# Molecular Mechanisms of AgRP Signaling

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA SANTA CRUZ · 2020 · $424,116

## Abstract

Project Summary
In the brain, key focal points for control of metabolic function and feeding behavior are
melanocortin receptors MC3R and MC4R. These receptors respond to two ligands,
alpha-melanocyte stimulating hormone (a-MSH) and the agouti-related protein (AgRP),
which act in opposite ways to promote negative and positive energy balance,
respectively. Recent research demonstrates the profound importance of AgRP releasing
neurons in metabolism and body weight homeostasis. The goal of this program is to
understand the molecular basis of AgRP action, thus enabling new strategies for treating
diverse conditions linked to obesity and metabolic diseases. New findings from our lab
are significantly reshaping our understanding of a-MSH and AgRP action. The current
paradigm posits that these molecules act to stimulate or suppress production of the
cAMP second messenger. However, using protein design, we demonstrated that AgRP
mutations in segments outside of the MCR binding core exert a profound influence on
long term feeding, while leaving receptor affinity and cAMP suppression completely
unchanged relative to wild-type. Moreover, new collaborative results find that AgRP
promotes the opening of inward rectifying potassium channels through a cAMP
independent mechanism, an effect that is directly dependent on these peripheral AgRP
segments. Aim 1 of this application will expand these studies by identifying how AgRP
sequence and conformation drive potassium channel currents. This will be tested
through protein design, NMR structure determination, as well as with a new human
AgRP obesity-linked mutant identified by whole exome analysis. Aim 2 will examine how
syndecan-3, a negatively charged, membrane bound proteoglycan, facilitates AgRP
signaling. This will be accomplished with biophysical experiments and through
comparison studies where designed proteins are administered to wild-type and
syndecan-3 knockout mice, followed by feeding trials and brain tissue imaging. Aim 3
will expand on AgRP design efforts to produce stable proteins to test the role of
proteolytic resistance in promoting long-term AgRP action, and as leads for treating
cancer cachexia, a wasting condition characterized by extreme loss of appetite and lean
tissue degradation.

## Key facts

- **NIH application ID:** 9919555
- **Project number:** 5R01DK110403-04
- **Recipient organization:** UNIVERSITY OF CALIFORNIA SANTA CRUZ
- **Principal Investigator:** GLENN L MILLHAUSER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $424,116
- **Award type:** 5
- **Project period:** 2017-05-01 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9919555

## Citation

> US National Institutes of Health, RePORTER application 9919555, Molecular Mechanisms of AgRP Signaling (5R01DK110403-04). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9919555. Licensed CC0.

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