Objectives: 

Changes in circadian rhythms have been related with obesity and diabetes. It has been shown that the nuclear receptor Rev-erb-alpha links circadian rhythms to metabolism in many peripheral tissues. In the present study, we analyzed the role of this clock gene in the pancreatic beta-cell function. Additionally, we studied its potential regulation by leptin and diet-induced obesity.

Materials: 

To dissect the role of Rev-erb-alpha, we knocked down its expression using small interfering RNA (siRNA) in mouse islet-cells and in insulin-releasing MIN-6 cells. Cell proliferation was assessed by BrdU incorporation, apoptosis by TUNEL, insulin secretion by radioimmunoassay and gene expression by real time PCR. Islets were isolated along the day (8:00, 14:00 and 20:00) after six weeks of high fat diet treatment and then, gene expression and insulin secretion were determined.

Results: 

Down-regulation of Rev-erb-alpha expression by siRNA treatment in islet-cells and MIN-6 cells led to an impaired glucose-induced insulin secretion. Additionally, it decreased the expression of lipogenic genes such as sterol regulatory element-binding protein 1c and fatty acid synthase as well as inhibited beta-cell proliferation. In vivo and in vitro experiments with leptin induced an up-regulation of Rev-erb-alpha expression in isolated islets, which was mediated by a mitogen activated protein kinase pathway. When obesity was induced in mice by high fat diet, both circadian Rev-erb-alpha gene oscillations and insulin secretion were impaired.

Conclusions: 

These findings show that the clock gene Rev-erb-alpha is a key regulator at multiple levels in the pancreatic beta-cell. The abnormal regulation of this transcription factor during obesity might leads to altered beta-cell function and, eventually, might promote type 2 diabetes.