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.

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, 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