METACYCLES · Uncovering metabolic cycles in mammals and dissecting their interplay with circadian clocks

The physiology and behavior of mammals are subject to daily oscillations that are driven by an endogenous circadian clock. The mammalian circadian timing system is composed of a central pacemaker in the brain that is entrained by daily light-dark cycles and in turn synchronizes subsidiary oscillators in virtually all cells of the body. The core clock molecular circuitry is based on interlocked negative transcription-translation feedback loops that generate daily oscillations of gene expression in cultured cells and living animals.Circadian clocks play a major role in orchestrating daily metabolism and their disruption can lead to metabolic diseases such as diabetes and obesity. Concomitantly, circadian clocks are tightly coupled to cellular metabolism and respond to feeding cycles. The molecular mechanisms through which metabolism regulates clocks’ function are just starting to emerge. Recent work of ours and others revealed that NAD+/NADH are implicated in the function of circadian clocks, yet the molecular mechanisms involved are largely unknown. We propose to intensively study the role of NAD+/NADH in the function of circadian clocks and to reveal the underlying mechanisms.The functional interplay between circadian clocks and metabolism raises the question whether there are daily cycles in cellular metabolism and intracellular metabolites. Hitherto, direct measurements of daily changes in cellular metabolism and intracellular metabolite levels are still in their infancy. Our overarching goal is to identify metabolic cycles in mammals and mechanistically address their interplay with circadian clocks. We will monitor metabolic outputs in intact cells and living animals and systemically measure daily changes in intracellular metabolites. Our findings are expected to push forward a paradigm shift in the circadian field from the current “transcriptional-translational clocks” to “metabolic clocks”.