Exosomal transfer of obesity adipose tissue for decreased miR-141-3p mediate insulin resistance of hepatocytes

Abstract

Exosomes, the nano-vesicles released from living cells, were the important mediator for cell-to-cell communication. In order to clarify whether the exosomes derived from obesity adipose tissue mediate insulin resistance of hepatocytes, we extract the exosomes from the adipose tissue of different mice models. Exosomes derived from ob/ob mice (Ob-exosomes), B6 mice fed with a high-fat diet (HFD-exosomes) and normal B6 mice (WT-exosomes) displayed similar size and molecular makers, but their effect on the insulin sensitivity of hepatocytes were obviously different or opposite. Abundant exosomal miRNAs in Ob-, HFD- and WT-exosomes were detected by the Next Generation Sequencing. The levels of miR-141-3p in Ob- and HFD-exosomes were significantly lower than WT-exosomes. MiR-141-3p can be effectively delivered into AML12 cells accompanied by the absorption of exosomes, but the absorption of miR-141-3p into AML12 cells could be blocked by GW4869, an inhibitor of exosome biogenesis and release. Importantly, the Ob-exosomes or miR-141-3p knockdown in WT--exosomes obviously inhibited the insulin response and glucose uptake of AML12 cells, however, the inhibitory effects on insulin function disappeared after the overexpression of miR-141-3p in Ob-exosomes or AML12 cells. The effects of miR-141-3p on insulin function could be achieved by improving the level of phosphorylation of AKT and enhancing insulin signal transduction. Therefore, the absorption of hepatocytes for exosomes released from obesity adipose tissue containing less miR-141-3p than healthy adipose tissue can significantly inhibit the insulin sensitivity and glucose uptake. Our study may certify a novel mechanism that the secretion of “harmful” exosomes from obesity adipose tissues cause insulin resistance.

The Effects of Type 2 Diabetes Mellitus on Organ Metabolism and the Immune System

“…In some cases, NAFLD may progress into an aggressive form of inflammatory fatty liver disease called non-alcoholic steatohepatitis (NASH), which might cause liver cirrhosis and organ failure ( 106 ). Dang et al have indicated that exosomes released from the adipose tissues of obese mice due to the smaller miR-141-3p content can promote insulin resistance in the murine hepatocyte cell line AML12 (alpha mouse liver 12) ( 107 ). The adipokine visfatin that is released from the adipose tissue of obese individuals has also been shown to activate the pro-inflammatory STAT3 signaling pathway and NF-κB in the human liver cell line HepG2 and promote their insulin resistant state ( 108 ).…”

miRNAs in Adipocyte-Derived Extracellular Vesicles: Multiple Roles in Development of Obesity-Associated Disease

“…miR-141-3p expression was decreased in AML12 cells co-cultured with exosomes from obese mice in vitro, and in liver tissue of obese mice. Furthermore, this study showed that exosomes released from obese adipose tissue transferred less miR-141-3p into hepatocytes than exosomes from lean adipose tissue, which resulted in inhibition of hepatocyte glucose uptake and induction of insulin resistance (Dang et al, 2019). Yu et al showed that miR-27a expression was increased in visceral adipose tissue of mice fed a high-fat diet.…”

“…Multiple reports have implicated EVs as a vehicle transferring miRNAs between cells (Dang et al, 2019;Li et al, 2019). Studies have shown that metabolic diseases affect the total amount of vesicle-transported miRNAs in circulation.…”

Extracellular Vesicles in the Development of the Non-Alcoholic Fatty Liver Disease: An Update

“…One example is miR-141-3p, which was significantly reduced in obese adipocyte-EVs [40]. MiR-141-3p is responsible for the normal phosphorylation of AKT upon the insulin stimulation; thus, the low level of miR-141-3p may explain the impaired insulin signaling and glucose uptake in the hepatocytes [40]. These previous findings suggest that adipocyte-EVs may influence other cell types based on the status of the adipocytes.…”

“…The effects of adipocyte-EVs on hepatocytes are partly due to the microRNAs residing in the adipocyte-EVs cargo. One example is miR-141-3p, which was significantly reduced in obese adipocyte-EVs [40]. MiR-141-3p is responsible for the normal phosphorylation of AKT upon the insulin stimulation; thus, the low level of miR-141-3p may explain the impaired insulin signaling and glucose uptake in the hepatocytes [40].…”