Undernutrition and stage of gestation influence fetal adipose tissue gene expression

Abstract

Low birthweight is a risk factor for neonatal mortality and adverse metabolic health, both associated with inadequate prenatal adipose tissue development. Here we investigated the impact of maternal undernutrition on expression of genes regulating fetal perirenal adipose tissue (PAT) development and function at gestation days 89 and 130 (term=145d). Singleton fetuses were taken from adolescent ewes fed control (C) intake to maintain adiposity throughout pregnancy or undernourished (UN) to maintain conception weight but deplete maternal reserves (n=7/group). Fetal weight was independent of maternal intake at day 89 but by day 130 fetuses from UN dams were 17% lighter with lower PAT mass containing fewer unilocular adipocytes. Relative PAT expression of IGF1, IGF2, IGF2R and peroxisome-proliferator-activated receptor-gamma (PPARG) mRNA was lower in UN than in C, predominantly at day 89. Independent of maternal nutrition, PAT gene expression of PPARG, glycerol-3-phosphate dehydrogenase, hormone sensitive lipase, leptin, uncoupling protein-1 and prolactin receptor increased and IGF1, IGF2, IGF1R, IGF2R decreased between 89 and 130 days. Fatty acid synthase and lipoprotein lipase (LPL) mRNAs were not influenced by nutrition or stage of pregnancy. Females had greater LPL and leptin mRNA than males, and LPL, leptin and PPARG mRNAs were decreased by UN at day 89 in females only. PAT gene expression correlations with PAT mass were stronger at day 89 than day 130. These data suggest that key genes regulating adipose tissue development and function are active from mid-gestation when they are sensitive to maternal undernutrition. This leads to reduced fetal adiposity by late pregnancy.

Differential impacts of late gestational over–and undernutrition on adipose tissue traits and associated visceral obesity risk upon exposure to a postnatal high‐fat diet in adolescent sheep

“…In fact, from ~90 to 125 days of gestation, there is significant increase (>7-fold) in the amount of perirenal adipose tissue formed, thereafter it declines by 145 days of gestation (Symonds, Phillips, Anthony, Owens, & McMillen, 1998), and in neonates the brown tissue is rapidly replaced by white adipose tissue in the perirenal fat depot (Symonds, Bryant, Clarke, Darby, & Lomax, 1992). Thus, maternal nutrient restriction resulted in a reduced expression of growth factors and adipogenesis markers was observed in sheep in perirenal fetal adipose tissue at 89 d of gestation giving rise to lower fetal and adipose tissue fetal mass in late gestation (Wallace et al, 2015) and nutrient restriction during late gestation leads to a reduced perirenal adipose tissue weight in the sheep fetus near term (Budge et al, 2004). These studies suggest that a considerable part of subcutaneous and perirenal adipose tissue remodeling takes place during late gestation, and insults at this stage could potentially interfere with their future functional maturation and expandability.…”

Ovine prenatal growth-restriction and sex influence fetal adipose tissue phenotype and impact postnatal lipid metabolism and adiposity in vivo from birth until adulthood

“…The mechanistic basis of the increase in relative adiposity in late gestation may begin earlier in pregnancy during the proliferative phase of adipocyte development when both maternal and fetal glucose concentrations in overnourished dams are high, and before placental size per se is constrained [44]. Although direct evidence to support such a hypothesis in the present overnourished model is not available, we have previously shown that the lean fetal phenotype that characterises the contrasting undernourished model emerges at mid-gestation when the expression of genes involved in adipose tissue proliferation and differentiation, namely PPARɤ;, IGF1, IGF2 and their receptors, were already attenuated by maternal undernutrition and the associated low glucose supply [22]. In addition to glucose, evidence is beginning to accumulate that maternal lipids (triglycerides and free fatty acids) are important substrates for fetal fat accretion and neonatal adiposity in human pregnancies characterised by nutrient excess at conception and fetal overgrowth [45][46][47].…”

“…In the undernourished model, further maternal growth during pregnancy is prevented and the gradual depletion of her body reserves limits fetal nutrient supply, independent of any change in placental size [21]. By late gestation the fetuses are modestly lighter with lower PAT mass and fewer unilocular adipocytes [22].…”

Competition for nutrients in pregnant adolescents: consequences for maternal, conceptus and offspring endocrine systems

“…Greater adiposity in these otherwise growth-restricted fetuses may be caused by exposure to higher maternal and thus fetal glucose early in gestation in overnourished dams (Redmer et al 2009) influencing adipocyte development before placental size and hence fetal glucose supply is impaired. Definitive causation in the overnourished model is lacking, but in the undernourished model, key genes involved in adipocyte proliferation and function are expressed in fetal perirenal fat tissue at mid-gestation when they are downregulated by maternal undernutrition and the associated low glucose supply leading to reduced fetal adiposity by late gestation (Wallace et al 2015). Glucose is the main fetal fuel and it is notable also that anorexigenic neuropeptide expression in the fetal hypothalamus is sensitive to fetal hyperglycaemia at mid-gestation with effects persisting throughout fetal life (Adam et al 2008(Adam et al , 2011.…”