The circadian clock as a sensor of cell metabolic state: Interactions between nutrients, growth factors, and the mammalian clock machinery

Interactions between the circadian clock and metabolism occur in mammals at multiple levels. While the clock regulates rhythmic metabolism in the whole organism to coordinate with daily fasting-feeding cycles, increasing evidence suggests that metabolites can interact with the clock machinery to alter clock oscillations at the cellular level. In this work, we investigate the role of glucose, one of the two major carbon sources that fuel cell growth and proliferation, in modulating gene expression and oscillatory behavior of the circadian clock, and explore the consequences of these interactions for regulating cell survival. We have found that glucose serves as the main carbon source for histone acetylation reactions in mammalian cells, thus gene expression is directly responsive to extracellular glucose levels. Glucose limitation, meanwhile, activates the bioenergetic sensing molecule AMP-activated protein kinase, which directly phosphorylates cryptochrome clock proteins, altering the amplitude and period length of circadian cycles. Cells lacking cryptochromes are less able to survive nutrient or growth factor withdrawal, due to decreased induction of fatty acid oxidation. The ability of clock components to sense and respond to glucose may therefore represent a key mechanism by which cells coordinate internal processes to initiate growth and maintain survival.