X chromosome dosage of histone demethylase KDM5C determines sex differences in adiposity
Jenny C. Link, Carrie B. Wiese, Xuqi Chen, Rozeta Avetisyan, Emilio Ronquillo, Feiyang Ma, Xiuqing Guo, Jie Yao, Matthew Allison, Yii-Der Ida Chen, Jerome I. Rotter, Julia S. El -Sayed Moustafa, Kerrin S. Small, Shigeki Iwase, Matteo Pellegrini, Laurent Vergnes, Arthur P. Arnold, Karen Reue
Jenny C. Link, Carrie B. Wiese, Xuqi Chen, Rozeta Avetisyan, Emilio Ronquillo, Feiyang Ma, Xiuqing Guo, Jie Yao, Matthew Allison, Yii-Der Ida Chen, Jerome I. Rotter, Julia S. El -Sayed Moustafa, Kerrin S. Small, Shigeki Iwase, Matteo Pellegrini, Laurent Vergnes, Arthur P. Arnold, Karen Reue
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Research Article Genetics Metabolism

X chromosome dosage of histone demethylase KDM5C determines sex differences in adiposity

Abstract

Males and females differ in body composition and fat distribution. Using a mouse model that segregates gonadal sex (ovaries and testes) from chromosomal sex (XX and XY), we showed that XX chromosome complement in combination with a high-fat diet led to enhanced weight gain in the presence of male or female gonads. We identified the genomic dosage of Kdm5c, an X chromosome gene that escapes X chromosome inactivation, as a determinant of the X chromosome effect on adiposity. Modulating Kdm5c gene dosage in XX female mice to levels that are normally present in males resulted in reduced body weight, fat content, and food intake to a degree similar to that seen with altering the entire X chromosome dosage. In cultured preadipocytes, the levels of KDM5C histone demethylase influenced chromatin accessibility (ATAC-Seq), gene expression (RNA-Seq), and adipocyte differentiation. Both in vitro and in vivo, Kdm5c dosage influenced gene expression involved in extracellular matrix remodeling, which is critical for adipocyte differentiation and adipose tissue expansion. In humans, adipose tissue KDM5C mRNA levels and KDM5C genetic variants were associated with body mass. These studies demonstrate that the sex-dependent dosage of Kdm5c contributes to male/female differences in adipocyte biology and highlight X-escape genes as a critical component of female physiology.

Authors

Jenny C. Link, Carrie B. Wiese, Xuqi Chen, Rozeta Avetisyan, Emilio Ronquillo, Feiyang Ma, Xiuqing Guo, Jie Yao, Matthew Allison, Yii-Der Ida Chen, Jerome I. Rotter, Julia S. El -Sayed Moustafa, Kerrin S. Small, Shigeki Iwase, Matteo Pellegrini, Laurent Vergnes, Arthur P. Arnold, Karen Reue

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Figure 1

XX mice gain more weight than XY mice on a high-fat diet.

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XX mice gain more weight than XY mice on a high-fat diet. (A) Body weigh...
(A) Body weight curves of gonadally intact FCG mice fed a chow diet. XX and XY refer to chromosome type; F, female gonads (ovaries); M, male gonads (testes). n = 11 XX female; n = 11 XX male; n = 12 XY female; n = 16 XY male. (B) Body weight and (C) percentage weight gained in FCG mice over 10 weeks on high-fat diet, starting at 14 weeks of age. n = 8 mice per genotype (B–G). (D) Body weight, fat mass, lean mass, percentage of fat mass, and percentage of lean mass on chow and (E) after 10 weeks of high-fat feeding. (F) Representative mice after 10 weeks of high-fat diet (individuals with median body weight shown for each genotype). (G) Gonadal and inguinal fat pad mass normalized to kidney mass. (H) Food intake measured at 1 week (left) and at 8 weeks (right) of high-fat diet feeding during the dark (black horizontal bar) and light (white horizontal bar) periods of the circadian cycle (note different y axis scales). n = 4 mice per genotype. Data are represented as mean ± SD. Data in A–C were analyzed by repeated measures 3-way ANOVA (factors of gonadal sex, sex chromosomes, and age). Data in D–H were analyzed by 2-way ANOVA. Statistically significant differences for sex chromosome complement and for gonadal sex are denoted by brackets. Int., significant interactions of sex chromosome complement and gonadal sex. *P < 0.05; **P < 0.01; ***P < 0.001; †P < 0.0001; ‡P < 0.00001. HFD, high-fat diet.