# Sex Hormones Differentially Regulate Production of a Distinct Adipocyte Population

> **NIH NIH U54** · UNIVERSITY OF COLORADO DENVER · 2021 · $314,586

## Abstract

PROJECT 3: PROJECT SUMMARY
The menopausal transition, an unavoidable aging related phenomenon in females, is accompanied by increased
abdominal adiposity and the concomitant incidence of adipose-related comorbidities. Although previous research
has primarily focused on body fat distribution, we have generated evidence that the cellular composition of
adipose tissue (AT) defines the phenotype of each individual depot, determining its overall influence on metabolic
health. The premise is that the loss of gonadal hormones alters the cellularity of AT, leading to changes in body
fat distribution and worsening metabolic health. We previously discovered a novel lineage of adipocytes in the
major white adipose depots of mice and humans generated from bone marrow derived cells of the hematopoietic
lineage rather than conventional mesenchymal precursors. In mice, bone marrow-derived adipocytes (BMDAs)
were detected in greater numbers in abdominal fat depots and displayed increased inflammatory cytokine but
decreased leptin and mitochondrial lipid oxidation gene expression, suggesting a critical role in influencing
metabolic health. Furthermore, ovariectomy (OVX) significantly increased BMDA production, which was
attenuated by estradiol (E2) replacement. In addition to declines in E2, menopause (or OVX) is also characterized
by rising follicle stimulating hormone (FSH) levels. Recent research questions whether the consequences of
menopause traditionally attributed to the specific loss of ovarian E2 may instead be resultant to the previously
unappreciated rise in FSH. Here we expand on our previous observations to test the central hypothesis that
E2 and FSH differentially regulate the production of BMDAs, altering the cellular composition of adipose
tissue and resulting in significant changes in metabolic and inflammatory phenotype. Three specific aims
will address this hypothesis: Aim 1: Determine whether E2 and/or FSH signaling regulate BMDA production in
female mice, Aim 2 (Interaction with Project 2): Test whether targeted depletion of BMDAs in female mice
reduces OVX-induced changes in energy adiposity, energy balance, inflammation and metabolic health and Aim
3 (Interaction with Project 1): Test the effects of altered circulating FSH and E2 levels on adipocyte precursor
sub-population accumulation in subcutaneous adipose tissue of women. Successful completion of these studies
will define the role of E2 and FSH in controlling the production of BMDAs, which may contribute to
postmenopausal metabolic pathology. These data have the tremendous potential to highlight BMDA production
as a new therapeutic target providing novel strategies for the prevention of menopausal and aging related chronic
disease risk.

## Key facts

- **NIH application ID:** 10225535
- **Project number:** 5U54AG062319-09
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Dwight J Klemm
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $314,586
- **Award type:** 5
- **Project period:** 2012-09-20 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10225535

## Citation

> US National Institutes of Health, RePORTER application 10225535, Sex Hormones Differentially Regulate Production of a Distinct Adipocyte Population (5U54AG062319-09). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10225535. Licensed CC0.

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