Editors' ChoiceMetabolism

It’s all about the X

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Science Translational Medicine  19 Aug 2020:
Vol. 12, Issue 557, eabd4937
DOI: 10.1126/scitranslmed.abd4937

Abstract

Genes expressed on the X chromosome affect body weight and body fat composition.

Sex differences in body composition and fat distribution and their correlation with metabolic outcomes were first described by Jean Vague in 1947. Since then, a large body of data has described the correlation with intra-abdominal fat and metabolic outcomes. Sex hormones have been shown to affect body composition and distribution, but the genetic effect of chromosomal sex independent of gonadal hormones is not as well delineated, including the effect of dosage X-escape genes—genes that are expressed on both X chromosomes but escape inactivation on one of the X chromosomes.

In the study by Link et al., the authors performed several experiments in mice to show the effect of X chromosome genes on body adiposity and validated the results in humans. First, they used four mouse models to show the differential effect of gonadal compared to chromosomal sex: XX with testes, XX with ovaries, XY with testes, and XY with ovaries. On a normal chow diet, the presence of testes correlated with higher weight, specifically in lean mass, whereas the presence of ovaries correlated with higher fat mass. However, after a high-fat diet, XX genotypes correlated with higher body fat, irrespective of testes or ovaries, compared to XY. In a second experiment, the authors examined the effect of transcription of two copies compared to one copy of an X chromosome expressed gene, Kdm5c, which is involved in adipocyte differentiation. In XX mice, expression of two copies of the Kdm5c gene was associated with higher weight gain, adiposity, and preadipocyte proliferation. Last, the authors showed that higher expression of KDM5C in human adipocytes of 776 female twins from the TwinsUK cohort positively correlated with BMI, and in the Multi-Ethnic Study of Atherosclerosis (MESA), gene variants in KDM5C associated with increased adiposity in African American and Hispanic men and Hispanic women.

Overall, this study shows that gene dosage, specifically on the X chromosome, in part explain sex differences seen in body composition and fat distribution independent of sex hormones. These findings may have implications for changes in body fat distribution and composition in gender-affirming therapy.

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