Maternal Dietary Restriction During the Periconceptional Period in Normal-Weight or Obese Ewes Results in Adrenocortical Hypertrophy, an Up-Regulation of the JAK/STAT and Down-Regulation of the IGF1R Signaling Pathways in the Adrenal of the Postnatal Lamb

Abstract

Maternal dietary restriction during the periconceptional period results in an increase in adrenal growth and in the cortisol stress response in the offspring. The intraadrenal mechanisms that result in the programming of these changes are not clear. Activation of the IGF and the signal transducer and activator of transcription (STAT)/suppressors of cytokine signaling (SOCS) pathways regulate adrenal growth. We have used an embryo transfer model in sheep to investigate the impact of exposure to either dietary restriction in normal or obese mothers or to maternal obesity during the periconceptional period on adrenal growth and function in the offspring. We assessed the adrenal abundance of key signaling molecules in the IGF-I and Janus kinase/STAT/SOCS pathways including IGF-I receptor, IGF-II receptor, Akt, mammalian target of rapamycin, ribosomal protein S6, eukaryotic translation initiation factor 4E-binding protein 1, eukaryotic translation initiation factor 4E, STAT1, STAT3, STAT5, SOCS1, and SOCS3 in female and male postnatal lambs. Maternal dietary restriction in the periconceptional period resulted in the hypertrophy of the adrenocortical cells in the zona fasciculata-reticularis and an up-regulation in STAT1, phospho-STAT1, and phospho-STAT3 (Ser727) abundance and a down-regulation in IGF-I receptor, Akt, and phospho-Akt abundance in the adrenal cortex of the postnatal lamb. These studies highlight that weight loss around the time of conception, independent of the starting maternal body weight, results in the activation of the adrenal Janus kinase/STAT pathway and adrenocortical hypertrophy. Thus, signals of adversity around the time of conception have a long-term impact on the mechanisms that regulate adrenocortical growth.

Maternal Caloric Restriction Implemented during the Preconceptional and Pregnancy Period Alters Hypothalamic and Hippocampal Endocannabinoid Levels at Birth and Induces Overweight and Increased Adiposity at Adulthood in Male Rat Offspring

“…These results are in agreement with Matias et al (2003), showing decreased levels of AEA in weaning offspring from dams previously exposed to a maternal caloric restriction during pregnancy and/or lactation. However, in our experiments we detected more robust alterations in endocannabinoid and NAE levels likely because preconceptional diet restriction may induce more exacerbating effects in the offspring, as reported in both cohort studies (Roseboom et al, 2006) and animal models of undernutrition (Edwards and McMillen, 2002; McMillen et al, 2004; Zhang et al, 2013), despite the lack of change in weight at birth. Consistently, we found reduced endocannabinoid levels in normoweight pups.…”

“…Thus, studies adopting animal models of suboptimal in vitro fertilization/culture have demonstrated robust metabolic alterations resulting in obesity and hepatic steatosis in the offspring (Fernández-Gonzalez et al, 2004; Serrano et al, 2014). Additionally, evidence from animal models have shown that either caloric restriction or weight loss during the periconceptional/gestational period could lead to epigenetic alterations (Raychaudhuri et al, 2008), developmental impairment of the hypothalamus (Sebert et al, 2011), altered leptin signaling (Bouret et al, 2004), alterations in blood pressure, adrenocortical growth or hypothalamus-pituitary adrenal axis in the offspring (Edwards and McMillen, 2002; McMillen et al, 2004; Zhang et al, 2013). These events may occur independently of the pre-pregnancy maternal body weight or whether an adequate maternal nutrition is provided in the later phases of pregnancy.…”

Effect of Advanced Maternal Age on Pregnancy Outcomes and Vascular Function in the Rat

“…However, the quantity of food provided was based on National Research Council recommendations, 16 and further reductions could affect nutrient status at conception and alter pregnancy outcomes. 22,23 The reduced litter sizes in dams of advanced maternal age could not be fully explained by the increased resorption rate and, therefore, may be attributed to implantation failure or peri-implantation loss; consistent with this idea, 52% of aged dams had no evidence of pregnancy at term. Previous studies have shown that advanced maternal age is associated with an impaired decidual reaction and reduced uterine prostaglandin synthesis, as well as changes in the microstructure of the uterine luminal epithelium, particularly in the microvillous architecture.…”

Long-Term Effects of Prenatal Exposure to Undernutrition on Cannabinoid Receptor-Related Behaviors: Sex and Tissue-Specific Alterations in the mRNA Expression of Cannabinoid Receptors and Lipid Metabolic Regulators

“…They include epigenetic regulation (Nijland et al, 2010; Martinez et al, 2014), leptin signaling (Yura et al, 2005; Palou et al, 2010), hypothalamic development (Sebert et al, 2009; García et al, 2010), and dopaminergic and serotonergic signaling systems (Manuel-Apolinar et al, 2014). Interestingly, recent studies have documented epigenetic modifications or affectation of adrenocortical growth in offspring after maternal dietary restriction around the time of conception (Nicholas et al, 2013; Zhang et al, 2013), pointing out the importance of the periconceptional window in the metabolic programming.…”