X-Linked Kdm5c Gene Dosage in Preadipocytes In Vivo Influences Adiposity and Food Intake
Avetisyan1,2, L. Vergnes2, C.B. Wiese2, K. Reue1,2,3
1Molecular Cellular and Integrative Physiology, University of California, Los Angeles, Los Angeles, CA; 2Human Genetics, University of California, Los Angeles, Los Angeles, CA; 3David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA
Metabolic Syndrome encompasses an array of abnormalities that increase the risk for type 2 diabetes and cardiovascular disease—the two most deadly and costly conditions in the United States. The components of metabolic syndrome and response to treatment differ between men and women. Important sex differences are present in the amount, distribution, and function of adipose tissues. In addition to well recognized effects of ovarian and testicular hormones on adipose tissue development, our previous work showed that X-chromosome dosage (XX vs. XY) and, specifically the dosage of X-linked Kdm5c histone demethylase, influence adipose tissue expansion independently from gonadal hormones. Knock-down of Kdm5c in the early stages of pre-adipocyte differentiation in vitro impairs adipocyte differentiation. To assess the action of Kdm5c in preadipocytes and in mature adipocytes in vivo, we generated mice in which Kdm5c is inactivated either in preadipocytes (using PdgfRα-Cre) or in mature adipocytes (using Adiponectin-CreR). We found no effect of homozygous Kdm5c deletion in mature adipocytes in vivo, but male mice with Kdm5c deletion on the single X chromosome in adipocyte precursor cells (PdgfRα-Cre, Kdm5cflox/y) exhibited reduced body weight and adiposity on chow and high-fat diets, and alterations in energy metabolism and food intake. We hypothesize that Kdm5c histone demethylase activity during early stages of preadipocyte differentiation influences gene expression to regulate adipocyte maturation and adipose tissue plasticity in response to a high-fat diet. These findings have implications for sex differences in obesity, as females have higher Kdm5c expression levels due to the fact that the Kdm5c gene is located on the X chromosome and escapes X chromosome inactivation.
Breakout Room: Avetisyan, Rozeta
View Poster: https://uclacns.org/symposium2021/2-Avetisyan-Rozeta.pdf