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.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Integrative Physiology of Obesity and Diabetes Study Section (IPOD)
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Pawlyk, Aaron
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University of California Los Angeles
Schools of Arts and Sciences
Los Angeles
United States
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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
Chen, Xuqi; Wang, Lixin; Loh, Dawn H et al. (2015) Sex differences in diurnal rhythms of food intake in mice caused by gonadal hormones and complement of sex chromosomes. Horm Behav 75:55-63
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
Itoh, Yuichiro; Arnold, Arthur P (2015) Are females more variable than males in gene expression? Meta-analysis of microarray datasets. Biol Sex Differ 6:18
Link, Jenny C; Chen, Xuqi; Prien, Christopher et al. (2015) Increased high-density lipoprotein cholesterol levels in mice with XX versus XY sex chromosomes. Arterioscler Thromb Vasc Biol 35:1778-86
Manwani, Bharti; Bentivegna, Kathryn; Benashski, Sharon E et al. (2015) Sex differences in ischemic stroke sensitivity are influenced by gonadal hormones, not by sex chromosome complement. J Cereb Blood Flow Metab 35:221-9
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
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
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

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