Treatment with EV-miRNAs Alleviates Obesity-Associated Metabolic Dysfunction in Mice

Abstract

Most cells release extracellular vesicles (EVs) that can be detected circulating in blood. We and others have shown that the microRNA contents of these vesicles induce transcriptomic changes in acceptor cells, contributing to the adjustment of metabolic homeostasis in response to environmental demands. Here, we explore the potential for modulating obesity- and exercise-derived EV-microRNAs to treat the metabolic dysfunction associated with obesity in mice. Treatment with EV-miRNAs alleviated glucose intolerance and insulin resistance in obese mice to an extent similar to that of high-intensity interval training, although only exercise improved cardiorespiratory fitness and decreased body weight. Mechanistically, EV-miRNAs decreased fatty acid and cholesterol biosynthesis pathways in the liver, reducing hepatic steatosis and increasing insulin sensitivity, resulting in decreased glycemia and triglyceridemia. Our data suggest that manipulation of EV-miRNAs may be a viable strategy to alleviate metabolic dysfunction in obese and diabetic patients who are unable to exercise, although actual physical activity is needed to improve cardiorespiratory fitness.

Lipids Metabolism and Cardiometabolic Diseases

“…Another miRNA, the miRNA-122, the most abundant liver-specific miRNA which protects against hepatic steatosis and inhibits cholesterol and fatty acid synthesis in NAFLD, was the focus of the study by Liu et al, whose results suggested that the serum levels of miRNA-122 gradually increased to the severity of the NAFLD, providing a new explanation for the pathogenesis of the hepatic lipid deposition in NAFLD, characterized by an increased miRNA-122 extra-hepatocyte excretion and the enhancement of the stability of the miRNA-122 related to its binding to circPI4KB [8]. Always in the miRNA field, Castano et al explore the potential for modulating obesity-and exercise-derived extracellular vesicles (EVs)-miRNA to treat the metabolic dysfunction associated with obesity in mice [9]. EV-miRNAs improve glucose intolerance and insulin resistance in obese mice similarly to high-intensity interval training stimulus, although only exercise improved cardiorespiratory fitness and decreased body weight; moreover, EV-miRNAs decreased fatty acid and cholesterol biosynthesis pathways in the liver, reducing hepatic steatosis and increasing insulin sensitivity, thus reducing glycemia and triglyceridemia.…”