# Unraveling the molecular connections that link circadian rhythms and lipid metabolism

> **NIH NIH R01** · UNIVERSITY OF MISSOURI-ST. LOUIS · 2021 · $317,939

## Abstract

PROJECT SUMMARY
Misalignments and disruption of the circadian clock lead to metabolic and physiological dysfunctions. The clock regulates
metabolism whereas metabolic activities feedback to influence circadian rhythms, and this interplay between the clock
and metabolism coordinates physiology. However, one major knowledge gap is the limited understanding of the
mechanism by which metabolism affects clock function. The goal of the proposed research is to elucidate the molecular
mechanism by which the circadian clock and lipid metabolism are interconnected through the interaction and reciprocal
regulation between lipid mediators and major clock regulators using the model organism Arabidopsis thaliana. The
feasibility of the proposed research is supported by recent findings that the central glycerolipid metabolic intermediate,
phosphatidic acid (PA), directly binds to the clock transcription factor LHY (LATE ELONGATED HYPOCOTYL),
manipulations of PA-metabolizing activities alter clock outputs, and disruptions of the clock perturb lipid accumulation in
Arabidopsis. The hypothesis is that the PA-LHY interaction functions as a cellular conduit to integrate the circadian clock
with lipid metabolism and mediate lipid production and organismal responses to changing environments. To test the
hypothesis, Aim 1 will characterize PA interaction with the clock regulators by determining the lipid binding specificity
to LHY, the amino acid residues involved in PA binding, and the intracellular location of the PA-LHY interaction using
subcellular-specific PA biosensors and mass spectrometry. Aim 2 will address how altered PA metabolism entrains the
circadian clock and mediates stress responses by identifying genes/enzymes responsible for producing PA species that
alter clock function. Through quantifying the effect of cellular PA changes on the expression of genes involved in clock
regulation, these data will be used to model how cellular PA changes lead to alterations in circadian rhythms and clock
outputs. Aim 3 will determine how the circadian clock affects lipid metabolism by using clock mutants to assess how
misalignments between internal circadian rhythms and the external environment affect lipid metabolism and
accumulation. In addition, clock-targeted genes in lipid metabolism will be identified and tested for roles in the circadian
regulation of lipid accumulation. The proposed studies will reveal new regulatory mechanisms for both the circadian clock
and lipid metabolism and will advance the current understanding of the interplay between these two pathways. The results
are relevant to human health because PA is a lipid mediator involved in mammalian clock regulation and various
pathological processes, and the basic molecular mechanism of the clock is conserved between plants and humans.
Therefore, the impact of the proposed work is to advance foundational knowledge for the molecular interconnection
between lipid metabolism and the clock in eukaryotes, an...

## Key facts

- **NIH application ID:** 10185527
- **Project number:** 1R01GM141374-01
- **Recipient organization:** UNIVERSITY OF MISSOURI-ST. LOUIS
- **Principal Investigator:** XUEMIN WANG
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $317,939
- **Award type:** 1
- **Project period:** 2021-03-10 → 2025-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10185527

## Citation

> US National Institutes of Health, RePORTER application 10185527, Unraveling the molecular connections that link circadian rhythms and lipid metabolism (1R01GM141374-01). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10185527. Licensed CC0.

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