title: Maternal protein restriction leads to enhanced hepatic gluconeogenic gene expression in adult male rat offspring due to impaired expression of the liver X receptor.
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 α (LXRα) maintains glucose homeostasis by inhibiting critical genes involved in gluconeogenesis including G6pase (G6pc), 11β-Hsd1 (Hsd11b1) and Pepck (Pck1). Therefore, we hypothesized that MPR with postnatal catch-up growth would impair LXRα in 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 on 11β-Hsd1 and G6pase. Finally, we demonstrated that the acetylation of histone H3 (K9,14) surrounding the transcriptional start site of hepatic Lxrα (Nr1h3) was decreased in LP offspring, suggesting MPR-induced epigenetic silencing of the Lxrα promoter. 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.
authors: Department of Physiology and Pharmacology, The University of Western Ontario, London, Ontario, Canada N6A 5C1.
authors: Thin Xuan
authors: TX
authors: Vo
authors: Andrew
authors: A
authors: Revesz
authors: Gurjeev
authors: G
authors: Sohi
authors: Noelle
authors: N
authors: Ma
authors: Daniel B
authors: DB
authors: Hardy
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000235:genetics / Q000378:metabolism; D000107:Acetylation; D000818:Animals; D018753:Diet, Protein-Restricted / Q000009:adverse effects*; D015536:Down-Regulation; D004790:Enzyme Induction; D005260:Female; D005317:Fetal Growth Retardation / Q000209:etiology / Q000503:physiopathology; D005943:Gluconeogenesis; D018149:Glucose Intolerance / Q000097:blood / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D005952:Glucose-6-Phosphatase / Q000235:genetics / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D000071518:Liver X Receptors; D008297:Male; D039382:Maternal Nutritional Physiological Phenomena; D057093:Orphan Nuclear Receptors / Q000378:metabolism*; D010729:Phosphoenolpyruvate Carboxykinase (GTP) / Q000235:genetics / Q000378:metabolism; D011247:Pregnancy; D011499:Protein Processing, Post-Translational; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D020218:Response Elements
chemical_list: D006657:Histones; D047908:Intracellular Signaling Peptides and Proteins; D000071518:Liver X Receptors; C000605215:Nr1h3 protein, rat; D057093:Orphan Nuclear Receptors; D012333:RNA, Messenger; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D005952:Glucose-6-Phosphatase; C582554:Pck1 protein, rat; D010729:Phosphoenolpyruvate Carboxykinase (GTP)
keywords: fetal programming; gluconeogenesis; liver X receptor; maternal protein restriction; nuclear receptors