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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.
Highlights
Our studies revealed that a High-fat diet (HFD) dramatically changes the lipid profile of intestinal epithelial exosomes from predominantly phosphatidylethanolamine (PE) to phosphatidylcholine (PC), which results in inhibition of the insulin response via binding of exosomal PC to aryl hydrocarbon receptor (AhR) expressed in hepatocytes and suppression of genes essential for activation of the insulin pathway
No inhibition of glucose uptake was observed in IRS-2 overexpressed in hepatocytes, adipocytes, or mouse muscular cells treated with extracts from the liver, adipose tissue, or muscular tissue of mice treated with H-Exo compared with L-Exo or phosphate-buffered saline (PBS) treatment (Fig. 6h, i)
In this study, we demonstrated that an HFD affects the composition of intestinal epithelial exosomes, an understudied intestinal
Summary
Western blot analysis indicated that over the time course of 3, 6, and 12 months of feeding on their respective diets, the levels of PEMT increased in intestinal tissue and liver of HFD mice compared to RCD mice (Supplementary Fig. 3d, e, respectively). While the effects were not as pronounced as those observed after H-Exo treatment, GTT and ITT results suggested that mice that received T2D-Exo developed glucose intolerance and insulin resistance (Fig. 2j).
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