The Clock Gene Rev-erbα Regulates Pancreatic β-Cell Function: Modulation by Leptin and High-Fat Diet

Disturbances of circadian rhythms have been associated with obesity and type 2 diabetes. The nuclear receptor Rev-erb alpha was suggested to link circadian rhythms and metabolism in peripheral tissues. The aim of the present study was to dissect the role of this clock gene in the pancreatic beta-cell function and to analyze whether its expression is modulated by leptin and diet-induced obesity. To address the function of Rev-erb alpha, we used small interfering RNA in mouse islet cells and in MIN-6 cells. Cell proliferation was measured by bromodeoxyuridine incorporation, apoptosis by the terminal deoxynucleotidyl transferase dUTP nick end labeling technique, insulin secretion by RIA, and gene expression by RT-PCR. Pancreatic islets were isolated at different zeitgeber times 0, 6, and 12 after 6 wk of high-fat diet treatment, and then gene expression and insulin secretion were determined. Rev-erb alpha down-regulation by small interfering RNA treatment in islet cells and MIN-6 cells impaired glucose-induced insulin secretion, decreased the expression of key lipogenic genes, and inhibited beta-cell proliferation. In vivo and in vitro leptin treatment increased Rev-erb alpha expression in isolated islets through a MAPK pathway. High-fat diet treatment disrupted the circadian Rev-erb alpha gene expression profile along with insulin secretion, indicating an important role of this clock gene in beta-cell function. These results indicate that the clock gene Rev-erb alpha plays multiple functions in the pancreatic beta-cell. Although the increase in Rev-erb alpha expression may promote beta-cell adaptation in different metabolic situations, its deregulation may lead to altered beta-cell function. (Endocrinology 153: 592-601, 2012)