# Bioenergetic Mechanisms Underlying Circadian Dietary Intervention

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2021 · $395,000

## Abstract

Project Summary
The rise in age-related metabolic disorders and obesity has reached epidemic proportions. We have made the
exciting discoveries that circadian clock mutant animals develop diet-induced obesity and metabolic syndrome,
and that high fat feeding dampens circadian oscillations and increases food consumption during the `wrong'
time of day (i.e., the normal rest period). In contrast, restricting access to high fat diet to the `right' (i.e., active)
time of day as a circadian dietary intervention prevents the development of obesity and diabetes. Together,
these findings suggest disrupted circadian control of feeding rhythms contributes to diet-induced obesity and its
comorbidities, similar to the adverse consequences of night-eating in humans, and provide a springboard for
our proposed studies here to elucidate the bioenergetics mechanisms underlying this circadian dietary
intervention. Importantly, we recently discovered that adipose thermogenesis is required for the metabolic
benefits of time-restricted feeding. Mounting evidence has also indicated that circadian and energetic pathways
are coupled at the molecular level through circadian clock control of NAD+, a cofactor for nutrient-sensing
sirtuin deacetylases which feedback to regulate both core clock activity and mitochondrial respiration.
Remarkably, we found that NAD+ supplementation augments mitochondrial oxidative metabolism in circadian
mutant mice and enhances rhythmic metabolic gene transcription during aging. Here, we will first test the
hypothesis that circadian dietary intervention (i.e., dark-only feeding) improves metabolic healthspan through
enhanced thermogenesis and oxidative metabolism in adipose and liver (Aim 1). To do so, we will determine
the impact of time-restricted feeding (i) on the metabolic health of mice with defective (Ucp1-/-) or enhanced
(Zfp423-/-) thermogenesis; (ii) on weight maintenance in animals following caloric restriction; (iii) on metabolic
flux in adipose- and liver-specific clock deficient mice (Bmal1∆adipose and Bmal1∆liver); and (iv) on transcriptional
rhythms. Results of Aim 1 will elucidate the mechanism through which the clock and time-restricted feeding
regulate the metabolic fate of dietary nutrient and body weight setpoint. In Aim 2, we will test the hypothesis
that NAD+ supplementation can augment time-restricted feeding as a countermeasure for metabolic decline
with aging and overnutrition (Aim 2). Specifically, we will examine whether NAD+ supplementation improves
circadian control of thermogenesis, metabolic flux, and transcriptional activity of the core clock in young and
old animals during time-restricted feeding. Results of Aim 2 will elucidate the role of NAD+ in circadian control
of the metabolic fate of dietary nutrient, thermogenesis, and healthspan. Collectively, the integration of
behavioral, genomic, and physiologic analyses in the present proposal will define the role of time-of-day in
nutrient flux and thermogenesis,...

## Key facts

- **NIH application ID:** 10165455
- **Project number:** 5R01AG065988-03
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Joseph Bass
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $395,000
- **Award type:** 5
- **Project period:** 2019-09-15 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10165455

## Citation

> US National Institutes of Health, RePORTER application 10165455, Bioenergetic Mechanisms Underlying Circadian Dietary Intervention (5R01AG065988-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10165455. Licensed CC0.

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