Figure 4. Identification of an X chromosome escape gene that promotes adiposity.

(A) Four Core Genotypes mice show greater adiposity in XX compared to XY mice in hypogonadal or high-fat diet conditions. XY* mice show greater adiposity in genotypes with two X chromosomes compared to those with one X chromosome, regardless of Y chromosome presence. This led to the hypothesis that an X chromosome escape gene may underlie this difference. Reduction of Kdm5c gene dosage in female mice to one copy present in male mice reduced adiposity. Reduced Kdm5c expression levels in cultured preadipocytes led to reduced adipocyte proliferation and differentiation in vitro. (B) Kdm5c encodes a histone demethylase that is expressed at higher levels in female XX cells compared to male XY cells due to escape from X inactivation. Modulation of Kdm5c expression in cultured preadipocytes leads to altered chromatin structure and gene expression levels, which contribute to the sex differences in adiposity. See text for additional details.