The Number of X Chromosomes Causes Sex Differences in Adiposity in Mice
Open accessAbstract
Sexual dimorphism in body weight, fat distribution, and metabolic disease has been attributed largely to differential effects of male and female gonadal hormones. Here, we report that the number of X chromosomes within cells also contributes to these sex differences. We employed a unique mouse model, known as the "four core genotypes," to distinguish between effects of gonadal sex (testes or ovaries) and sex chromosomes (XX or XY). With this model, we produced gonadal male and female mice carrying XX or XY sex chromosome complements. Mice were gonadectomized to remove the acute effects of gonadal hormones and to uncover effects of sex chromosome complement on obesity. Mice with XX sex chromosomes (relative to XY), regardless of their type of gonad, had up to 2-fold increased adiposity and greater food intake during daylight hours, when mice are normally inactive. Mice with two X chromosomes also had accelerated weight gain on a high fat diet and developed fatty liver and elevated lipid and insulin levels. Further genetic studies with mice carrying XO and XXY chromosome complements revealed that the differences between XX and XY mice are attributable to dosage of the X chromosome, rather than effects of the Y chromosome. A subset of genes that escape X chromosome inactivation exhibited higher expression levels in adipose tissue and liver of XX compared to XY mice, and may contribute to the sex differences in obesity. Overall, our study is the first to identify sex chromosome complement, a factor distinguishing all male and female cells, as a cause of sex differences in obesity and metabolism.
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The four core genotypes mouse model has helped identify the influence of sex chromosomes on physical traits, such as obesity and food intake.
“the four core genotypes mouse model which incorporates mice with four different combinations of gonads and sex chromosomes [66, 67], has helped identify the influence of sex chromosomes on physical traits, such as obesity and food intake [68, 69].”
From Integrating Transwomen and Female Athletes with Differences of Sex Development (DSD) into Elite Competition: The FIMS 2021 Consensus Statement (2021) · cites this paper as [68]
When placed on a high-fat diet, XX mice gained adiposity and developed fatty liver and insulin resistance regardless of their original gonadal sex.
“When placed on a high-fat diet, XX mice gained adiposity and developed fatty liver and insulin resistance regardless of their original gonadal sex.”
From Sex differences in metabolic homeostasis, diabetes, and obesity (2015) · cites this paper as [74]
Male and female XX mice exhibit increased fat depots and increased food intake compared to XY mice.
“Using this model, Chen et al. showed that male and female XX mice exhibit increased fat depots and increased food intake compared to XY mice.”
From Sex differences in metabolic homeostasis, diabetes, and obesity (2015) · cites this paper as [74]
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- Authors
- Chen, X., McClusky, R., Chen, J., Beaven, S. W., Tontonoz, P., Arnold, A. P., & Reue, K.
- Affiliations
- University of California, Los Angeles (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Reue, Karen
- Venue
- PLoS Genetics
- Publisher
- Public Library of Science (PLoS)
- Published
- 2012-05-10
- Volume
- 8
- Issue
- 5
- Pages
- e1002709
- ISSN
- 1553-7390 (ISSN-L)
- 1553-7404
- PMC
- PMC3349739
- OpenAlex
- W1978661176
- Cited by
- 326
- References
- 68
- Citations by year
- 2026: 16 · 2025: 21 · 2024: 34 · 2023: 22 · 2022: 42 · 2021: 29 · 2020: 19 · 2019: 25 · 2018: 27 · 2017: 21 · 2016: 14 · 2015: 18 · 2014: 20 · 2013: 17 · 2012: 1
- FWCI
- 10.76
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS Genetics (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- eScholarship (California Digital Library) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- Figshare (submittedVersion, cc-by)
- Funders
- Howard Hughes Medical Institute
- National Heart, Lung, and Blood Institute (P01HL090553, P01 HL90553)
- National Institute of General Medical Sciences (GM 007185, T32GM007185)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK83561, R01DK083561)
- National Institute of Neurological Disorders and Stroke (R01NS043196)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and Clinical Aspects of Sex Determination and Chromosomal Abnormalities
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sexual Differentiation and Disorders
- Keywords
- sex differences in obesity, X chromosome dosage, sex chromosome complement, adiposity, gonadal hormones, gonadectomy, X chromosome inactivation escape, high-fat diet, hepatic steatosis, insulin, lipid metabolism, dietary intake, adipose tissue, liver
- MeSH terms
- Animals, Female, Gonads, Insulin, Lipids, Male, Obesity, Sex Characteristics, X Chromosome, Y Chromosome, Weight Gain, Sex Determination Processes, Gonadal Hormones, Adiposity, Lipid Metabolism, Mice, Diet, High-Fat
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