# Investigating the requirement of MRAP2 for ghrelin function

> **NIH NIH R01** · UNIVERSITY OF IOWA · 2024 · $456,520

## Abstract

PROJECT SUMMARY
Ghrelin is secreted by the stomach and act on hypothalamic AGRP neurons to promote food intake. Due to the
potent orexigenic action of ghrelin, the ghrelin receptor GHSR1a is considered a promising target for the
treatment of obesity. Our discoveries made during the first period of this project revealed that, in vivo, GHSR1a
is in complex with the accessory protein MRAP2 and that, in this physiologically relevant environment, the
pharmacology of GHSR1a is vastly different than what was depicted in heterologous systems. Indeed, in the
presence of MRAP2, GHSR1a does not display its well documented elevated constitutive activity, has an
enhanced response to ghrelin and only weekly interacts with b-arrestins. Those findings challenge our
understanding of ghrelin action and GHSR1a signaling in vivo and, thus, may warrant a reevaluation of the drug
development strategies targeting GHSR1a for the treatment of obesity. The goal of this proposal is to accurately
elucidate the physiological relevance of each known signaling component of GHSR1a in vivo and their regulation
by MRAP2 by 1) determining the contribution of MRAP2-mediated inhibition of b-arrestin recruitment to GHSR1a
for ghrelin action in AGRP neurons; 2) Investigate the importance of MRAP2-mediated abrogation of GHSR1a
basal activity on ghrelin action in AGRP neurons and 3) Assessing the requirement of MRAP2-mediated
enhancement of ghrelin-stimulated Gaq/11 signaling in AGRP neurons. Using new tools developed in our lab, and
state of the art technics for targeted gene silencing in specific neurons and feeding studies, we will accurately
determine, in vivo, the role of each of those aspects of GHSR1a signaling for ghrelin function. We will also
comprehensively investigate the relative importance of each of MRAP2 actions on GHSR1a signaling for the
orexigenic action of ghrelin. Completion of this project will provide a clear understanding of GHSR1a signaling
and regulation in its endogenous environment and establish the functional importance of the modulation of G-
protein and b-arrestin dependent signaling by MRAP2. These results will have tremendous implications in
informing future efforts to modulate GHSR1a signaling to promote weight loss and demonstrate the importance
of studying GPCRs in their endogenous context and in the presence of their modulatory accessory proteins.

## Key facts

- **NIH application ID:** 10800053
- **Project number:** 2R01DK115567-06
- **Recipient organization:** UNIVERSITY OF IOWA
- **Principal Investigator:** Julien Albert Sebag
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $456,520
- **Award type:** 2
- **Project period:** 2018-02-01 → 2024-09-01

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10800053

## Citation

> US National Institutes of Health, RePORTER application 10800053, Investigating the requirement of MRAP2 for ghrelin function (2R01DK115567-06). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10800053. Licensed CC0.

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