Abstract Body: Cardiovascular and metabolic disease risks are impacted by biological sex, which is encompasses two components: gonadal hormones and sex chromosome complement. Using mouse models to dissociate gonadal and chromosomal sex, we identified sex chromosome-dependent regulation of circulating lipoproteins, atherosclerosis, and adiposity. Mice with XX sex chromosomes had higher adiposity compared to mice with XY sex chromosomes, irrespective of gonad type (ovaries or testes). In cells with two X chromosomes, one X chromosome is inactivated; however, specific X chromosome genes escape this process resulting in higher expression in XX (female) compared to XY (male) tissues. We identified Kdm6a, an X escape gene encoding a histone demethylase enzyme, as a regulator of mature adipocyte function influencing adiposity. Mice with mature adipocyte-specific Kdm6a reduction (Ad-Kdm6a^–/–) had lower body weight and adiposity compared to wildtype females. White adipose triglycerides in Ad-Kdm6a^–/– mice were enriched in unsaturated fatty acids, corresponding to increased levels of SCD1, a fatty acid desaturase, in white adipose tissue. Given that KDM6A is a histone demethylase, we assessed the Kdm6a dosage effect on adipocyte gene expression and histone modifications across the genome. Differential gene expression associated with protein kinase C signaling cascade was identified in Ad-Kdm6a^–/– mice and reduced protein levels of phosphorylated protein kinase C delta (PKCδ) were confirmed. Since PKCδ and SCD1 have previously been implicated in autophagy, we assessed Kdm6a gene dosage effects on autophagy. We identified increased autophagosomes in Ad-Kdm6a^–/– white adipose tissue and heightened autophagic flux in cultured adipocytes with reduced Kdm6a levels. Evaluating histone modifications and potential KDM6A binding sites with CUT&RUN, genes associated with autophagy were identified as potential KDM6A targets. We conclude that differential Kdm6a gene dosage between female and male tissues is a determinant of adiposity sex differences by modulating histone modifications and gene expression, affecting adipocyte lipid composition, autophagy, and tissue mass. These findings highlight a role for Kdm6a in sex differences in obesity susceptibility and cardiometabolic disease risk.