ABSTRACT
The recent discovery of an association between body composition, energy intake and the fat mass and obesity-associated (FTO) gene represents a promising new therapeutic target in obesity prevention. In a well, pre-established large animal model, we investigated the regulation of FTO gene expression under conditions either leading to obesity or increased risk of obesity related disorders: i) a sedentary 'Western' lifestyle and ii) prenatal exposure to nutrient restriction. Pregnant sheep were either fed to fully meet their nutritional requirements throughout gestation or 50% of this amount from early-to-mid gestation. Following weaning, offspring were either made obese through exposure to a sedentary obesogenic environment or remained lean. A significant positive relationship between placental FTO gene expression and fetal weight was found at 110 days gestation. In both the newborn and adult offspring, the hypothalamus was the major site of FTO gene expression. Hypothalamic FTO gene expression was upregulated by obesity and was further increased by prenatal nutrient restriction. Importantly, we found a strong negative relationship between the hypothalamic FTO gene expression and food intake in lean animals only that may imply FTO as a novel controller of energy intake. In contrast, FTO gene expression in the heart was downregulated in obese offspring born to nutrient restricted mothers. In addition, FTO gene expression was unaffected by obesity or prenatal diet in insulin-dependent tissues, where it changed with age possibly reflecting adaptations in cellular energetic activity. These findings extend information gained from human epidemiology and provide new insights into the regulation of in vivo energy metabolism to prevent obesity.
Subject(s)
Gene Expression Regulation, Developmental , Maternal Nutritional Physiological Phenomena , Overweight/metabolism , Prenatal Exposure Delayed Effects/metabolism , Proteins/genetics , Aging/metabolism , Animals , DNA, Complementary/chemistry , Female , Fetal Weight , Hypothalamus/metabolism , Male , Obesity/prevention & control , Organ Size , Organ Specificity , Placenta/metabolism , Pregnancy , Proteins/chemistry , Proteins/metabolism , RNA, Messenger/metabolism , Sequence Alignment , Sheep, Domestic , Thinness/metabolismABSTRACT
Nutrient restriction (NR) during critical windows of pregnancy has differential effects on placento-fetal growth and development. Our study, therefore, investigated developmental and metabolic adaptations within the ovine placenta following NR at different critical windows during the first 110 days of gestation (term=147 days). Thus, the effects of NR on cell proliferation, glucocorticoid sensitivity, IGF1 and 2 receptor, peroxisome proliferator-activated receptor gamma (PPARG), and uncoupling protein (UCP)2 gene expression in the placenta were examined. Singleton bearing sheep (n=4-8 per group) were fed either 100% of their total metabolizable energy requirements throughout the study or 50% of this amount between 0-30, 31-65, 66-110, and 0-110 days gestation. A significant reduction in cell proliferation and increased gene expression for the glucocorticoid and IGF2 receptors, PPARG, and UCP2 were detected in placentae sampled from mothers who were nutrient restricted between days 66 and 110 of gestation, only, relative to controls. This window of gestation coincides with the maximum placental growth and the start of exponential growth of the fetus when there are substantially increased metabolic demands on the placenta compared with earlier in gestation. Consequently, increased glucocorticoid sensitivity and suppressed IGF2 action could contribute to a switch in the placenta from proliferation to differentiation, thereby improving its nutrient transfer capacity. Upregulation of PPARG and UCP2 would promote placental fatty acid metabolism thereby limiting glucose utilization. These compensatory placental responses may serve to maintain fetal growth but could result in adverse adaptations such as the early onset of the metabolic syndrome in later life.
Subject(s)
Caloric Restriction/veterinary , Cell Proliferation , Glucocorticoids/pharmacology , Placenta/drug effects , Pregnancy, Animal , Sheep , Animal Feed , Animals , Caloric Restriction/adverse effects , Cell Proliferation/drug effects , Drug Resistance/drug effects , Female , Food , Ion Channels/genetics , Ion Channels/metabolism , Lipid Metabolism/genetics , Maternal Nutritional Physiological Phenomena , Mitochondrial Proteins/genetics , Mitochondrial Proteins/metabolism , PPAR gamma/genetics , PPAR gamma/metabolism , Placenta/metabolism , Pregnancy , Pregnancy, Animal/genetics , Pregnancy, Animal/physiology , Sheep/embryology , Sheep/genetics , Sheep/metabolism , Sheep/physiology , Time Factors , Uncoupling Protein 2ABSTRACT
The tibial speed of sound (SOS) was measured in 91 healthy singleton infants between 31 and 42 weeks of gestation and 12 sick preterm infants. In healthy infants, the tibial SOS was associated with corrected gestational age (r = 0.40, p < 0.001) but not birth weight. The median tibial SOS in 12 sick preterm infants (2,772, range 2,566-2,934 m/s), whose corrected gestational age was between 31 and 42 weeks, was lower (p < 0.001) than that of 69 healthy gestation-matched healthy infants (3,100, range 2,870-3,381 m/s). Tibial SOS measurements may allow radiation-free assessment of metabolic bone disease of prematurity.
