Identification of early biomarkers of metabolic functions with implications on health and related to obesity using animal models of intervention in early life

Abstract

The main aim of the present PhD thesis was to identify early transcriptome-based biomarkers of metabolic functions with implications on health (metabolic health) and those related to body weight control and obesity in peripheral blood mononuclear cells (PBMCs) of rats, which as a result of interventions in the perinatal period are more susceptible to obesity (model of maternal calorie restriction during pregnancy) or have developed certain protection against overweight and other associated alterations (model of maternal calorie restriction during lactation). Results show that moderate maternal calorie restriction of 20% during the first part of gestation programs the offspring for a lower capacity to respond to insulin and to central leptin action, which leads to hyperphagia and metabolic alterations in both genders and higher body weight in males. Moreover, these animals showed reduced brown adipose tissue burning capacity caused by both impairment of sympathetic drive and alteration in thyroid hormone signaling. It may cause the greater sensitivity to cold that undergo these animals and contribute to the higher propensity for fat accumulation and other metabolic alterations later in life. Adverse outcomes of moderate maternal calorie restriction during pregnancy could be associated with the absence of a transient rise in plasma leptin levels in offspring during the suckling period. Oral supplementation with physiological doses of leptin during the suckling period to the offspring of calorie-restricted dams during pregnancy is able to revert, at least partly, most of the malprogrammed effects studied caused by maternal undernutrition during gestation. Specifically, leptin treatment normalized altered cellularity in the hypothalamus, and particularly the number of orexigenic NPY cells in arcuate nucleus, associated with normalization of gene expression patterns in this tissue. Moreover, leptin-treated male animals displayed restored sympathetic drive into white adipose tissue (WAT), accompanied by amelioration of catabolic capacity in this tissue. Microarray analysis performed in PBMCs from male pups showed that, out of the 224 genes which expression was altered due to maternal undernutrition during gestation, leptin treatment normalized the expression of 218 of them to control levels. These markers may be useful for early identification and subsequent monitoring of individuals who are at risk of later diseases and would specifically benefit with the intake of appropriate amounts of leptin during lactation. Unlike the effects of maternal calorie restriction during gestation, moderate maternal calorie restriction of 20% during lactation in rats programs the offspring for better metabolic health in terms of body weight and lipid handling. This condition during lactation affected lipogenic and oxidative capacity in WAT and liver and increased their sensitivity to the peripheral effects of leptin and insulin. These adaptations were partially maintained throughout life but were particularly evident when animals were exposed to high-fat diet feeding. Microarray analysis of PBMCs from weaned rat identified a number of 278 genes, which expression was different in the offspring of dams submitted to calorie restriction during lactation compared to controls. Among lipid metabolism-related genes, Cpt1a, Fasn and Star emerged as particularly interesting, as their expression levels in PBMCs were significantly correlated with expression profiles in WAT and/or liver. All in all, results from this PhD thesis enabled to identify a number of easily accessible predictive biomarkers of metabolic health and dysfunction, which may potentially provide a valid biological readout for the study of metabolic processes in humans.