PROJECT SUMMARY The physiological and functional properties of adipose tissue differ between females and males, which leads to differences in obesity and metabolic syndrome risk between the sexes. While the gonadal hormones contribute to these physiological sex differences, the Reue lab has demonstrated that the presence of XX or XY sex chromosomes further impacts adipose development and function in a sex-dependent manner. Specifically, the presence of two X chromosomes causes higher body weight and adiposity compared to XY animals. When two X chromosomes are present, genes on one X chromosome are inactivated to normalize gene expression to XY cells. However, a subset of these X chromosome genes escape inactivation resulting in higher expression in XX cells compared to XY cells. This leads to the hypothesis that higher X chromosome gene dosage impacts sex differences in adiposity. We identified two X chromosome genes, Kdm5c and Kdm6a, that impact adiposity in vivo by altering preadipocyte and mature adipocyte cellular function, respectively. Reduction of Kdm5c gene dosage in preadipocytes decreased body weight and adiposity, while reduced Kdm5c gene dosage in mature adipocytes had no impact on body weight or adiposity. Conversely, reduction of Kdm6a gene dosage in mature adipocytes reduced body weight and adiposity. Both Kdm5c and Kdm6a encode histone demethylase enzymes that modify chromatin structure to regulate gene expression across the genome. Thus, the combined actions of KDM5C in preadipocytes and KDM6A in mature adipocytes may coalesce to impact total adiposity in XX animals. The proposed studies will elucidate the mechanisms by which KDM5C and KDM6A influence sex differences in adiposity and metabolism through studies of mouse models with altered gene dosage, and in cultured adipocytes to identify KDM5C and KDM6A genomic targets. There are three Specific Aims: 1. Uncover physiological mechanisms by which Kdm6a dosage alters adiposity in vivo. 2. Identify KDM5C and KDM6A genomic targets in white adipose tissue. 3. Determine the contribution of Kdm5c and Kdm6a gene dosage to weight gain and increased adiposity in mouse menopause models. Completion of the proposed studies will significantly improve our understanding of physiological and molecular mechanisms that regulate sex differences in obesity and metabolic disease. The proposed research and training plan will prepare me to transition into an independent investigator position with a research emphasis on understanding genetic mechanisms driving sex differences in metabolism. The training in sex differences and adipose tissue biology research in the Reue lab will complement my prior research experience in metabolic disease and gene regulation to achieve my career goals. The extensive resources available within the UCLA research environment will further promote my professional development to accelerate my path to independence as an academic scientist. Importantly, the proposed research p...