# Crosstalk between Estrogen and Metabolic Hormone Signaling in Kisspeptin Neurons

> **NIH NIH R56** · OREGON HEALTH & SCIENCE UNIVERSITY · 2020 · $261,800

## Abstract

Project Summary
The long range goals of our research program has been to elucidate the mechanism(s) by which metabolic
states and 17β-estradiol (E2) regulate arcuate nucleus kisspeptin (Kiss1ARH) neuronal circuits that are critical
for coordinating energy homeostasis and reproduction in females. It is well known that E2 is anorexigenic, and
that Kiss1 neurons, which are directly regulated by E2, are essential for pubertal development and adult
reproductive success. However, their role in the control of other homeostatic functions is just emerging.
Earlier, we found that Kiss1ARH neurons are depolarized/excited by leptin and insulin via canonical transient
receptor potential (TRPC) 5 channel signaling and proposed that they may serve as an important hub in the
control of energy homeostasis. Recently, we found that high frequency optogenetic stimulation of Kiss1ARH
neurons releases glutamate to excite the anorexigenic proopiomelanocortin (POMC) neurons but inhibit the
orexigenic neuropeptide Y/agouti-related peptide (AgRP) neurons. E2 increases vesicular glutamate
transporter 2 (Vglut2) mRNA expression and glutamate release from female Kiss1ARH neurons to augment the
POMC excitation and AgRP inhibition. Also, Kiss1ARH neurons project to and excite AVPV/PeN Kiss1 neurons
via glutamate, which drives the GnRH and LH surges. Thus, Kiss1ARH neurons appear to integrate metabolic
hormone and gonadal steroid signaling to regulate both energy homeostasis and reproduction via multiple
neurotransmitters. Key excitatory cationic channels are upregulated by E2 leading to increased excitability and
glutamatergic synaptic transmission, whereas peptide expression and transmission are attenuated by the
classical estrogen receptor (ER) signaling pathways. Recently, we have found that the selective membrane
estrogen receptor (GqmER) agonist STX increases the excitability of Kiss1ARH neurons without downregulating
the peptide expression. Therefore, we hypothesize that estrogenic signaling in Kiss1ARH neurons is important
for increasing Kiss1ARH neuronal excitability and maintenance of homeostatic functions critical for reproductive
success. Our multidisciplinary approach incorporates a powerful set of cellular, molecular, genetic and
optogenetic tools, and our combined expertise in molecular biology, electrophysiology, and whole animal
physiology to address the following aims: (1) to measure the estrogenic-mediated increase in excitability of
Kiss1ARH neurons using GCaMP6 and Voltron recordings; (2) to elucidate the estrogenic modulation of the
synaptic input from Kiss1ARH to hypothalamic paraventricular nucleus neurons using optogenetic stimulation
and its effects on food intake; and (3) to elucidate the estrogenic modulation of synaptic input from Kiss1ARH
neurons to hypothalamic dorsomedial nucleus neurons and its effects on energy expenditure. Elucidating the
circuits and signaling cascades underlying the actions of E2 and the selective GqmER agonist STX will prov...

## Key facts

- **NIH application ID:** 10246663
- **Project number:** 2R56DK068098-13
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** Martin Jeffrey Kelly
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $261,800
- **Award type:** 2
- **Project period:** 2005-03-01 → 2021-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10246663

## Citation

> US National Institutes of Health, RePORTER application 10246663, Crosstalk between Estrogen and Metabolic Hormone Signaling in Kisspeptin Neurons (2R56DK068098-13). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10246663. Licensed CC0.

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