# Role of the Melanocortin-3 Receptor in Regulation of the HPG Axis

> **NIH NIH K99** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2024 · $111,954

## Abstract

Project Summary:
Reproduction is energetically demanding and as a result, the hypothalamic-pituitary-gonadal (HPG) axis is
tightly regulated by metabolic factors. However, the specific neural circuitry underlying the interaction between
metabolic and reproductive state remains incompletely understood. The melanocortin-3 receptor (MC3R) plays
a critical role in the bi-directional communication between metabolic state and reproductive function, and the
utility of the MC3R to address reproductive disorders is untested. The MC3R is ideally positioned both
anatomically and functionally, to mediate direct communication between metabolic state and the reproductive
axis. MC3R is expressed in nearly 100% of the AgRP neurons, the primary neurons of the central melanocortin
system, as well as in secondary target sites of the melanocortin system, such as the kisspeptin neurons.
Furthermore, female mice lacking MC3R exhibit altered reproductive cycle lengths and do not suppress
reproductive cycles in response to fasting. Both mice and humans with MC3R mutations show delays in
pubertal onset, demonstrating the highly conserved role of this receptor. Our preliminary data show that male
MC3RKO mice are significantly delayed in pubertal onset, whereas female MC3RKO mice have a delay to first
estrus. Hypothalamic MC3R expression follows a sexually dimorphic pattern in both mice and humans,
however sex differences in MC3R control of reproductive function have not been explored. For example, little is
known about the role of this receptor in the physiology and pathophysiology of HPG axis control. In this
application, I will study the neuroendocrine role of MC3R in the physiology and pathophysiology of HPG axis
control. The principal investigator in this training grant, Dr. Danielle Porter, has extensive experience in
reproductive neuroendocrinology and neuroanatomy. In this training grant, Dr. Porter will receive additional
training in metabolic physiology and pharmacology from the primary research mentor, Dr. Roger Cone.
Furthermore, under the guidance of an expert team of collaborators, Dr. Porter will receive hands on training in
whole brain imaging and further training in neuroendocrinology. Together, the mentorship and training in this
K99/R00 application will provide the necessary technical and conceptual background for Dr. Porter to initiate
an independent research program focusing on MC3R neural circuits as therapeutic targets for disorders at the
interface of reproduction and metabolism.

## Key facts

- **NIH application ID:** 10984158
- **Project number:** 1K99HD113878-01A1
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Danielle Tiffany Porter
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $111,954
- **Award type:** 1
- **Project period:** 2024-08-01 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10984158

## Citation

> US National Institutes of Health, RePORTER application 10984158, Role of the Melanocortin-3 Receptor in Regulation of the HPG Axis (1K99HD113878-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10984158. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*