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

Abstract

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 4a (HNF4a), but sex steroids suppressed these recruitments on the CAR responsive element. Moreover, CAR ligand suppressed the recruitment of FOXO1 and HNF4a 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.

Treatment with constitutive androstane receptor ligand during pregnancy prevents insulin resistance in offspring from high-fat diet-induced obese pregnant mice

“…Recent in vivo studies have demonstrated that the activation of CAR improves insulin sensitivity via glucose and lipid metabolic pathways; moreover, CAR null mice had spontaneous insulin insensitivity that could be relieved by CAR ligand (7,8), suggesting that CAR plays some roles in insulin resistance. We have recently demonstrated that the activation of CAR-mediated signaling can ameliorate insulin resistance under relatively high concentrations of estradiol and progesterone, which are compatible with pregnancy via decreased activities of transcription factors in gluconeogenesis in combination with CAR (19). We also observed that HFD-induced obese pregnant mice had high blood pressure and proteinuria, whereas treatment with CAR ligands ameliorated these signs (20).…”

Female fetus is associated with greater maternal insulin resistance in pregnancy

“…The main limitation of the present study is that we only had data on crude surrogate measures of insulin sensitivity; however, this may tend to increase noise variations and bias the differences towards the null. In addition, we had no data on maternal oestriol and placental lactogen levels, which are associated with the normal increase in insulin resistance in pregnancy [3,4], and have been reported (but not validated) to be higher in women bearing a female than in women bearing a male fetus [5,6]. Future studies may validate whether maternal oestriol and placental lactogen levels are elevated in pregnancies with a female fetus, and whether such elevations are correlated with higher insulin resistance in pregnancy.…”

Small-molecule modulators of the constitutive androstane receptor

“…High concentrations of estrogens, which occur during pregnancy, are sufficient to activate CAR to induce CYP2B6 expression [68]. Estradiol and progesterone concentrations within this elevated physiological range during pregnancy may play a role in glucose tolerance and insulin resistance working through CAR [69]. Furthermore, CAR represses estrogen receptor (ER)-mediated transcriptional activation in cell-based transfection assays, and this action is proposed to occur by competition of CAR with ER for the existing coregulator pool, thus limiting availability for ER transactivation [70].…”