Potential role of estradiol and progesterone in insulin resistance through constitutive androstane receptor

Normal pregnancy is characterized by insulin resistance, which contributes to the development of gestational diabetes mellitus and preeclampsia by incompletely understood mechanisms. The constitutive androstane receptor (CAR) may participate in insulin resistance in pregnancy, and sex steroids, estradiol (E(2)) and progesterone, may also be involved. We applied glucose and insulin tolerance tests and measured the expression of gluconeogenic and lipogenic genes in the livers of oophorectomized mice treated with E(2) and progesterone with or without CAR ligands. We also investigated how E(2) and progesterone affected CAR-mediated signaling and the activity of transcription factors in gluconeogenesis in vitro. Mice with the concentrations of E(2) and progesterone within normal physiological range during pregnancy exhibited increased insulin resistance along with increased expression of gluconeogenic and lipogenic genes, and CAR activation rescued the abnormal glucose metabolism. In HepG2 cells, CAR ligands suppressed the gluconeogenic and lipogenic gene expression in the presence of E(2) and/or progesterone. DNA affinity immunoblotting and chromatin immunoprecipitation assay revealed that CAR ligand enhanced the recruitment of the gluconeogenic transcription factors, forkhead box O1 (FOXO1) and hepatocyte nuclear factor 4 alpha (HNF4 alpha), but sex steroids suppressed these recruitments on the CAR responsive element. Moreover, CAR ligand suppressed the recruitment of FOXO1 and HNF4 alpha on their responsive element in gluconeogenic gene promoters and E(2) and progesterone augmented these recruitments on their responsive element. Taken together, these findings suggest that the activation of CAR-mediated signaling may ameliorate insulin resistance under relatively high concentrations of E(2) and progesterone, which were compatible with pregnancy via decreased activities of transcription factors in gluconeogenesis in combination with CAR. Journal of Molecular Endocrinology (2011) 47, 229-239