# Sexually Dimorphic Expression and Function of the Melanocortin-3 Receptor

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2022 · $350,941

## Abstract

Neural systems regulating feeding behavior and reproduction communicate bidirectionally to
gate reproductive events and to regulate energy stores for changes in reproductive states, such
as pregnancy. The melanocortin-3 receptor (MC3R) is expressed in multiple nuclei that regulate
reproduction and energy homeostasis such as the AgRP neurons of the arcuate nucleus, and
exhibits a large sexual dimorphism in its level of expression in both humans and mice. Loss of
the MC3R has particularly profound consequences for female animals. First, we demonstrate
that MC3R is essential for fasting-induced suppression of the HPG axis in females. Second, we
have identified fascinating sexual dimorphisms in feeding behavior in the absence of MC3R. For
example, In the novelty suppressed feeding (NSF) assay in which fasted animals must enter an
open field to retrieve food, MC3RKO males eat equivalent amounts to WT mice, while female
MC3RKO fail to explore, and cease feeding entirely. In contrast, male but not female mice
exhibit enhanced anorexia in response to restraint stress. AgRP neurons, the majority of which
express MC3R, send information regarding nutritional state directly to reproductive and
metabolic control centers, like the PVH and AVPV, and to behavioral control centers like the
ventral tegmental area (VTA), paraventricular nucleus of the thalamus (PVT), and lateral
parabrachial nucleus (PBl), and project indirectly to the insular cortex, involved in sensory
interpretation of food cues and implicated in the pathophysiology of anorexia nervosa. This
proposal will conduct the first systematic mapping and characterization of the MC3R neurons
involved in the coordination of energy homeostasis, reproduction and feeding behavior,
determine the mechanism(s) underlying the requirement of MC3R for fasting-induced
suppression of the HPG axis, and identify the MC3R neurons and circuits mediating sexually
dimorphic feeding behaviors.

## Key facts

- **NIH application ID:** 10468942
- **Project number:** 5R01DK126715-03
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Roger D. Cone
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $350,941
- **Award type:** 5
- **Project period:** 2020-09-20 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10468942

## Citation

> US National Institutes of Health, RePORTER application 10468942, Sexually Dimorphic Expression and Function of the Melanocortin-3 Receptor (5R01DK126715-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10468942. Licensed CC0.

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