妊娠中のアディポサイトカインとインスリン抵抗性 : 耐糖能異常, 妊娠高血圧症候群の病態への関与と新たな治療標的の検討 [in Japanese] Adipocytokine and Insulin Resistance during Pregnancy : Potential Role of Adipocytokines in Pathophysiology of Glucose Intolerance and Pregnancy-induced Hypertension and Investigation for Novel Therapeutic Target [in Japanese]
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Normal pregnancy is characterized by insulin resistance, which contributes to the development of gestational diabetes mellitus and preeclampsia (PE) by incompletely understood mechanisms. PE is characterized by the onset of high blood pressure and proteinuria. It occurs in about 5% of all pregnancies and results in substantial maternal and neonatal morbidity and mortality. The pathogenesis of PE is thought to involve three steps: defective placentation, placental ischemia and endothelial cell dysfunction. Abnormal vascular growth and impaired endothelial function in the placenta are associated with abnormal pregnancy conditions such as PE, resulting from inadequate trophoblast invasion of maternal spiral arteries during early gestation. Defective placental development may be reflected in the maternal circulation, and can be detected as alterations in the concentration of biological markers such as angiogenic factors. Also, an increased body mass index (BMI) doubled the risk of PE and obesity is one of risk factors for PE. Adipose tissue expresses various secretory proteins such as leptin, tumor necrosis factor-α and adiponectin, which regulate energy expenditure, lipid metabolism and insulin resistance. Blood levels of adipocytokines differ in PE compared to controls and may also play an important role in disease pathogenesis of obese pregnancies. In this study, we examined the differences in circulating levels of these molecules between matched normotensive controls and women with PE with onset before or at/after 32 weeks and according to whether the women were of normal weight (BMI<25) or overweight. Serum concentrations of soluble fms-like tyrosine kinase 1 (sFlt1), placental growth factor (PlGF), soluble endoglin, adiponectin, and leptin were measured in women with PE and in normotensive controls matched for age, gestational week, parity, and body mass index. The sFlt-1/PlGF ratio in early-onset PE was significantly higher than that in late-onset PE. There was a significant elevation of leptin in both subtypes compared to controls, but adiponectin was increased only in late-onset PE. Significant differences in angiogenic factors and adiponectin were found between normal and overweight patients only in late-onset PE. Homeostasis model assessment as an index of insulin resistance in overweight patients with late-onset preeclampsia were significantly higher than in overweight controls carrying normal pregnancies and in normal weight women with late-onset preeclampsia. In contrast, there were no significant differences between the overweight and normal weight groups among patients with early-onset preeclampsia and in healthy pregnant women. These data suggested that a marked circulating anti-angiogenic state and elevated leptin might play an important role in early-onset PE. Minor alterations in angiogenic factor concentrations and a mild elevation of adiponectin may be involved in the pathophysiology of late-onset PE, especially in overweight patients. The constitutive androstane receptor (CAR) may participate in insulin resistance in pregnancy, and sex steroids, estradiol (E2) and progesterone (P), may also be involved. We applied glucose and insulin tolerance tests and measured the expressions of gluconeogenic and lipogenic genes in the livers of oophorectomized mice treated with E2 and P with or without CAR ligands. We also investigated how E2 and P affected CAR-mediated signaling and the activity of transcription factors in gluconeogenesis in vitro. Mice with the concentrations of E2 and P within normal physiological range during pregnancy exhibited increased insulin resistance along with the increased expressions of gluconeogenic and lipogenic genes, and CAR activation rescued the abnormal glucose metabolisms. In HepG2 cells, CAR ligands suppressed the gluconeogenic and lipogenic gene expressions in the presence of E2 and/or P. DNA affinity immunoblotting and chromatin immunoprecipitation assay revealed CAR ligand enhanced the recruitment of the gluconeogenic transcription factors, Foxol and HNF-4α, but sex steroids suppressed these recruitments on the CAR responsive element. Moreover, CAR ligand suppressed the recruitment of FoxOl and HNF-4α on their responsive element in gluconeogenic gene promoters and E2 and P augmented these recruitments on their responsive element. Taken together, these findings suggest the activation of CAR-mediated signaling may ameliorate insulin resistance under relatively high concentrations of E2 and P, which were compatible with pregnancy via decreased activities of transcription factors in gluconeogenesis in combination with CAR. We also examined whether CAR might be a potential therapeutic target for obese preeclampsia patients with insulin resistance. We examined whether CAR ligands can ameliorate the signs of preeclampsia in high-fat diet (HFD)-induced obese pregnant mice to examine a possibility of CAR as a therapeutic target. We employed five groups including non-pregnant mice, HFD-fed and control diet-fed pregnant mice with or without treatment of CAR ligands. In HFD pregnant mice, insulin resistance increased with increasing expression of gluconeogenic and lipogenic genes and abnormal adipocytokine levels. Treatment with CAR ligands improved glucose tolerance with significant changes of hepatic gluconeogenic and lipogenic genes and adipocytokine genes in the adipose tissue. HFD pregnant mice had high blood pressure and proteinuria, while treatment with CAR ligands ameliorated these signs. In conclusion, our data suggested that there are different profiles of angiogenic factors and adipocytokines between women who develop early- and late-onset PE and adiponectin might play important roles in the pathophysiology of obese late-onset preeclampsia patients. In addition, CAR might be a potential therapeutic target for obese preeclampsia patients with insulin resistance.
日本産科婦人科學會雜誌 64(11), 2279-2289, 2012-11-01