Bmal1 and β-Cell Clock Are Required for Adaptation to Circadian Disruption, and Their Loss of Function Leads to Oxidative Stress-Induced β-Cell Failure in Mice

Apr 3, 2013Molecular and cellular biology

The body's daily clock and insulin-producing cell clock help adjust to time disruptions, and losing them causes stress-related failure of insulin cells in mice

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Abstract

Mice lacking the Bmal1 gene in β cells develop diabetes due to impaired insulin secretion.

β-Bmal1(-/-) mice experience a significant reduction in glucose-stimulated insulin secretion (GSIS).
Accumulation of reactive oxygen species (ROS) is observed in β-Bmal1(-/-) islets, leading to mitochondrial dysfunction.
Scavenging of ROS or inhibiting uncoupling protein 2 can fully restore GSIS in β-Bmal1(-/-) mice.
The expression of antioxidant factors regulated by Nrf2 is decreased in β-Bmal1(-/-) islets, potentially increasing ROS levels.
Nrf2 is identified as a direct transcriptional target of Bmal1, linking circadian regulation to antioxidant defense.
Circadian misalignment in mice simulating shift work mirrors many defects found in β-Bmal1(-/-) islets.

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Circadian disruption has deleterious effects on metabolism. Global deletion of Bmal1, a core clock gene, results in β-cell dysfunction and diabetes. However, it is unknown if this is due to loss of cell-autonomous function of Bmal1 in β cells. To address this, we generated mice with β-cell clock disruption by deleting Bmal1 in β cells (β-Bmal1(-/-)). β-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 β-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 β-cell function by mitigating oxidative stress and serves to preserve β-cell function in the face of circadian misalignment.

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Bmal1 and β-Cell Clock Are Required for Adaptation to Circadian Disruption, and Their Loss of Function Leads to Oxidative Stress-Induced β-Cell Failure in Mice

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