Effects of moderate maternal energy restriction on the offspring metabolic health, in terms of obesity and related diseases, and identification of determinant factors and early biomarkers

Abstract

Introduction A growing body of evidence, from epidemiological studies in humans and animal models, indicate that maternal health and nutritional status during gestation and lactation can program the propensity to develop obesity in their offspring. Huge efforts are now being directed toward understanding the molecular mechanisms underlying this developmental programming. Identification of these mechanisms could give some clues about potential strategies to prevent or revert programmed propensity to develop obesity, and may help in the identification of early biomarkers. Therefore, the main aim of this PhD-Thesis has been: To characterize in rats the programming effects of moderate maternal energy restriction during pregnancy or lactation on the metabolic health of their offspring in terms of obesity and related metabolic alterations, as well as to identify new preventing strategies against programmed obesity and early biomarkers of metabolic health. Investigation content We have characterized an animal model previously described to exhibit higher propensity to develop obesity and related metabolic alterations - the offspring of rat dams exposed to moderate food restriction during gestation (CRG) - to find out some of the potential mechanisms underlying their negative outcomes. Expression levels of key energy homeostasis-related genes in the hypothalamus and adipose tissue, and the measurement of some circulating parameters, showed that these animals were programmed, already from early ages, for a lower capacity to respond to insulin and to central leptin action. This could explain the hyperphagia observed in these animals and the greater propensity for obesity, manifested particularly in males. Some of these programmed disturbances, such as the impaired insulin and leptin sensitivity, and the increased systolic blood pressure, characteristic of CRG-animals, were reverted by enhancing hepatic fatty acid oxidation at early ages, through adeno-associated virus-mediated gene transference of the cDNA of Cpt1am (encoding for a permanently active form of CPT1A insensitive to its physiological inhibitor malonyl-CoA). Unlike calorie restriction during gestation, we show here that moderate calorie restriction in rat dams during lactation protects their offspring (CRL) against diet-induced obesity and related metabolic alterations, such as dyslipidemia, insulin resistance and hyperleptinemia. This condition during lactation determines early changes at gene expression level in WAT and liver, affecting lipogenic and oxidative capacity and increasing their sensitivity to the peripheral effects of leptin and insulin. Some of these adaptations were partially maintained in adulthood. Adult CRL-animals showed gender-dependent changes at gene expression level in adipose tissue and hypothalamus, suggesting that males were more protected against high-fat diet induced peripheral insulin resistance and they also showed improved capacity to respond centrally to leptin, while CRL-females were programmed for a better sensitivity to the peripheral actions of leptin and to the central action of insulin. We used this animal model to identify early transcriptome-based biomarkers of improved metabolic health by whole-genome microarray analysis in peripheral blood mononuclear cells (PBMCs). Concerning the factors potentially involved in the benefits of maternal calorie restriction during lactation on their offspring, the diminished content of markers of protein damage by oxidation and glycation found in breast milk from CRL-dams, in comparison to milk from controls, could be relevant. Conclusion Maternal nutrition during the perinatal period may be an important determinant of insulin and leptin sensitivity in their offspring. While calorie restriction during pregnancy programs their offspring for a lower capacity to respond to insulin and to central leptin action, the offspring of calorie restricted lactating dams show enhanced sensitivity to these hormones. Expression levels in blood cells of a set of genes are proposed as potential early biomarkers of metabolic health, and hence may provide a valid biological readout for the study of metabolic processes in humans.