# Dissecting the autonomy of the liver circadian clock

> **NIH NIH F32** · UNIVERSITY OF CALIFORNIA-IRVINE · 2020 · $65,310

## Abstract

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.

## Key facts

- **NIH application ID:** 10093971
- **Project number:** 5F32DK121425-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA-IRVINE
- **Principal Investigator:** Kevin B Koronowski
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $65,310
- **Award type:** 5
- **Project period:** 2019-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10093971

## Citation

> US National Institutes of Health, RePORTER application 10093971, Dissecting the autonomy of the liver circadian clock (5F32DK121425-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10093971. Licensed CC0.

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