# Sex Differences in the Metabolic Syndrome

> **NIH NIH U54** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2020 · $1,520,214

## Abstract

PROJECT SUMMARY - Overall: Sex Differences in the Metabolic Syndrome
 The objective of our SCORE on “Sex Differences in the Metabolic Syndrome” is to elucidate sex
differences in risk factors and treatments for Metabolic Syndrome (MetSyn) components such as obesity,
insulin resistance/diabetes, dyslipidemia, and fatty liver. Differences between men and women in susceptibility
to cardio-metabolic disease are well known, but the underlying genetic and physiological mechanisms remain
poorly defined. Our goal is to identify factors that determine sex-specific MetSyn risk, which may lead to better
diagnosis and treatment for both sexes. A unique feature of our program is the investigation of sex differences
in MetSyn from multiple perspectives, including effects of estrogen, of XX vs. XY sex chromosome
complement, and of genetic variation. Our program consists of three research projects and three cores, and
will use preclinical models and human tissue samples. Project 1, “Sex chromosome effects on metabolic
syndrome risk and treatment,” will build on the finding that the presence of XX compared to XY chromosomes
increases susceptibility to obesity and related traits. Much of the XX effect is attributable to the Kdm5c gene,
which escapes X chromosome inactivation and encodes a histone modifying enzyme. Our studies will define
the effects of Kdm5c dose on the epigenetic regulation of gene expression, energy balance, and adipose
tissue remodeling during obesity. They will also elucidate the XX chromosome effect on increased female risk
for diabetes secondary to statin drug therapy, and test a dietary co-therapy that may alleviate this sex-biased
adverse drug response. Project 2, “Gene-by-sex interactions in mitochondrial functions and metabolic traits,”
seeks to understand the roles of both genetics and sex in MetSyn traits. Results of a “systems genetics”
approach have implicated sex- and tissue-specific action of specific genes on MetSyn traits. Our studies will
elucidate sex effects on mitochondrial functions in insulin resistance, sex-specific effects of the adipokine
lipocalin 2 on adiposity and insulin resistance, and the sex-specific role of the PKLR pyruvate kinase in hepatic
steatosis. The gene-by-sex interactions discovered in the mouse will be tested in tissues from human cohorts.
Project 3, “The impact of estrogen receptor (ER)  in metabolic health,” will test the hypothesis that muscle
ER protects against metabolic dysfunction in mice and women, will identify ER regulatory sites across the
genome in females and males, and elucidate the effect of ER on the regulation of mitochondrial function.
Results may provide proof-of-concept evidence that skeletal muscle ER is an effective therapeutic target to
combat metabolic dysfunction and type 2 diabetes. The Genomic Technologies Core will perform RNA-seq,
ChIP-seq and related technologies for all three projects. The Career Enhancement Core will foster research
in sex differences in metabolism ...

## Key facts

- **NIH application ID:** 10004046
- **Project number:** 5U54DK120342-03
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** Karen Reue
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $1,520,214
- **Award type:** 5
- **Project period:** 2018-09-20 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10004046

## Citation

> US National Institutes of Health, RePORTER application 10004046, Sex Differences in the Metabolic Syndrome (5U54DK120342-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10004046. Licensed CC0.

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