Men and women show different incidence and patterns of obesity, which is a major risk factor for diabetes, cardiovascular disease, and other metabolic and reproductive diseases. In mouse models, mice with two X chromosomes have much greater adiposity and dysregulation of lipid metabolism compared with mice with one X chromosome. Thus, the X chromosome encodes factors that contribute to sex differences in metabolism and adiposity. This project aims to understand the metabolic impact of one class of X chromosome genes that are represented differently in nearly all XX and XY cells. These are X genes that escape X inactivation ubiquitously and are expressed from both X chromosomes in XX cells, at a higher level than from the single X chromosome in XY cells. The difference in X gene dosage is hypothesized to give rise to XX vs. XY differences in metabolic disease. Preliminary evidence indicates that one gene escaping X inactivation, histone demethylase Kdm5c, accounts in part for large differences in adiposity and lipid metabolism of mice with one vs. two X chromosomes. The project will investigate the physiological and genomic effects of one vs. two copies of Kdm5c. We will determine the mechanism by which Kdm5c dosage influences adiposity by measuring energy balance, circadian regulation, and related metabolic parameters. We will determine the tissue site(s) of Kdm5c action that account for its effects on adiposity using anatomical and genetic Cre recombinase-mediated strategies. To address the molecular mechanism of Kdm5c dosage effects on adiposity, we will identify which genes are targets of KDM5C histone demethylase activity, resulting in changes in chromatin structure and gene expression. This will inform us about specific gene pathways that are altered by Kdm5c dosage that result in changes in adiposity and metabolism. Because the closely similar Y chromosome paralog Kdm5d appears not to have the same metabolic effects as X-linked Kdm5c, the comparison of the physiological effects, chromatin modifications, and gene expression modulated by Kdm5c and Kdm5d will help to recognize the gene pathways that are regulated by Kdm5c and relevant to metabolism. The results will shed light on fundamental sex differences in obesity and metabolic disease, leading to greater understanding of factors that ameliorate or exacerbate disease.

Public Health Relevance

Men and women show significant differences in obesity, diabetes, and related metabolic diseases. The proposed research aims to understand how dose of a specific X chromosome gene (Kdm5c), which differs in male and female cells, leads to differences in metabolic disease. Understanding the molecular basis and physiological effects of Kdm5c gene dosage will shed light on factors that can prevent metabolic disease in both sexes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
High Priority, Short Term Project Award (R56)
Project #
2R56DK083561-06A1
Application #
9336059
Study Section
Integrative Physiology of Obesity and Diabetes Study Section (IPOD)
Program Officer
Teff, Karen L
Project Start
2010-07-01
Project End
2017-08-31
Budget Start
2016-09-22
Budget End
2017-08-31
Support Year
6
Fiscal Year
2016
Total Cost
$154,000
Indirect Cost
$54,000
Name
University of California Los Angeles
Department
Genetics
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Arnold, Arthur P; Cassis, Lisa A; Eghbali, Mansoureh et al. (2017) Sex Hormones and Sex Chromosomes Cause Sex Differences in the Development of Cardiovascular Diseases. Arterioscler Thromb Vasc Biol 37:746-756
Link, Jenny C; Hasin-Brumshtein, Yehudit; Cantor, Rita M et al. (2017) Diet, gonadal sex, and sex chromosome complement influence white adipose tissue miRNA expression. BMC Genomics 18:89
Link, Jenny C; Reue, Karen (2017) Genetic Basis for Sex Differences in Obesity and Lipid Metabolism. Annu Rev Nutr 37:225-245
Reue, Karen (2017) Sex differences in obesity: X chromosome dosage as a risk factor for increased food intake, adiposity and co-morbidities. Physiol Behav 176:174-182
Arnold, Arthur P (2017) Y chromosome's roles in sex differences in disease. Proc Natl Acad Sci U S A 114:3787-3789
Mauvais-Jarvis, Franck; Arnold, Arthur P; Reue, Karen (2017) A Guide for the Design of Pre-clinical Studies on Sex Differences in Metabolism. Cell Metab 25:1216-1230
Arnold, Arthur P (2017) A general theory of sexual differentiation. J Neurosci Res 95:291-300
Arnold, Arthur P; Reue, Karen; Eghbali, Mansoureh et al. (2016) The importance of having two X chromosomes. Philos Trans R Soc Lond B Biol Sci 371:20150113
Burgoyne, Paul S; Arnold, Arthur P (2016) A primer on the use of mouse models for identifying direct sex chromosome effects that cause sex differences in non-gonadal tissues. Biol Sex Differ 7:68
Itoh, Yuichiro; Mackie, Ryan; Kampf, Kathy et al. (2015) Four core genotypes mouse model: localization of the Sry transgene and bioassay for testicular hormone levels. BMC Res Notes 8:69

Showing the most recent 10 out of 12 publications