title: The number of x chromosomes causes sex differences in adiposity in mice.
abstract: 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.
authors.affiliation: Department of Integrative Biology and Physiology and Laboratory of Neuroendocrinology or the Brain Research Institute, University of California Los Angeles, Los Angeles, California, United States of America.
authors.forename: Xuqi
authors.initials: X
authors.lastname: Chen
authors.forename: Rebecca
authors.initials: R
authors.lastname: McClusky
authors.forename: Jenny
authors.initials: J
authors.lastname: Chen
authors.forename: Simon W
authors.initials: SW
authors.lastname: Beaven
authors.forename: Peter
authors.initials: P
authors.lastname: Tontonoz
authors.forename: Arthur P
authors.initials: AP
authors.lastname: Arnold
authors.forename: Karen
authors.initials: K
authors.lastname: Reue
mesh_terms: D050154:Adiposity / Q000235:genetics / Q000502:physiology; D000818:Animals; D059305:Diet, High-Fat; D005260:Female; D042341:Gonadal Hormones / Q000378:metabolism; D006066:Gonads / Q000166:cytology / Q000378:metabolism; D007328:Insulin / Q000097:blood; D050356:Lipid Metabolism / Q000235:genetics; D008055:Lipids / Q000097:blood; D008297:Male; D051379:Mice; D009765:Obesity / Q000235:genetics*; D012727:Sex Characteristics; D019849:Sex Determination Processes; D015430:Weight Gain / Q000235:genetics; D014960:X Chromosome / Q000235:genetics* / Q000502:physiology; D014998:Y Chromosome / Q000235:genetics / Q000502:physiology
chemical_list: D042341:Gonadal Hormones; D007328:Insulin; D008055:Lipids