# A novel MC4R neural pathway in feeding

> **NIH NIH R01** · UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON · 2024 · $383,208

## Abstract

Project Summary
The development of therapeutic drugs to cure obesity has not been successful due to unwanted side effects
and limited efficacy. My long term research goal is to delineate neural pathways responsible for body weight
homeostasis, and provide a framework for effective and specific therapeutics against obesity. Despite exciting
progress has been made in understanding feeding behavior regulated by melanocortin receptors 4 (Mc4Rs)
and paraventricular hypothalamus, downstream neurons that mediate their action on feeding are not clear.
Our preliminary data showed that PVH neurons sent abundant projections to the ventral part of lateral septum
(LSv), where a subset of leptin receptor (LepR)-expressing neurons are located. In vivo optogenetic stimulation
of channelrhodopsin 2 (ChR2)-expressing PVH→LSv fibers potently inhibited feeding, suggesting a previously
unappreciated role for LSv neurons in mediating the PVH action on feeding. Importantly, LSv local
administration of glutamate receptor antagonists increased feeding, suggesting an ongoing tonic glutamatergic
action in LSV on feeding inhibition. Based on our strong preliminary data and the established role for PVH
Mc4R neurons in feeding, we hypothesize that monosynaptic PVH Mc4R→LSv glutamatergic projections
regulate feeding through controlling LSv LepR neuron activity. Aim 1 will test the effects on inhibiting PVH
Mc4R-LSv firers on anxiety and anxiety related hypophagia. Aim 2 will determine the role of Mc4Rs and
glutamate release from LSv-projecting PVH neurons in body weight regulation. Aim 3 will determine whether
the role of PVH direct downstream neurons the LSv in body weight regulation.
This proposal utilizes a combination of optogenetics and mouse genetics to reveal a previously unknown
PVH→LSV neural pathway in feeding regulation and will establish LepR neurons in LSV as a novel direct
downstream target of PVH for feeding regulation. This novel circuit will potentially bridge hypothalamic feeding
regulation with functions associated with limbic LSV regions such as stress and anxiety, representing a
significant step in understanding the complex feeding behavior with more relevance to human obesity
associated with anxiety-related overeating.

## Key facts

- **NIH application ID:** 10816481
- **Project number:** 5R01DK131446-03
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
- **Principal Investigator:** Qingchun Tong
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $383,208
- **Award type:** 5
- **Project period:** 2022-05-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10816481

## Citation

> US National Institutes of Health, RePORTER application 10816481, A novel MC4R neural pathway in feeding (5R01DK131446-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10816481. Licensed CC0.

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