The circadian clock generates anticipatory insulin secretory cycles by regulating β-cell enhancers

Mark Perelis

doi:https://doi.org/10.21985/N2V96N

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The circadian clock generates anticipatory insulin secretory cycles by regulating β-cell enhancers

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The circadian clock is a biological oscillator present in all terrestrial life forms that aligns organismal functions with the daily rising and setting of the sun. In mammals clocks are expressed both in pacemaker cells in the brain that are directly entrained by light as well as in all peripheral cells where they coordinate the timing of anabolic and catabolic processes in anticipation of daily changes in nutrient availability. It has long been recognized that humans exhibit a robust variation in blood glucose levels that are regulated in part by rhythmic secretion of the glucose-lowering hormone insulin across the sleep/wake cycle and there is now strong evidence that disruption of circadian cycles contribute to metabolic disorders including diabetes mellitus. Experimental genetic analyses in mice have recently revealed that circadian clock genes play an essential role in regulating insulin secretion in pancreatic β-cells. However, whether the circadian influence on β-cell insulin secretion is a consequence of cell-intrinsic or extrinsic timekeeping and the underlying transcriptional mechanisms were largely unknown. The studies presented in this dissertation demonstrate that the core circadian transcriptional activators CLOCK and BMAL1 act cell-autonomously to coordinate 24-hr rhythmic cycles in β-cell secretory capacity by regulating the transcription of genes that regulate the assembly, packaging, transport, and exocytosis of insulin containing vesicles. Examining the genome-wide binding patterns of CLOCK and BMAL1 in β-cells revealed that they regulate rhythmic genes by binding to cell-type specific transcriptional enhancers, providing a possible explanation for the marked differences in clock-controlled genes across mammalian organs. Finally, acute inhibition of circadian transcription in β-cells of adult mice inhibits insulin secretion and causes severe glucose intolerance. Therefore, the developmentally established repertoire of transcriptional enhancers enables the circadian control of β-cells and regulates glucose metabolism throughout life.

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