title: Reversal of glucose intolerance in rat offspring exposed to ethanol before birth through reduction of nuclear skeletal muscle HDAC expression by the bile acid TUDCA.
abstract: Prenatal ethanol exposure causes cellular stress, insulin resistance, and glucose intolerance in adult offspring, with increased gluconeogenesis and reduced muscle glucose transporter-4 (glut4) expression. Impaired insulin activation of Akt and nuclear translocation of histone deacetylases (HDACs) in the liver partly explain increased gluconeogenesis. The mechanism for the reduced glut4 is unknown. Pregnant rats were gavaged with ethanol over the last week of gestation and adult female offspring were studied. Some ethanol exposed offspring was treated with tauroursodeoxycholic acid (TUDCA) for 3 weeks. All these rats underwent intraperitoneal glucose tolerance and insulin tolerance tests. The expression of glut4, HDACs, and markers of endoplasmic reticulum (ER) unfolded protein response (XBP1, CHOP, ATF6) was examined in the gastrocnemius muscle fractions, and in C2C12 muscle cells cultured with ethanol, TUDCA, and HDAC inhibitors. Non-TUDCA-treated rats exposed to prenatal ethanol were insulin resistant and glucose intolerant with reduced muscle glut4 expression, increased ER marker expression, and increased nuclear HDACs, whereas TUDCA-treated rats had normal insulin sensitivity and glucose tolerance with normal glut4 expression, ER marker expression, and HDAC levels. In C2C12 cells, ethanol reduced glut4 expression, but increased ER makers. While TUDCA restored glut4 and ER markers to control levels and HDAC inhibition rescued glut4 expression, HDAC inhibition had no effect on ER markers. The increase in nuclear HDAC levels consequent to prenatal ethanol exposure reduces glut4 expression in adult rat offspring, and this HDAC effect is independent of ER unfolded protein response. HDAC inhibition by TUDCA restores glut4 expression, with improvement in insulin sensitivity and glucose tolerance.
authors.affiliation: Department of Internal Medicine, University of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: Xing-Hai
authors.initials: XH
authors.lastname: Yao
authors.affiliation: Department of Internal Medicine, University of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: Khanh H
authors.initials: KH
authors.lastname: Nguyen
authors.affiliation: Department of Internal Medicine, University of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: B L Grégoire
authors.initials: BL
authors.lastname: Nyomba
keywords: Endoplasmic reticulum; histone deacetylase; insulin resistance; prenatal alcohol exposure