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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Background/Aims: Previous results on the association between MTR gene A2756G polymorphism and PCa risk are inconclusive.Methods: We used odds ratios (ORs) with corresponding 95% confidence intervals (95% CIs) to evaluate the correlation between MTR A2756G polymorphism and risk of PCa in meta-analysis. Serum expression of MTR was detected by ELISA and in-silico tools were utilized to assess this variant.Results: Our study included 2,921 PCa patients and 3,095 control subjects. The results indicated that the MTR A2756G polymorphism is linked with an increased risk of PCa using three genetic models (G-allele vs. A-allele: OR = 1.16, 95%CI = 1.04 - 1.30; GA vs. AA: OR = 1.17, 95%CI = 1.02 - 1.33; GG+GA vs. AA: OR = 1.18, 95%CI = 1.04 - 1.34). Stratified analysis produced similar results. A significant association was also indicated in advanced PCa from the meta-analysis. Finally, our experiments showed evidence that serum MTR levels in PCa patients with AA genotypes were statistically higher than in those with GG/GA genotypes.Conclusions: Our present study suggests that the MTR A2756G polymorphism may contribute to the risk of developing PCa, particularly in Asian and hospital-based studies. Moreover, serum MTR might be utilized in diagnosis of PCa.

N6-methyladenosine (m6A), the most abundant internal modification in eukaryotic mRNA, is installed by a multi-component writer complex; however, the exact roles of each component remain poorly understood. Here we show that a potential E3 ubiquitin ligase Hakai colocalizes and interacts with other m6A writer components, and Hakai mutants exhibit typical m6A pathway defects in Drosophila, such as lowered m6A levels in mRNA, aberrant Sxl alternative splicing, wing and behavior defects. Hakai, Vir, Fl(2)d and Flacc form a stable complex, and disruption of either Hakai, Vir or Fl(2)d led to the degradation of the other three components. Furthermore, MeRIP-seq indicates that the effective m6A modification is mostly distributed in 5’ UTRs in Drosophila, in contrast to the mammalian system. Interestingly, we demonstrate that m6A modification is deposited onto the Sxl mRNA in a sex-specific fashion, which depends on the m6A writer. Together, our work not only advances the understanding of mechanism and regulation of the m6A writer complex, but also provides insights into how Sxl cooperate with the m6A pathway to control its own splicing.