title: Dimethylesculetin ameliorates maternal glucose intolerance and fetal overgrowth in high-fat diet-fed pregnant mice via constitutive androstane receptor.
abstract: The constitutive androstane receptor (CAR) has been reported to decrease insulin resistance along with obesity. 6,7-dimethylesculetin (DE) is an active component of Yin Zhi Huang which is a traditional Asian medicine used to treat neonatal jaundice via CAR. In this study, we examined whether DE could affect the expression of gluconeogenic and lipogenic genes via human CAR pathway using human HepG2 cells in vitro. We also studied whether DE treatment during pregnancy could prevent maternal hypertension, glucose intolerance and hyperlipidemia, and fetal overgrowth in high-fat diet (HFD)-induced obese pregnant mice. Dimethylesculetin suppressed the mRNA expression of gluconeogenic genes, phosphoenolpyruvate carboxykinase and glucose-6-phosphatase, and lipogenic genes, sterol regulatory element-binding protein 1 and stearoyl-CoA desaturase 1, and enhanced CAR-mediated transcription. Blocking the CAR-mediated pathway abolished the effect of DE in vitro. DE treatment during pregnancy could prevent maternal hypertension, glucose intolerance and hyperlipidemia, and fetal overgrowth in HFD-induced obese pregnant mice in vivo. Our data indicate that DE might be a potential therapeutic agent for obese pregnant patients with insulin resistance through CAR to prevent the perinatal outcomes such as preeclampsia, gestational diabetes, and macrosomia. Further analysis of possible complications and side effects using animal models is required.
authors.affiliation: Department of Obstetrics and Gynecology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata, Kita-ku, Okayama, 700-8558, Japan. masuyama@cc.okayama-u.ac.jp.
authors.forename: Hisashi
authors.initials: H
authors.lastname: Masuyama
authors.affiliation: Department of Obstetrics and Gynecology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata, Kita-ku, Okayama, 700-8558, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Mitsui
authors.affiliation: Department of Obstetrics and Gynecology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata, Kita-ku, Okayama, 700-8558, Japan.
authors.forename: Jota
authors.initials: J
authors.lastname: Maki
authors.affiliation: Department of Obstetrics and Gynecology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata, Kita-ku, Okayama, 700-8558, Japan.
authors.forename: Kazumasa
authors.initials: K
authors.lastname: Tani
authors.affiliation: Department of Obstetrics and Gynecology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata, Kita-ku, Okayama, 700-8558, Japan.
authors.forename: Keiichiro
authors.initials: K
authors.lastname: Nakamura
authors.affiliation: Department of Obstetrics and Gynecology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata, Kita-ku, Okayama, 700-8558, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Hiramatsu
mesh_terms: D000818:Animals; D000090702:Constitutive Androstane Receptor; D004041:Dietary Fats / Q000009:adverse effects* / Q000494:pharmacology; D005260:Female; D005333:Fetus / Q000378:metabolism*; D018149:Glucose Intolerance / Q000097:blood / Q000139:chemically induced / Q000517:prevention & control*; D056945:Hep G2 Cells; D006801:Humans; D046110:Hypertension, Pregnancy-Induced / Q000097:blood / Q000139:chemically induced / Q000517:prevention & control*; D051379:Mice; D008813:Mice, Inbred ICR; D011247:Pregnancy; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D014468:Umbelliferones / Q000494:pharmacology*
chemical_list: C012923:6,7-dimethylaesculetin; D000090702:Constitutive Androstane Receptor; D004041:Dietary Fats; D018160:Receptors, Cytoplasmic and Nuclear; D014468:Umbelliferones
keywords: Adiponectin; Constitutive androstane receptor; Fetal growth; High-fat diet; Insulin resistance; Leptin