Circadian Clock Nuclear Receptor REV-ERBa Is a Novel Regulator of Beta-Cell Function, Survival, and Autophagy under Diabetogenic Conditions

The circadian clock regulates diverse cellular and molecular rhythms employing CLOCK-BMAL1 transcriptional heterodimer with nuclear receptor REV-ERBα (encoded by gene Nr1d1) playing an important role as a clock repressor through modulation of Bmal1 transcription. Importantly, in addition to its core circadian clock function, recent studies have identified REV-ERBα as a potent transcriptional repressor of autophagy. Therefore, in the current study we set out to address whether impaired beta-cell function and survival associated with exposure to diabetogenic stressors (e.g., glucotoxicity and inflammation) is attributed in part to REV-ERBα-mediated inhibition of autophagy. Exposure of beta-cells (INS-1E cell line) to either glucotoxicity (30 mM glucose) or cytokines (cytomix of IL-1β, TNFα and IFNγ) resulted in robust induction of REV-ERBα expression (1.5-2 fold, p<0.05) and corresponded with impaired autophagy flux characterized by increased protein levels of p62 (also known SQSTM1) (1.5-2 fold, p<0.05). Consistent with these data, exposure of beta-cells to a REV-ERBα agonist (SR9011) was characterized by impaired autophagy (increased p62 levels and aggregated forms, p<0.05), defective glucose-stimulated insulin secretion (70% decrease) and increased beta-cell apoptosis (increased cleaved caspase-3, p<0.01 vs. vehicle). In contrast, REV-ERBα specific antagonist (SR8278) partly protected beta-cells from deleterious effects of glucotoxicity or cytokines-induced inflammation by enhancing autophagy flux and attenuating beta-cell apoptosis (∼30%). Taken together, these data reveal for the first time an underexplored link between the core circadian clock nuclear receptor REV-ERBα, autophagy and beta-cell failure under diabetogenic conditions. These data also suggest a therapeutic potential of modulating REV-ERBα levels in beta-cells to enhance function and survival in diabetes. Disclosure S. Costes: None. D. Laouteouet: None. M.A. Ravier: None. M. Delobel: None. G. Bertrand: None. S. Dalle: None. A. Matveyenko: None.