes Mellitus, Type 2 - metabolism / Diabetes Mellitus, Type 2 - pathology / Diet / Diet, High-Fat / Dyslipidemias - complications / Dyslipidemias - genetics / Dyslipidemias - pathology / Epithelial Cells - metabolism / Exosomes / Exosomes - metabolism / Fatty Liver - complications / Fatty Liver - genetics / Fatty Liver - pathology / Feces / Gene expression / Gene Expression Regulation / Genes / Glucose Intolerance / Green Fluorescent Proteins - metabolism / Hepatocytes / High fat diet / Humanities and Social Sciences / Humans / Insulin / Insulin - metabolism / Insulin resistance / Insulin Resistance - genetics / Interleukin-6 - blood / Intestine / Intestines - cytology / Lecithin / Lipid composition / Lipids / Lipids - chemistry / Liver - metabolism / Liver - pathology / Macrophage Activation / Macrophages / Mice / Mice, Inbred C57BL / multidisciplinary / Phosphatidylcholine / Phosphatidylcholines - metabolism / Phosphatidylethanolamine / Receptors, Aryl Hydrocarbon - metabolism / Science / Science (multidisciplinary) / Signal Transduction / Signaling / Tetraspanin 30 - metabolism / Transcription activation / Tumor Necrosis Factor-alpha - blood / Up-Regulation - genetics