Hyperlipidic hypercholesterolemic diet in prepubertal rabbits affects gene expression in the embryo, restricts fetal growth and increases offspring susceptibility to obesity.

Maternal hypercholesterolemia has been shown to lead to fetal intra-uterine growth retardation (IUGR) in rabbits. The effects of a long term maternal hyperlipidemic and hypercholesterolemic diet on embryo, fetal and post-natal development, have not been addressed so far. Rabbit does were fed either a hypercholesterolemic (0.2%) hyperlipidic (8%) (HH) or a control (C) diet from 10 weeks of age. Sixteen does (N = 8 HH and N = 8 C) were euthanized at 18 weeks to assess the effect of the diet on dams before mating. Embryos from 18 females (N = 9 HH and N = 9 C) were collected from the oviducts at the 16-20 cell stage (embryonic genome activation stage) for gene expression analysis (micro array and quantitative RT-PCR). Thirty females (N = 16 HH and N = 14 C) were mated naturally and fetal growth was monitored by ultrasound. Six of them (N = 4 HH and N = 2 C) were euthanized at D28 of gestation to collect fetuses and placentas. Finally, the remaining 24 does delivered at term and litters were cross fostered and equilibrated in number to create 4 groups according to the biological dam and the foster dam (C-C, C-HH, HH-C, HH-HH). Growth was monitored until weaning. A subset of 26 offspring from the 4 groups was fed the control diet until 25 weeks of age and then fed the HH diet for three weeks. All does had similar growth rates and bodyweight. Transcriptomic analyses evidenced an overexpression of Adipophilin in HH embryos at the stage of embryonic genome activation. This was confirmed by quantitative RT-PCR. During pregnancy, IUGR was observed from D9 by ultrasound and subsequently, fetal weight at 28 days, birthweight and fat deposition in newborn offspring were significantly decreased in HH (P < 0.05). After weaning, there was no significant difference for weight between HH-HH and HH-C offspring and both groups became significantly heavier (P < 0.0001) than C-C and C-HH offspring. During the 3 weeks when offspring were fed the HH diet, the differences in feed intake were no longer significant between groups but the differences in body weight remained. At post-mortem, offspring from HH does had significantly more abdominal and inter-scapular fat than offspring from C does (P < 0.05). These data illustrate the importance of maternal nutrition before and during gestation in the establishment and control of the growth trajectory of the conceptus and in the onset of disease in adult life.