Pancreatic β cells control glucose homeostasis via the secretion of exosomal miR-29 family.

Jing Li,Yujing Zhang,Yuchen Liu,Shibei Wang,Yangyang Ye,Antonio Vidal‐Puig,Mingliang Zhang,Xiang Zhang,Weiping Jia,Chen‐Yu Zhang,Dameng Li,Xiaohong Jiang,Eunyoung Lee,Junfeng Zhang,Ke Zen,Xin Dai

doi:10.1002/jev2.12055

Abstract

Secreted microRNAs (miRNAs) are novel endocrine factors that play essential pathological and physiological roles. Here, we report that pancreatic β cell‐released exosomal miR‐29 family members (miR‐29s) regulate hepatic insulin sensitivity and control glucose homeostasis. Cultured pancreatic islets were shown to secrete miR‐29s in response to high levels of free fatty acids (FFAs) in vitro. In vivo, high levels of FFAs, promoted by either high‐fat diet (HFD) feeding (physiopathological) or fasting (physiological), increased the secretion of miR‐29s into plasma. Intravenous administration of exosomal miR‐29s attenuated insulin sensitivity. The overexpression of miR‐29s in the β cells of transgenic (TG) mice promoted the secretion of miR‐29s and inhibited the insulin‐mediated suppression of glucose output in the liver. We used selective overexpression of traceable heterogenous mutant miR‐29s in β cells to confirm that islet‐derived exosomal miR‐29s target insulin signalling in the liver and blunt hepatic insulin sensitivity. Moreover, in vivo disruption of miR‐29s expression in β cells reversed HFD‐induced insulin resistance. In vitro experiments demonstrated that isolated exosomes enriched in miR‐29s inhibited insulin signalling in the liver and increased hepatic glucose production. These results unveil a novel β cell‐derived secretory signal—exosomal miR‐29s—and provide insight into the roles of miR‐29s in manipulating glucose homeostasis.

Highlights

Exosomal microRNAs have been proposed to be an alternative form of cell-to-cell communication and have received increasing attention over the past decade. miRNAs, a class of single-stranded non-coding RNAs consisting of 19–22 nucleotides, negatively regulate gene expression at the posttranscriptional level (Bartel, 2004)
Exosomes were collected from conditioned medium using ultracentrifugation (Figure 1a) and identified by Transmission electron microscopy (TEM), Nanoparticle tracking analysis (NTA) and specific biomarker assessment
We found that the levels of miR-29s in pancreatic islets increased upon treatment with free fatty acids (FFAs) (Figure S1B). miR-29s were secreted from the MIN 6 β cell line upon FFA administration (Figure 1f)

Summary

Introduction

Exosomal microRNAs (miRNAs) have been proposed to be an alternative form of cell-to-cell communication and have received increasing attention over the past decade. miRNAs, a class of single-stranded non-coding RNAs consisting of 19–22 nucleotides, negatively regulate gene expression at the posttranscriptional level (Bartel, 2004). Mounting evidence shows that miRNAs in cells can be packaged in exosomes and released into the circulation (Valadi et al, 2007; Zhang et al, 2010). Exosomal miRNAs can be transferred into recipient cells through exosome trafficking. Inside the cell, these miRNAs modulate the expression of target genes and regulate biological functions (Skog et al, 2008; Zhang et al, 2010). Exosomal miRNAs released from other organs and their functional roles in recipient organs are worthy of further study

Methods

Results

Conclusion