# Epigenetic mechanisms underlying sex differences in obesity

> **NIH NIH F32** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2024 · $45,182

## Abstract

PROJECT SUMMARY
 The physiological and functional properties of adipose tissue differ between females and males, which
leads to differences in obesity and metabolic syndrome risk between the sexes. While the gonadal hormones
contribute to these physiological sex differences, the Reue lab has demonstrated that the presence of XX or XY
sex chromosomes further impacts adipose development and function in a sex-dependent manner. Specifically,
the presence of two X chromosomes causes higher body weight and adiposity compared to XY animals. When
two X chromosomes are present, genes on one X chromosome are inactivated to normalize gene expression to
XY cells. However, a subset of these X chromosome genes escape inactivation resulting in higher expression in
XX cells compared to XY cells. This leads to the hypothesis that higher X chromosome gene dosage impacts
sex differences in adiposity. We identified two X chromosome genes, Kdm5c and Kdm6a, that impact adiposity
in vivo by altering preadipocyte and mature adipocyte cellular function, respectively. Reduction of Kdm5c gene
dosage in preadipocytes decreased body weight and adiposity, while reduced Kdm5c gene dosage in mature
adipocytes had no impact on body weight or adiposity. Conversely, reduction of Kdm6a gene dosage in mature
adipocytes reduced body weight and adiposity. Both Kdm5c and Kdm6a encode histone demethylase enzymes
that modify chromatin structure to regulate gene expression across the genome. Thus, the combined actions of
KDM5C in preadipocytes and KDM6A in mature adipocytes may coalesce to impact total adiposity in XX animals.
The proposed studies will elucidate the mechanisms by which KDM5C and KDM6A influence sex differences in
adiposity and metabolism through studies of mouse models with altered gene dosage, and in cultured adipocytes
to identify KDM5C and KDM6A genomic targets. There are three Specific Aims: 1. Uncover physiological
mechanisms by which Kdm6a dosage alters adiposity in vivo. 2. Identify KDM5C and KDM6A genomic targets
in white adipose tissue. 3. Determine the contribution of Kdm5c and Kdm6a gene dosage to weight gain and
increased adiposity in mouse menopause models. Completion of the proposed studies will significantly improve
our understanding of physiological and molecular mechanisms that regulate sex differences in obesity and
metabolic disease.
 The proposed research and training plan will prepare me to transition into an independent investigator
position with a research emphasis on understanding genetic mechanisms driving sex differences in metabolism.
The training in sex differences and adipose tissue biology research in the Reue lab will complement my prior
research experience in metabolic disease and gene regulation to achieve my career goals. The extensive
resources available within the UCLA research environment will further promote my professional development to
accelerate my path to independence as an academic scientist. Importantly, the proposed research p...

## Key facts

- **NIH application ID:** 10793508
- **Project number:** 5F32DK134148-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** Carrie Beth Wiese
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $45,182
- **Award type:** 5
- **Project period:** 2023-03-01 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10793508

## Citation

> US National Institutes of Health, RePORTER application 10793508, Epigenetic mechanisms underlying sex differences in obesity (5F32DK134148-02). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10793508. Licensed CC0.

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