Epidemiological studies demonstrate that the link between impaired fetal development and glucose intolerance in later life is exacerbated by postnatal catch-up growth. Maternal protein restriction (MPR) during pregnancy and lactation in the rat has been previously demonstrated to lead to impaired glucose tolerance in adulthood, however the effects of protein restoration during weaning on glucose homeostasis are largely unknown. Recentin vitrostudies have identified that the liver X receptor α (LXRα) maintains glucose homeostasis by inhibiting critical genes involved in gluconeogenesis includingG6pase(G6pc),11β-Hsd1(Hsd11b1) andPepck(Pck1). Therefore, we hypothesized that MPR with postnatal catch-up growth would impair LXRαin vivo, which in turn would lead to augmented gluconeogenic LXRα-target gene expression and glucose intolerance. To examine this hypothesis, pregnant Wistar rats were fed a control (20%) protein diet (C) or a low (8%) protein diet during pregnancy and switched to a control diet at birth (LP). At 4 months, the LP offspring had impaired glucose tolerance. In addition, LP offspring had decreased LXRα expression, while hepatic expression of 11β-HSD1 and G6Pase was significantly higher. This was concomitant with decreased binding of LXRα to the putative LXRE on11β-Hsd1andG6pase. Finally, we demonstrated that the acetylation of histone H3 (K9,14) surrounding the transcriptional start site of hepaticLxrα(Nr1h3) was decreased in LP offspring, suggesting MPR-induced epigenetic silencing of theLxrαpromoter. In summary, our study demonstrates for the first time the important role of LXRα in mediating enhanced hepatic gluconeogenic gene expression and consequent glucose intolerance in adult MPR offspring.
Epigenetic changes in gene expression: focus on “The liver X-receptor gene promoter is hypermethylated in a mouse model of prenatal protein restriction”