The long non-coding RNA βFaar regulates islet β-cell function and survival during obesity in mice

Despite obesity being a predisposing factor for pancreatic beta -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 beta -cell function and apoptosis regulator (beta Faar). beta Faar is dramatically downregulated in the islets of the obese mice, and a low level of beta Faar is necessary for the development of obesity-associated beta -cell dysfunction and apoptosis. Mechanistically, beta Faar 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 beta Faar. We demonstrate that SMURF1 ubiquitin ligase activity is essential for TRAF3IP2 ubiquitination and activation of NF-kappa B-mediate beta -cell apoptosis. Our experiments provide direct evidence that dysregulated beta Faar contributes to the development of obesity-induced beta -cell injury and apoptosis. Beta-cell function is often impaired in obesity through incompletely understood mechanisms. Here the authors show that the long noncoding RNA beta Faar is reduced by diet-induced obesity in mice, which leads to impaired beta-cell function via miR-138-5p and survival via TRAF3 Interacting Protein 2.