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. This project aims to understand the biological origins of these sex differences. We will use the novel mouse model, the "four core genotypes" (FCG), which includes mice with testes that have XX or XY sex chromosomes, and mice with ovaries that also have either XX or XY sex chromosomes. Thus, the FCG model offers significant advantages for discriminating among several classes of biological factors that lead to sex differences, including organizational and activational effects of gonadal hormones, and direct effects of X and Y genes that create an inherent sex bias in the function of XX and XY cells. We propose to use the FCG model to tease apart the effects of sex hormones (testicular or ovarian secretions) vs. sex chromosomes (XX vs. XY genotype) on energy balance, adipose tissue function, glucose and lipid homeostasis, and other aspects of metabolism. Physiological variables will be measured during manipulations of gonadal hormonal levels after gonadectomy and hormone replacement. The X-linked genes that cause sex chromosome effects on obesity will be identified by linkage studies, gene expression, and analysis of transgenic mice. The results will shed light on fundamental sex differences in obesity and metabolic disease, leading to greater understanding of sex-specific 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 the biological origins of such sex differences, especially those differences that are caused by the sex differences in genomic representation of X and Y genes. Understanding the molecular basis of sex differences 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
Research Project (R01)
Project #
5R01DK083561-05
Application #
8639549
Study Section
Integrative Physiology of Obesity and Diabetes Study Section (IPOD)
Program Officer
Pawlyk, Aaron
Project Start
2010-07-01
Project End
2015-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
5
Fiscal Year
2014
Total Cost
$316,355
Indirect Cost
$110,930
Name
University of California Los Angeles
Department
Physiology
Type
Schools of Arts and Sciences
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Seu, E; Groman, S M; Arnold, A P et al. (2014) Sex chromosome complement influences operant responding for a palatable food in mice. Genes Brain Behav 13:527-34
Li, Jingyuan; Chen, Xuqi; McClusky, Rebecca et al. (2014) The number of X chromosomes influences protection from cardiac ischaemia/reperfusion injury in mice: one X is better than two. Cardiovasc Res 102:375-84
Itoh, Yuichiro; Arnold, Arthur P (2014) X chromosome regulation of autosomal gene expression in bovine blastocysts. Chromosoma 123:481-9
Arnold, Arthur P (2014) Conceptual frameworks and mouse models for studying sex differences in physiology and disease: why compensation changes the game. Exp Neurol 259:2-9
Arnold, Arthur P; Chen, Xuqi; Link, Jenny C et al. (2013) Cell-autonomous sex determination outside of the gonad. Dev Dyn 242:371-9
Chen, Xuqi; McClusky, Rebecca; Itoh, Yuichiro et al. (2013) X and Y chromosome complement influence adiposity and metabolism in mice. Endocrinology 154:1092-104
Arnold, Arthur P; Lusis, Aldons J (2012) Understanding the sexome: measuring and reporting sex differences in gene systems. Endocrinology 153:2551-5