Prenatal Ethanol Exposure Causes Glucose Intolerance with Increased Hepatic Gluconeogenesis and Histone Deacetylases in Adult Rat Offspring: Reversal by Tauroursodeoxycholic Acid

Abstract

Prenatal ethanol exposure results in increased glucose production in adult rat offspring and this may involve modulation of protein acetylation by cellular stress. We used adult male offspring of dams given ethanol during gestation days 1–7 (early), 8–14 (mid) and 15–21 (late) compared with those from control dams. A group of ethanol offspring was treated with tauroursodeoxycholic acid (TUDCA) for 3 weeks. We determined gluconeogenesis, phosphoenolpyruvate carboxykinase (PEPCK), glucose-6-phosphatase, hepatic free radicals, histone deacetylases (HDAC), acetylated foxo1, acetylated PEPCK, and C/EBP homologous protein as a marker of endoplasmic reticulum stress. Prenatal ethanol during either of the 3 weeks of pregnancy increased gluconeogenesis, gluconeogenic genes, oxidative and endoplasmic reticulum stresses, sirtuin-2 and HDAC3, 4, 5, and 7 in adult offspring. Conversely, prenatal ethanol reduced acetylation of foxo1 and PEPCK. Treatment of adult ethanol offspring with TUDCA reversed all these abnormalities. Thus, prenatal exposure of rats to ethanol results in long lasting oxidative and endoplasmic reticulum stresses explaining increased expression of gluconeogenic genes and HDAC proteins which, by deacetylating foxo1 and PEPCK, contribute to increased gluconeogenesis. These anomalies occurred regardless of the time of ethanol exposure during pregnancy, including early embryogenesis. As these anomalies were reversed by treatment of the adult offspring with TUDCA, this compound has therapeutic potentials in the treatment of glucose intolerance associated with prenatal ethanol exposure.

Prenatal alcohol exposure programmes offspring disease: insulin resistance in adult males in a rat model of acute exposure

“…; Yao et al . ). Clinical studies have also reported that growth restriction is not a prerequisite for development of metabolic syndrome (Euser et al .…”

Maternal alcohol intake around the time of conception causes glucose intolerance and insulin insensitivity in rat offspring, which is exacerbated by a postnatal high‐fat diet

“…Key effectors are DNMTs, histone acetyltransferases, and histone deacetylase (HDAC) proteins, respectively. Maternal alcohol consumption (E1‐E7) has previously been linked to increased adult hepatic gluconeogenesis in association with increased class II HDAC protein activity (42). Although we did not observe changes in fetal liver Hdac mRNA expression, we cannot rule out the possibility that protein activity of these chromatin modifiers is altered in our model to impact on chromatin accessibility.…”

FOXO1 is regulated by insulin and IGF1 in pituitary gonadotropes

“…We investigated whether GnRH induced FOXO1 acetylation, which would permit an increase in FOXO1 phosphorylation in the presence of insulin of IGF1 despite blunted AKT activity. Using a 10 nM GnRH time course from 0–6 hours and a FOXO1 acetylation antibody (Santa Cruz sc-49437) (75–79) we found that GnRH had no effect on FOXO1 acetylation in LβT2 cells (data not shown).…”