# A sex-biased obesity gene on the X chromosome

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2024 · $550,812

## Abstract

The leading cause of death in women in the United States is cardiovascular disease (CVD). Progress in reducing
CVD in women has lagged behind progress in men. Obesity is a prevalent risk factor for CVD, and becomes
more prevalent in women following menopause. We have shown that XX chromosome complement promotes
increased adiposity in female compared to male mice, and this effect is amplified when gonadal hormone levels
are diminished, as occurs after menopause in humans. We have identified the Kdm5c gene on the X
chromosome as a key contributor to XX effects on adiposity. Kdm5c is expressed at higher levels in female
compared to male humans and mice due to escape from X chromosome inactivation. Kdm5c encodes a histone
demethylase that modulates chromatin structure and gene expression. Reducing Kdm5c gene dosage in XX
females to that normally present in XY males reduces adipose tissue mass and alters histone marks in
preadipocytes to favor induction of beige adipocytes and enhanced whole body energy expenditure. We
hypothesize that sex differences in histone modifications throughout the genome, which likely change in
hypogonadal states such as menopause, influence sex differences in adipose tissue function. We will investigate
key questions regarding the role of Kdm5c gene dosage, and more generally, histone modifications and gene
regulation, as determinants of sex differences in adipose tissue. Aim 1: Is Kdm5c gene dosage a determinant
of weight/fat gain in hypogonadal states? We hypothesize that Kdm5c gene dosage is partially responsible
for the impact of X chromosome dosage on weight gain when gonadal hormone levels are diminished. We will
test the impact of Kdm5c gene dosage on weight gain, adiposity, and energy balance in female and male mice
with preadipocyte Kdm5c deficiency under normal and reduced hormone levels. Aim 2: What is the effect of
sex, gonadal hormones, and Kdm5c gene dosage on adipocyte histone and gene expression profiles at
the tissue and single-cell levels? We will map the histone landscape and corresponding gene expression
profile in adipose tissue to identify effects of sex, gonadal hormones, and Kdm5c gene dosage (A) at the tissue
level using CUT&RUN and RNA-seq, and (B) and the single-nucleus level using Paired-Tag to simultaneously
profile histone marks and gene expression in individual nuclei. Aim 3: How do sex and gonadal hormone
status impact the histone landscape in human adipocytes? There is a dearth of information regarding the
effect of sex on histone modifications in human adipose tissue, and whether changes in histone profile underlie
alterations in adipose tissue following menopause/andropause. We will map histone profiles in adipose tissue of
women vs. men, and in pre- vs. post-menopausal women. Our studies will shed light on how sex influences the
epigenetic regulation of adipose tissue gene expression, composition, and function through histone
modifications. This knowledge may inform therapeutic strategies...

## Key facts

- **NIH application ID:** 10872674
- **Project number:** 1R01DK143368-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** Karen Reue
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $550,812
- **Award type:** 1
- **Project period:** 2024-09-20 → 2028-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10872674

## Citation

> US National Institutes of Health, RePORTER application 10872674, A sex-biased obesity gene on the X chromosome (1R01DK143368-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10872674. Licensed CC0.

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