# Arcuate ERa Signaling in Central Control of Female Bone Metabolism

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2023 · $468,356

## Abstract

Project Summary/Abstract
In this revised R01 application we will ask how estrogen signaling in the central nervous system controls
bone metabolism in a sex dependent manner. It is well known that peripheral estrogen affects bone in
both mice and humans. As part of our efforts to understand how estrogen neural circuits in mice affect
female metabolism, we discovered that estrogen signaling in the arcuate nucleus (ARC) of the
hypothalamus normally suppresses cortical and trabecular bone mass in female mice. Ablating estrogen
receptor alpha (ERa) in three intersectional and independent mouse models leads to a striking high bone
mass phenotype in female mice; male bones are unaffected. Mutant females exhibit exceptionally dense
trabecular and cortical bones, whose strengths surpass other reported mouse models. Stereotaxic-
guided deletion of brain ERa confirmed the central origin of this bone phenotype and uncoupled this
phenotype from changes in circulating estradiol, testosterone, or leptin. Our work defines central
regulation of bone metabolism, alongside reproduction and energy balance, as a fundamental sex-
difference in physiology. These data also offer proof for the concept that the brain is a major determinant
of female bone metabolism, thus expanding the gatekeeper function of the hypothalamus in energy
expenditure to non-classical metabolic tissues, such as bone. Although our research is in the earliest
pre-clinical stages, understanding how our models build massively dense and strong bones could
transform current rational design of therapeutics for hormonal and age-related bone loss. Why and how
female ARC neurons normally inhibit bone metabolism remain a mystery. In the following three aims, we
seek to unravel this puzzle. We will define and then confirm which ARC neurons mediate this brain-bone
connection, ask if manipulating these neurons via chemogenetics and pharmacology mimics high bone
phenotype or normalizes the bone phenotype in mutants, and then begin determining the molecular
basis for this sex-dependent high bone phenotype.

## Key facts

- **NIH application ID:** 10634591
- **Project number:** 5R01AG062331-05
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** HOLLY A. INGRAHAM
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $468,356
- **Award type:** 5
- **Project period:** 2019-09-30 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10634591

## Citation

> US National Institutes of Health, RePORTER application 10634591, Arcuate ERa Signaling in Central Control of Female Bone Metabolism (5R01AG062331-05). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10634591. Licensed CC0.

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