# The Role of the Ghrelin System in the Metabolic Responses to Exercise

> **NIH NIH P01** · UT SOUTHWESTERN MEDICAL CENTER · 2021 · $486,460

## Abstract

PROJECT SUMMARY
Exercise is often highly effective for prevention of weight gain, for prevention of weight regain after weight loss,
and for weight loss, however the hormonal and neuronal mediators that influence the complicated and highly
variable exercise-associated changes in appetite and food intake and the exercise-associated effects on
energy expenditure and related physiology such as exercise endurance, are poorly understood. In the current
proposal, we aim to investigate the role of the hormone ghrelin and its receptor, the growth hormone
secretagogue receptor (GHSR), in mediating the effects of exercise on food intake as well as in mediating
exercise endurance. The proposal follows up on recently published findings in mice demonstrating that
exercise transiently raises circulating levels of the hormone ghrelin and that without the action of this increased
ghrelin, post-exercise food intake and exercise endurance are both markedly diminished. The proposal uses a
unique collection of genetically-engineered mouse models to investigate the mechanisms regulating exercise-
induced ghrelin release and the neuronal sites and other mechanisms through and by which ghrelin and its
receptor mediate metabolic responses to exercise and exercise endurance. In particular, we will determine if
ghrelin-dependent or ghrelin-independent (constitutive) signaling via GHSRs is required for the metabolic
responses to exercise by evaluating the effects of ghrelin deletion and a GHSR mutation (which eliminates
GHSR constitutive activity) on food intake, energy expenditure, neuronal excitability, and exercise endurance.
We will use a mouse model lacking β1-adrenergic receptors exclusively in ghrelin cells to determine if
activation of these ghrelin cell β1-adrenergic receptors, as induced by the sympathoadrenal system, is required
for the ghrelin response to exercise. We also will use mice lacking GHSRs selectively from arcuate
hypothalamic AgRP neurons or ventromedial hypothalamic SF1 neurons and mice with chemogenetically-
inhibited mediobasal hypothalamic GHSR-expressing neurons to determine if those populations of
hypothalamic neurons mediate the exercise-associated effects of the ghrelin system on metabolism and
exercise endurance. Our studies will provide fundamental insight into the metabolic effects of exercise,
exercise endurance, arcuate hypothalamic AgRP and POMC neuronal excitability, ghrelin cell physiology, and
ghrelin action. Ultimately, we hope that studying the role of the ghrelin system in the metabolic responses to
exercise may allow us to determine and therapeutically harness the mechanisms by which exercise promotes
whole-body health.

## Key facts

- **NIH application ID:** 10242072
- **Project number:** 5P01DK119130-03
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Jeffrey M Zigman
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $486,460
- **Award type:** 5
- **Project period:** 2019-09-20 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10242072

## Citation

> US National Institutes of Health, RePORTER application 10242072, The Role of the Ghrelin System in the Metabolic Responses to Exercise (5P01DK119130-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10242072. Licensed CC0.

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