# Investigating the requirement of MRAP2 for ghrelin function

> **NIH NIH R01** · UNIVERSITY OF IOWA · 2021 · $380,462

## Abstract

PROJECT SUMMARY
Ghrelin is a circulating orexigenic hormone mainly secreted by the stomach during fasting periods to signal
hunger to the brain. Ghrelin regulates food intake and energy expenditure by acting at its receptor the Growth
Hormone Secretagogue Receptor 1a (GHSR1a). The effect of ghrelin on food intake and energy homeostasis
are mediated centrally through the activation of AGRP/NPY neurons, and global or central deletion of the ghrelin
receptor protects from diet-induced obesity. For this reason, GHSR1a is a promising target for the treatment of
obesity and antagonists of the ghrelin receptor have been developed for this purpose, however, their promiscuity
or low bioavailabilty precludes them from being used in the clinic. New compounds with improved pharmaco-
chemical properties and better in-vivo efficacy could likely be identified by using more relevant drug discovery
strategies. Improvement of screening strategies will require a better understanding of GHSR1a regulation. We
have recently discovered that the orexigenic effect of ghrelin is lost in mice in which the Melanocortin Receptor
Accessory Protein 2 (MRAP2) was deleted. Our preliminary results demonstrate that MRAP2 interacts with
GHSR1a and strongly potentiates ghrelin-stimulated signaling downstream of the receptor. Additionally, we show
that MRAP2 is expressed in the ghrelin responsive AGRP/NPY neurons. Consistent with those findings, we show
that AGRP neurons from MRAP2 KO mice fail to activate in response to starvation. Experiments proposed in
this project will take advantage of several animal models that allow the targeted modulation of MRAP2 
expression and the measurement of ghrelin signaling in specific neurons. The goal of this proposal is to 1) Identify the
role of MRAP2 in promoting ghrelin signaling and starvation response of AGRP neurons; 2) Identify the 
mechanisms through which MRAP2 enhances to efficacy of GHSR1a signaling. The studies in aim 1 will test the 
hypothesis that the modulation of MRAP2 expression in AGRP neurons alters hunger sensing and ghrelin actions
in the brain. The studies in aim 2 will test the hypothesis that MRAP2 potentiates GHSR1a signaling, both 
in-vivo and in-vitro, by interfering with the desensitization of the receptor. This research is significant because
successful completion will provide fundamental information on the role and mechanism of action of MRAP2 in
AGRP neurons as it pertains to ghrelin functions, advance our understanding of AGRP neurons regulation and
hypothalamic control of energy homeostasis. This research is innovative because completion will generate novel
knowledge on the regulation of G-Protein Coupled receptors by accessory proteins and identify MRAP2 as a
novel energy sensor in AGRP neurons. We will also be using innovative mouse model generated in our 
laboratory to accurately detect and genetically modulate the expression of MRAP2 in a tissue specific manner. 
Ultimately, the completion of this project wil...

## Key facts

- **NIH application ID:** 10101648
- **Project number:** 5R01DK115567-04
- **Recipient organization:** UNIVERSITY OF IOWA
- **Principal Investigator:** Julien Albert Sebag
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $380,462
- **Award type:** 5
- **Project period:** 2018-02-01 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10101648

## Citation

> US National Institutes of Health, RePORTER application 10101648, Investigating the requirement of MRAP2 for ghrelin function (5R01DK115567-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10101648. Licensed CC0.

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