The long non-coding RNA \u03b2Faar regulates islet \u03b2-cell function and survival during obesity in mice

Fangfang Zhang,Qiong Wei,Yuhong Liu,Yue Liu,Qianxing Hu,Ling Li,Yanfeng Zhang,Xi Chen,Dechen Liu,Liang Jin,Guoqing Li,Yue Yang,Rui Liang,Yi Pan,Bin Huang

doi:10.1038/s41467-021-24302-6

Abstract

Despite obesity being a predisposing factor for pancreatic β-cell dysfunction and loss, the mechanisms underlying its negative effect on insulin-secreting cells remain poorly understood. In this study, we identify an islet-enriched long non-coding RNA (lncRNA), which we name β-cell function and apoptosis regulator (βFaar). βFaar is dramatically downregulated in the islets of the obese mice, and a low level of βFaar is necessary for the development of obesity-associated β-cell dysfunction and apoptosis. Mechanistically, βFaar promote the synthesis and secretion of insulin by upregulating islet-specific genes Ins2, NeuroD1, and Creb1 through sponging miR-138-5p. In addition, using quantitative mass spectrometry, we identify TRAF3IP2 and SMURF1 as interacting proteins that are specifically associated with βFaar. We demonstrate that SMURF1 ubiquitin ligase activity is essential for TRAF3IP2 ubiquitination and activation of NF-κB-mediate β-cell apoptosis. Our experiments provide direct evidence that dysregulated βFaar contributes to the development of obesity-induced β-cell injury and apoptosis.

Highlights

Despite obesity being a predisposing factor for pancreatic β-cell dysfunction and loss, the mechanisms underlying its negative effect on insulin-secreting cells remain poorly understood
To identify long non-coding RNA (lncRNA) potentially contributing to the development of obesity-associated dysfunction and apoptosis of β-cell, we performed global lncRNA expression profiling in pancreatic islets obtained from db/db mice
We found that 14 lncRNAs were downregulated in islets of db/db mice more than 8-fold (Fig. 1a, right), these lncRNAs were annotated using UCSC and Ensemble

Summary

Introduction

Despite obesity being a predisposing factor for pancreatic β-cell dysfunction and loss, the mechanisms underlying its negative effect on insulin-secreting cells remain poorly understood. We identify an islet-enriched long non-coding RNA (lncRNA), which we name β-cell function and apoptosis regulator (βFaar). Arnes and colleagues identified lncRNA βlinc[1] as a cis regulator of the islet transcription factor NKX2.2 and showed that βlinc[1] KO mice exhibit impaired glucose tolerance due to defects in insulin secretion[13]. Our most recent work demonstrated that lncRNA Roit expression was downregulated in the islets of obese mice, impairing the transcription of the insulin gene and glucose homeostasis[15]. These studies provided an important groundwork documenting the function of lncRNAs in β-cell, how these lncRNAs contribute to obesity-mediated βcell dysfunction and apoptosis remains to be determined. This study identifies a mechanism of obesity mediated β-cell failure induced by βFaar inhibition

Methods

Results

Conclusion