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.

Highlights

  • The prevalence of type 2 diabetes mellitus (T2DM) has risen dramatically in the past couple of decades [1]

  • We first examined if adipose tissue macrophages (ATMs) (F4/80+CD11b+) can release extracellular vesicles (EVs) harboring miRNAs that are delivered into β Cells

  • More miR-155 molecules were bound with Ago proteins of GFP+ β Cells after treatment of NCD MIPGFP islets with obese ATM EVs (Figure 1D)

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Summary

Introduction

The prevalence of type 2 diabetes mellitus (T2DM) has risen dramatically in the past couple of decades [1]. Adipose tissue undergoes significant expansion, concomitant with a state of chronic and unresolved inflammation [4,6,7,8,9,10] Numerous studies in both humans and rodents have demonstrated that a remarkable accumulation of proinflammatory macrophages is one of the striking components of obesity-induced adipose tissue inflammatory responses [11,12,13,14,15,16]. Our previous studies have demonstrated that obese ATMs preferentially secreted miR-155 enriched EVs, leading to an accumulation of this miRNA in the local target cells or at distal sites [32]. The depletion of miR-155 partially prevents the effects of obese ATM EVs on β Cell responses

Animals
Flow Cytometry Analysis
Isolation of Islets
EV Purification and Pharacterization
2.14. Glucose-Stimulated Insulin Secretion Assays
2.15. Statistics
Results
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