A Novel Mechanism Affecting Sex Differences in Adiposity

PROJECT SUMMARY Males and females differ in adipose tissue development and function, which leads to differences in susceptibility to metabolic disorders such as type 2 diabetes.

In addition to the appreciated roles of sex hormones as determinants of sex differences, the Reue lab previously showed that the presence of XX or XY sex chromosomes plays an important role in determining adiposity. Particularly, the presence of two X chromosomes is associated with increased body weight and fat tissue.

This led to the hypothesis that some X chromosome genes that have different expression levels in males and females are effectors of sex differences in adiposity.

Most X chromosome genes are expressed only from one X chromosome in both sexes, since in females the second X is inactivated. However, certain genes escape X chromosome inactivation and are expressed at higher levels in XX compared to XY cells. One such X chromosome inactivation escapee gene is Kdm5c, a member of histone 3 lysine 4 demethylases.

In 3T3-L1 preadipocytes, the KDM5 family is required for the activation of the pro-proliferative cell cycle genes that are essential for the early stages of adipocyte differentiation.

Importantly, treatment of the 3T3-L1 pre-adipocyte cell line with shRNA against Kdm5c blocks differentiation to mature adipocytes.

In vivo, female mice with global Kdm5c haploinsufficiency in all tissues have reduced adipose tissue compared to wild-type littermates.

Consistent with Kdm5c dosage having an influence on adipocyte gene expression levels, RNA-sequencing analysis of an adipocyte cell line showed that induction of enhanced Kdm5c expression altered mRNA levels of several metabolic genes.

The proposed studies will further characterize the effect of Kdm5c dosage on adipogenesis and adipocyte gene expression. 1. Investigate the physiological mechanisms by which Kdm5c gene dosage affects adiposity. 2. Uncover the molecular mechanisms through which Kdm5c dosage affects adipocyte differentiation in vivo.

The realization of this proposed project will significantly augment our understanding of physiological and molecular mechanisms that influence sex differences in adiposity and metabolic disease.

In particular, they will shed light on a novel basis for sex differences in epigenetic regulation due to intrinsic genetic differences that exist between XX and XY adipocytes.

Additionally, I suspect that these mechanisms will be important across tissues and will contribute to sex differences in many phenotypes that differ between males and females.