Project 1 (Reue), “Sex chromosome effects on metabolic syndrome risk and treatment,” will build on the finding that the presence of XX compared to XY chromosomes increases susceptibility to obesity and related traits. Much of the XX effect is attributable to a specific X chromosome gene that escapes X chromosome inactivation and acts a higher levels in female (XX) compared to male (XY) cells. We will define the effects of this gene dosage on the epigenetic regulation of gene expression, energy balance, and adipose tissue remodeling during obesity. We will also elucidate the XX chromosome effect on increased female risk for diabetes secondary to statin drug therapy, and test a dietary co-therapy that may alleviate this sex-biased adverse drug response.
Project 2 (Lusis), “Gene-by-sex interactions in mitochondrial functions and metabolic traits,” seeks to understand the roles of both genetics and sex in MetSyn traits. Results of a systems genetics approach have implicated sex- and tissue-specific action of specific genes on MetSyn traits. We will elucidate sex effects on mitochondrial functions in insulin resistance, and sex-specific effects of genes that we have implicated in insulin resistance and hepatic steatosis. The gene-by-sex interactions discovered in the mouse will be tested in tissues from human cohorts.
Project 3 (Hevener), “The impact of estrogen receptor (ER) a in metabolic health,” will test the hypothesis that muscle ERa protects against metabolic dysfunction in mice and women, will identify ERa regulatory sites across the genome in females and males, and elucidate the effect of ERa on the regulation of mitochondrial function. Results may provide proof-of-concept evidence that skeletal muscle ERa is an effective therapeutic target to combat metabolic dysfunction and type 2 diabetes.