Adipose Tissue Macrophages Modulate Obesity-Associated Beta Cell Adaptations Through Secreted Mirna-Containing Extracellular Vesicles

Obesity induces an adaptive expansion of beta cell mass and insulin secretion abnormality. Expansion of adipose tissue macrophages (ATMs) is a hallmark of obesity. Here, we assessed a novel role of ATMs in mediating obesity-induced beta cell adaptation through the release of miRNA-containing extracellular vesicles (EVs). In both in vivo and in vitro experiments, we show that ATM EVs derived from obese mice notably suppress insulin secretion and enhance beta cell proliferation. We also observed similar phenotypes from human islets after obese ATM EV treatment. Importantly, depletion of miRNAs blunts the effects of obese ATM EVs, as evidenced by minimal effects of obese DicerKO ATM EVs on beta cell responses. miR-155 is a highly enriched miRNA within obese ATM EVs and miR-155 overexpressed in beta cells impairs insulin secretion and enhances beta cell proliferation. In contrast, knockout of miR-155 attenuates the regulation of obese ATM EVs on beta cell responses. We further demonstrate that the miR-155-Mafb axis plays a critical role in controlling beta cell responses. These studies show a novel mechanism by which ATM-derived EVs act as endocrine vehicles delivering miRNAs and subsequently mediating obesity-associated beta cell adaptation and dysfunction.