# Characterization of Kiss1 neurons as mediators of the reproductive regulation of energy balance

> **NIH NIH R01** · BRIGHAM AND WOMEN'S HOSPITAL · 2024 · $543,565

## Abstract

ABSTRACT
Reproduction and metabolism are closely regulated to ensure the survival of the organism and the species. The
central control of energy balance depends on the intricate interaction of central and peripheral signals that
ultimately regulate food intake and energy expenditure (EE). Among the central signals involved in the control of
energy balance, melanocortins (a-MSH) produced by proopiomelanocortin (POMC) neurons play a critical role
inducing satiety and increasing EE. a-MSH binds the melanocortin receptor 4 (MC4R) at the level of the
paraventricular nucleus to induce satiety, however, the site of action of melanocortins to regulate EE remains
under-characterized. Recently, the reproductive neuropeptide kisspeptin, encoded by Kiss1, has been identified
as a metabolic factor in several animal models, for example, kisspeptin signaling deficient mice develop obesity.
Kisspeptin has been demonstrated to be essential for the activation of the reproductive axis, however, its role in
metabolism requires further investigation. Our preliminary data expands on these findings and suggest that
melanocortin signaling to Kiss1 neurons is involved in the control of EE. We have showed that Kiss1
neurons a) express MC4R, b) respond directly to the stimulation by a-MSH, c) are direct targets of POMC
neurons, which post-synaptically regulate Kiss1 neurons, and d) innervate and activate Lepr neurons in the
dorsomedial hypothalamus (DMH) through glutamate release. In addition, we have demonstrated that the
specific removal of MC4R from Kiss1 neurons induces an increase in body weight (BW) due to a decrease in EE
without changes in overall food intake or activity and without causing hypogonadism. Therefore, we hypothesize
that Kiss1 neurons serve as mediators of the melanocortin action to regulate EE through the control of LeprDMH
neurons, thus uncovering a novel pathway of action for melanocortins in the control of energy balance that links
reproduction and metabolism. We propose to 1) evaluate the changes in EE after ablation or chronic activation
of Kiss1 neurons; 2) assess the overall contribution of Kiss1 neurons to the melanocortin regulation of EE
through the re-insertion of MC4R in Kiss1 neurons of MC4RKO mice; 3) map the neurocircuitry underlying this
role through the identification of neuronal projections and optogenetic activation of Kiss1 neuron terminals; 3)
assess the contribution of kisspeptin co-transmitters in the control of EE. Kiss1 neurons are the nodal
regulatory center of reproductive function and are, therefore, sensitive to changes in the circulating levels of sex
steroids. Thus, the successful completion of this proposal may offer the first approach to a comprehensive
pathway linking reproductive status and the regulation of energy expenditure that could explain the frequently
observed increase in BW after menopause in women or men with low testosterone. Moreover, the
characterization of Kiss1 neurons as an active player in the cont...

## Key facts

- **NIH application ID:** 10851797
- **Project number:** 5R01DK133760-03
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** Victor Manuel Navarro
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $543,565
- **Award type:** 5
- **Project period:** 2022-08-12 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10851797

## Citation

> US National Institutes of Health, RePORTER application 10851797, Characterization of Kiss1 neurons as mediators of the reproductive regulation of energy balance (5R01DK133760-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10851797. Licensed CC0.

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