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.
Highlights
Hostile intrauterine environment is accepted to play an important role in the pathogenesis of obesity and type 2 diabetes
Increased gluconeogenesis was explained by increased expression of major genes phosphoenolpyruvate carboxykinase (PEPCK) and G6Pase in the liver, consistent with our previous studies where rats were prenatally exposed to ethanol throughout the whole duration of pregnancy [10,12]
The current study further shows that adult rats prenatally exposed to ethanol for only one week have increased expression of histone deacetylases involved in gluconeogenesis
Summary
Hostile intrauterine environment is accepted to play an important role in the pathogenesis of obesity and type 2 diabetes. Prenatal alcohol exposure has been reported to associate with alterations of glucose and lipid homeostasis in humans [1,2] and animals in association with insulin resistance [3,4,5,6], and recent epidemiologic surveys suggest that parental alcoholism is a predictor of obesity in offspring [7] In animal studies, this insulin resistance is explained by impairment of insulin signaling through the phosphoinositide 3-kinase pathway due to reduced intrinsic tyrosine kinase [6] or inhibition of Akt and protein kinase Cf phosphorylation by increased expression of the inhibitors Pten (phosphatase and tensin homologue deleted on chromosome 10) and Trb (tribbles 3) [8,9,10]. Insulin resistance could result from endoplasmic reticulum (ER) stress, and we have shown in liver of rat offspring prenatally exposed to ethanol an increased expression of several ER markers [10,16]
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