UCLA

Metabolic syndrome (MetS) is a cluster of cardiometabolic risk factors, including visceral fat accumulation, dyslipidemia, insulin resistance and hypertension that significantly increase the risk for cardiometabolic disease. Males and females differ in body fat content, basal metabolic rate, and metabolic fuel utilization, which lead to sex differences in the prevalence and progression of MetS. In addition to the recognized roles of sex hormones, we have identified the sex chromosome complement (XX or XY) is an additional determinant of sex differences in adiposity and related metabolic traits. Specifically, the presence of a second X chromosome in the XX karyotype compared to the XY karyotype promotes increases fat mass accumulation. We hypothesized that XX chromosome dosage promotes fat accumulation through the action of specific X chromosome genes that are differentially expressed between XX and XY cells due to their escape from X-chromosome inactivation. We show that the dosage of the X-linked Kdm5c gene, which has consistently higher expression in XX (female) compared to XY (male) cells, contributes to the sex difference in adiposity observed between XX and XY animals. In vivo, female mice with global Kdm5c haploinsufficiency in all tissues have reduced adipose tissue compared to wild-type littermates. In vitro, Kdm5c knockdown impairs differentiation of cultured adipocytes. Generation of male and female mice with reduced or absent Kdm5c gene dosage selectively in preadipocytes leads to reduced white adipose tissue mass, increased energy expenditure, increased mitochondrial content, and improved tolerance to acute cold exposure. Consistent with Kdm5c function as a histone demethylase, adipose tissues and cultured adipocytes with reduced Kdm5c gene dosage have altered chromatin structure and gene expression levels. In particular, Kdm5c-deficient adipose tissue is characterized by activation of transcription programs that enhance thermogenesis and energy dissipation, and by altered histone methylation at the promoters of key genes for mitochondrial metabolism. In summary, this project elucidates physiological and molecular mechanisms that influence sex differences in adiposity and metabolic disease. We describe how intrinsic genetic differences that exist between XX and XY cells lead to altered epigenetic regulation of gene expression in preadipocytes, with critical effects on whole body energy balance. We postulate that this same mechanism will act across additional tissues and contribute to sex differences in many phenotypes in normo- and pathophysiology.