# Vagal REV-ERB as a Circadian Regulator of Satiation Signaling

> **NIH NIH F32** · UNIVERSITY OF PENNSYLVANIA · 2022 · $72,302

## Abstract

Project Summary
Obesity is an international epidemic with significant health and economic consequences. Excess caloric intake
and dysregulated feeling of hunger/fullness largely contribute to the failure of lifestyle modifications to maintain
weight loss. Accordingly, basic science research investigating the physiological mechanisms regulating feeding
behavior and energy homeostasis for the development of effective anti-obesity therapeutics is more pertinent
than ever. The normal diurnal patterns of food intake (high during the active phase, low during the inactive phase)
are muted in obesity. Gastric vagal afferent nerves convey nutritional information from the gastrointestinal (GI)
tract (mechanical distension of the stomach and GI-released neuropeptides) to the brain to regulate feeding
behavior. Interestingly, vagal afferents are more sensitive to gastric distension during the inactive phase and
similarly the GI-neuropeptide cholecystokinin (CCK) is more satiating during the inactive phase. We propose that
diurnal variations in the potency of postprandial satiety mechanisms reinforces diurnal patterns of food intake.
Obesity, however, eliminates the circadian rhythms of vagal nerve sensitivity to gastric distension and diminishes
the satiating effects of GI satiety factors through incompletely understood mechanisms, leading to the hypothesis
that obesity-induced hyperphagia is due in part to dysregulated circadian patterns of ingestive behavior. Clock
genes are molecular regulators of circadian dependent processes and our preliminary data show that vagal
afferent nerves express the clock genes REV-ERBα and β. REV-ERBα/β uniquely coordinate energy
homeostasis with circadian cues, yet their role in peripheral satiation signaling and diurnal control of food intake
is completely unexplored. The research proposed in this application utilizes the novel model of vagal REV-
ERBα/β double knockdown (DKD) mice to test the hypothesis that vagal REV-ERBα/β regulate diurnal
sensitivity to GI-derived satiation signals. Specific Aim 1 will assess the impact of vagal REV-ERB DKD on
meal patterning using a BioDAQ Food Intake Monitoring System and the satiating effect of CCK, glucagon-like
peptide-1, and gastric distension at 4 different circadian timepoints. Diurnal patterns of eating and wakefulness
are highly coupled, and obesity disrupts sleep patterns in addition to feeding behavior. Accordingly, Specific Aim
II will use CLAMS metabolic cages to investigate the role of vagal REV-ERB DKD on diurnal patterns of
locomotor activity, and indicator of sleep behavior. Additionally, we will use RNA-seq to analyze circadian
patterns of vagal gene expression and identify REV-ERBα/β regulated genes in satiation signaling and
neurotransmission. As we propose that altered vagal REV-ERBα/β signaling underlies obesity-induced
dysregulations in feeding behavior, we expect that vagal REV-ERB DKD will blunt diurnal variations in food
intake, sensitivity to satiation signal...

## Key facts

- **NIH application ID:** 10457287
- **Project number:** 5F32DK127591-02
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Caroline Elyse Geisler
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $72,302
- **Award type:** 5
- **Project period:** 2021-07-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10457287

## Citation

> US National Institutes of Health, RePORTER application 10457287, Vagal REV-ERB as a Circadian Regulator of Satiation Signaling (5F32DK127591-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10457287. Licensed CC0.

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