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Title: Bmal1 and Beta cell clock are required for adaptation to circadian disruption, and their loss of function leads to oxidative stress-induced Beta cell failure in mice

Author
item LEE, JEONGKYUNG - Baylor College Of Medicine
item MOULIK, MOUSUMI - Baylor College Of Medicine
item FANG, ZHE - Baylor College Of Medicine
item SAHA, PRADIP - Baylor College Of Medicine
item ZOU, FANG - Children'S Nutrition Research Center (CNRC)
item XU, YONG - Children'S Nutrition Research Center (CNRC)
item NELSON, DAVID - Baylor College Of Medicine
item MA, KE - Baylor College Of Medicine
item MOORE, DAVID - Children'S Nutrition Research Center (CNRC)
item YECHOOR, VIJAY - Baylor College Of Medicine

Submitted to: Molecular and Cellular Biology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 3/12/2013
Publication Date: 4/1/2013
Citation: Lee, J., Moulik, M., Fang, Z., Saha, P., Zou, F., Xu, Y., Nelson, D.L., Ma, K., Moore, D.D., Yechoor, V.K. 2013. Bmal1 and Beta cell clock are required for adaptation to circadian disruption, and their loss of function leads to oxidative stress-induced Beta cell failure in mice. Molecular and Cellular Biology. 33 (11):2327-2338.

Interpretive Summary: Diabetes is a serious global health problem. Disruptions in the 24-hour circadian rhythms have been implicated in dysfunctions of pancreatic beta cells, which may contribute to deficits in insulin release and diabetes. The mechanisms underlying these effects remain unknown. We generated mouse models in which a key circadian gene, called Bmal1, was deleted only in beta cells. We showed that these mutant mice have decreased insulin secretion and develop diabetes. These findings provide direct evidence that circadian regulation of beta cells is essential for normal insulin secretion and glucose balance.

Technical Abstract: Circadian disruption has deleterious effects on metabolism. Global deletion of Bmal1, a core clock gene, results in Beta cell dysfunction and diabetes. However, it is unknown if this is due to loss of cell-autonomous function of Bmal1 in Beta cells. To address this, we generated mice with Beta cell clock disruption by deleting Bmal1 in Beta cells (Beta-Bmal1(-/-)). Beta-Bmal1(-/-) mice develop diabetes due to loss of glucose-stimulated insulin secretion (GSIS). This loss of GSIS is due to the accumulation of reactive oxygen species (ROS) and consequent mitochondrial uncoupling, as it is fully rescued by scavenging of the ROS or by inhibition of uncoupling protein 2. The expression of the master antioxidant regulatory factor Nrf2 (nuclear factor erythroid 2-related factor 2) and its targets, Sesn2, Prdx3, Gclc, and Gclm, was decreased in Beta-Bmal1(-/-) islets, which may contribute to the observed increase in ROS accumulation. In addition, by chromatin immunoprecipitation experiments, we show that Nrf2 is a direct transcriptional target of Bmal1. Interestingly, simulation of shift work-induced circadian misalignment in mice recapitulates many of the defects seen in Bmal1-deficient islets. Thus, the cell-autonomous function of Bmal1 is required for normal Beta cell function by mitigating oxidative stress and serves to preserve Beta cell function in the face of circadian misalignment.