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Adipose Tissue Macrophages Modulate Obesity-Associated β Cell Adaptations through Secreted miRNA-Containing Extracellular Vesicles.

ABSTRACT: Obesity induces an adaptive expansion of β 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 β 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 β 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 β cell responses. miR-155 is a highly enriched miRNA within obese ATM EVs and miR-155 overexpressed in β cells impairs insulin secretion and enhances β cell proliferation. In contrast, knockout of miR-155 attenuates the regulation of obese ATM EVs on β cell responses. We further demonstrate that the miR-155-Mafb axis plays a critical role in controlling β cell responses. These studies show a novel mechanism by which ATM-derived EVs act as endocrine vehicles delivering miRNAs and subsequently mediating obesity-associated β cell adaptation and dysfunction.

SUBMITTER: Gao H

PROVIDER: S-EPMC8472266 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Opiate abuse increases the risk of HIV transmission and exacerbates HIV neuropathology by increasing inflammation and modulating immune cell function. Exosomal EVs(xEV) contain miRNAs that may be differentially expressed due to HIV infection or opiate abuse. Here we develop a preliminary exosomal-miRNA biomarker profile of HIV-infected PBMCs in the context of opiate use. PBMCs infected with HIV were treated with increasing dosages of morphine for 72 hours, the culture supernatants were collected, and the exosomes isolated using differential centrifugation. Exosomal miRNAs were extracted, expression levels determined via Nanostring multiplexed microRNA arrays, and analyzed with Webgestalt. The effect of the exosomes on neuronal function was determined by measuring calcium. Preliminary findings show that HIV-1 infection altered the miRNA profile of PBMC-derived EVs concurrently with opiate exposure. MicroRNA, hsa-miR-1246 was up-regulated 12-fold in the presence of morphine, relative to uninfected control. PBMCs infected with HIV-1 MN, an X4-tropic HIV-1 strain and exposed to morphine, displayed a trend which suggests potential synergistic effects between HIV-1 infection and morphine exposure promoting an increase in viral replication. Dose-dependent differences were observed in miRNA expression as a result of opiate exposure. The xEVs derived from PBMCs exposed to morphine or HIV modulated neuronal cell function. SH-SY5Y cells, treated with xEVs derived from ART-treated PBMCs, exhibited increased viability while for SH-SY5Ys exposed to xEVs derived from HIV-1 infected PBMCs viability was decreased compared to the untreated control. Exposing SH-SY5Y to xEVs derived from HIV-infected PBMCs resulted in significant decrease in calcium signaling, relative to treatment with xEVs derived from uninfected PBMCs. Overall, HIV-1 and morphine induced differential miRNA expression in PBMC-derived exosomes, potentially identifying mechanisms of action or novel therapeutic targets involved in opiate use disorder, HIV neuropathology, TNF signaling pathway, NF-κB signaling pathway, autophagy, and apoptosis in context of HIV infection.

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Adipose Tissue Macrophages Modulate Obesity-Associated β Cell Adaptations through Secreted miRNA-Containing Extracellular Vesicles.

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