British Journal of Nutrition

Short Communication

Increasing the folic acid content of maternal or post-weaning diets induces differential changes in phosphoenolpyruvate carboxykinase mRNA expression and promoter methylation in rats

Samuel P. Hoilea1, Karen A. Lillycropa2, Leonie R. Grenfella1, Mark A. Hansona1 and Graham C. Burdgea1 c1

a1 Academic Unit of Human Development and Health, Faculty of Medicine, Institute of Developmental Sciences Building (MP887), Southampton General Hospital, Tremona Road, Southampton SO16 6YD, UK

a2 Faculty of Natural and Environmental Sciences, University of Southampton, Southampton, UK


Environmental exposures throughout the life course, including nutrition, may induce phenotypic and epigenetic changes. There is limited information about how timing affects the nature of such effects induced by a specific nutritional exposure. We investigated the effect of increased exposure to folic acid before birth or during the juvenile–pubertal period in rats on the epigenetic regulation of glucose homeostasis. Rats were fed either a folic acid-adequate (AF; 1 mg/kg feed) or a folic acid-supplemented (FS; 5 mg/kg feed) diet from conception until delivery and then an AF diet during lactation. Juvenile rats were fed either the AF or the FS diet from weaning for 28 d and then an AF diet. Liver and blood were collected after a 12 h fast between postnatal days 84 and 90. Maternal FS diet increased plasma glucose concentration significantly (P < 0·05) in females, but not in males. Post-weaning FS diet decreased glucose concentration significantly in females, but increased glucose concentration in males. There were no effects of the FS diet on phosphoenolpyruvate carboxykinase (PEPCK) mRNA expression in males, while the pattern of expression was related to plasma glucose concentration in females. The FS diet induced specific changes in the methylation of individual CpG in females, but not in males, which were related to the time of exposure. Methylation of CpG − 248 increased the binding of CCAAT-enhancer-binding protein β to the PEPCK promoter. Together, these findings show that both the period during the life course and sex influence the effect of increased exposure to folic acid on the epigenetic regulation of PEPCK and glucose homeostasis.

(Received March 17 2011)

(Revised October 03 2011)

(Accepted October 13 2011)

(Online publication December 05 2011)


c1 Corresponding author: Dr G. C. Burdge, fax +44 23 80795255, email


Abbreviations: AF, folic acid-adequate; C/EBPβ, CCAAT-enhancer-binding protein β; FS, folic acid-supplemented; PEPCK, phosphoenolpyruvate carboxykinase