No abstract

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. Recent in vitro studies have identified that the liver X receptor a (LXRa) maintains glucose homeostasis by inhibiting critical genes involved in gluconeogenesis including G6pase (G6pc), 11b-Hsd1 (Hsd11b1) and Pepck (Pck1). Therefore, we hypothesized that MPR with postnatal catch-up growth would impair LXRa in vivo, which in turn would lead to augmented gluconeogenic LXRa-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 LXRa expression, while hepatic expression of 11b-HSD1 and G6Pase was significantly higher. This was concomitant with decreased binding of LXRa to the putative LXRE on 11b-Hsd1 and G6pase. Finally, we demonstrated that the acetylation of histone H3 (K9,14) surrounding the transcriptional start site of hepatic Lxra (Nr1h3) was decreased in LP offspring, suggesting MPR-induced epigenetic silencing of the Lxra promoter. In summary, our study demonstrates for the first time the important role of LXRa in mediating enhanced hepatic gluconeogenic gene expression and consequent glucose intolerance in adult MPR offspring.

Epidemiological studies have suggested that metabolic programming begins during fetal life and adverse events in utero are a critical factor in the etiology of chronic diseases and overall health. While the underlying molecular mechanisms linking impaired fetal development to these adult diseases are being elucidated, little is known about how we can intervene early in life to diminish the incidence and severity of these long-term diseases. This paper highlights the latest clinical and pharmaceutical studies addressing how dietary intervention in fetal and neonatal life may be able to prevent aspects of the metabolic syndrome associated with IUGR pregnancies.