Dissecting the autonomy of the liver circadian clock

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Summary/Abstract Mammals rely on the circadian clock system to orchestrate daily systemic metabolism and physiology. Within this system, the central clock or pacemaker in the suprachiasmatic nucleus (SCN) is synchronized daily by light and is considered hierarchically dominant over “subordinate” tissue clocks in the periphery. Whereas the SCN clock is responsive to light, clocks in peripheral tissues are largely influenced by nutritional cues (e.g. feeding- fasting) and can be synchronized to an inverted feeding schedule even when it opposes the light-based timing signals of the SCN. Mouse models of tissue-specific clock deficiency indicate further that both central clocks in the brain and local clocks in the periphery are necessary for full circadian rhythmicity in a particular tissue, a notion exemplified in the liver. Thus, the circadian clock system is a seemingly federated network of interdependent tissue clocks that work in concert to achieve organismal homeostasis. Although we know that this interplay between body clocks exists, the mechanisms through which clocks communicate and the levels of regulation where this cross talk integrates locally are not known. This notion raises important questions. Are peripheral tissue clocks truly autonomous, meaning can they oscillate without influence from other clocks? To what extent does their function depend on extrinsic rhythmic signals like timed metabolic cues? To answer these questions, we have generated mice which are devoid of clocks in all tissues except for the liver, where the clock is reconstituted (Liver-Reconstituted [RE] mice). Our preliminary data show that the liver clock of Liver-RE mice oscillates autonomously under light-dark conditions, recapitulating only ~10% of the normally rhythmic transcriptional output, but ceases to oscillate under dark-dark conditions. Therefore, in Specific Aim 1 we will determine the liver clock's autonomous response to light and identify potential light-responsive molecular mediators. In Specific Aim 2 we will determine whether time-restricted feeding, a synchronizer and driver of rhythmic transcripts in the liver, can reinstate a portion of the missing ~90% of normally rhythmic transcriptional output. Moreover, we will test if this is achieved through metabolic signaling to the clock via NAD+. The overall goal of this proposal is to identify the interactions between specifically the autonomous liver clock and the two main factors that drive the circadian system, light and food. In doing so, we will reveal the intrinsic capacity of the liver clock and begin to tease apart its interactions with other clocks and systemic physiology. Given the established relationship between disruption of the circadian clock and metabolic disease, as well as the pervasiveness of light and food in every day life, these findings will improve our understanding of the clock- metabolism intersection and inform on human health.