Maternal Low-Protein Diet Induces Gender-Dependent Changes in Epigenetic Regulation of the Glucose-6-Phosphatase Gene in Newborn Piglet Liver

Abstract

Glucose-6-phosphatase (G6PC) plays an important role in glucose homeostasis because it catalyzes the final steps of gluconeogenesis and glycogenolysis. Maternal malnutrition during pregnancy affects G6PC activity, yet it is unknown whether epigenetic regulations of the G6PC gene are also affected. In this study, we fed primiparous, purebred Meishan sows either standard-protein (SP; 12% crude protein) or low-protein (LP; 6% crude protein) diets throughout gestation and analyzed hepatic G6PC expression in both male and female newborn piglets. The epigenetic regulation of G6PC, including DNA methylation, histone modifications, and micro RNA (miRNA), was determined to reveal potential mechanisms. Male, but not female, LP piglets had a significantly lower serum glucose concentration and greater hepatic G6PC mRNA expression and enzyme activity. Also, in LP males, glucocorticoid receptor binding to the G6PC promoter was lower compared with SP males, which was accompanied by hypomethylation of the G6PC promoter. Modifications in histones also were gender dependent; LP males had less histone H3 and histone H3 lysine 9 trimethylation and more histone H3 acetylation and histone H3 lysine 4 trimethylation on the G6PC promoter compared with the SP males, whereas LP females had more H3 and greater H3 methylation compared with their SP counterparts. Moreover, two miRNA, ssc-miR-339-5p and ssc-miR-532-3p, targeting the G6PC 3' untranslated region were significantly upregulated by the LP diet only in females. These results suggest that a maternal LP diet during pregnancy causes hepatic activation of G6PC gene expression in male piglets, which possibly contributes to adult-onset hyperglycemia.

High or low dietary carbohydrate:protein ratios during first-feeding affect glucose metabolism and intestinal microbiota in juvenile rainbow trout

“…In this respect, the concept of nutritional programming appears promising. Indeed, numerous studies in (omnivorous) mammals have shown that modifying macronutrient (carbohydrates, proteins, lipids) intakes at early life stages can cause long-term modifications to metabolism, especially glucose metabolism (Ozanne et al, 1996;Patel and Srinivasan, 2002;Burdge and Lillycrop, 2010;Waterland and Jirtle, 2003;Metges et al, 2014;Jia et al, 2012). To the best of our knowledge, no such data are available for strict mammalian carnivores such as the cat Felis catus or mink Mustela vison.…”

“…Rainbow trout also has a high dietary protein requirement, i.e. more than 35% of diet dry matter (NRC, 2011), probably linked to persistent amino acid catabolism for energy purposes (Kaushik and Seiliez, 2010 (Ozanne et al, 1996;Patel and Srinivasan, 2002; Burdge and Lillycrop, 2010;Waterland and Jirtle, 2003;Metges et al, 2014;Jia et al, 2012). To the best of our knowledge, no such data are available for strict mammalian carnivores such as the cat Felis catus or mink Mustela vison.…”

Glucose metabolism ontogenesis in rainbow trout (Oncorhynchus mykiss) in the light of the recently sequenced genome: new tools for intermediary metabolism programming

“…Nutritional programming, a currently promising nutritional strategy, is based on early-life modifications induced during a 'sensitive' period by environmental stimuli (strictly nutritional or not, such as temperature, hypoxia, etc.) that result in long-term modifications in metabolism, especially glucose metabolism, later in life (Jia et al, 2012;Metges et al, 2014;Ozanne et al, 1996;Patel and Srinivasan, 2002). Several studies have demonstrated that one decisive point in this concept is that the susceptibility of organisms is limited to a critical ontogenic period, also known as a window of metabolic plasticity, during which an environmental stimulus may affect metabolism in the long-term (for review, see McMillen and Robinson, 2005).…”

Enhanced Trimethylation of Histone H3 Mediates Impaired Expression of Hepatic Glucose 6-Phosphatase Expression in Offspring From Rat Dams Exposed to Hypoxia During Pregnancy

“…Interestingly, in a model of undernutrition (eg, low protein diet) during pregnancy in piglets, the low-protein male offspring had increased hepatic G6Pase expression associated with lower trimethylated histone H3 [K9] in the proximal promoter of porcine G6Pase compared to the controls. 37 Collectively, these studies suggest that the expression of hepatic G6Pase is tightly governed by the trimethylation status of histone H3 [K9] in the short and long term. Although previous studies have demonstrated that uterine artery ligation can also lead to the long-term silencing of gene expression (eg, PDX-1) in postnatal life due to increases in histone H3 [K9] methylation, 12 this is the first study to demonstrate that the maternal hypoxia in pregnancy can also lead to hypermethylation of gene promoters in the long term.…”