# Cross-talk between Estrogen and Metabolic Hormone Signaling in Kisspeptin Neurons

> **NIH NIH R01** · OREGON HEALTH & SCIENCE UNIVERSITY · 2022 · $491,422

## 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 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 in both females and males. E2 increases vesicular glutamate transporter 2 (Vglut2)
mRNA expression and glutamate release from female Kiss1ARH neurons to augment the POMC excitation and
AgRP inhibition. In contrast, Vglut2 mRNA expression and glutamate release are increased in castrates as
compared to intact males, illustrating an important sex difference in the synthesis and release of glutamate. Key
excitatory cationic channels are upregulated by E2 leading to increased excitability and glutamatergic synaptic
transmission. Recently, we have found that the selective membrane estrogen receptor (GqmER) agonist STX
increases the excitability of Kiss1ARH neurons without downregulating the peptide expression. It also decreases
food-intake in both females and males. 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 in E2 (STX)-treated females and STX-treated males; and (3) to elucidate the estrogenic
modulation of synaptic input from Kiss1ARH neurons to hypothalamic dorsomedial nucleus neurons and its effects
on energy expenditure in E2 (STX)-treated females and STX-treated males. Elucidating the circuits and signaling
cascades underlying the actions of E2 and STX will provide a neurophysiological/neuropharmacological
framework for a more thoroug...

## Key facts

- **NIH application ID:** 10473890
- **Project number:** 5R01DK068098-14
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** Martin Jeffrey Kelly
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $491,422
- **Award type:** 5
- **Project period:** 2005-03-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10473890

## Citation

> US National Institutes of Health, RePORTER application 10473890, Cross-talk between Estrogen and Metabolic Hormone Signaling in Kisspeptin Neurons (5R01DK068098-14). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10473890. Licensed CC0.

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