Maternal protein restriction during lactation induces early and lasting plasma metabolomic and hepatic lipidomic signatures of the offspring in a rodent programming model.

Perinatal undernutrition affects not only fetal and neonatal growth but also adult health outcome, as suggested by the metabolic imprinting concept. However, the exact mechanisms underlying offspring metabolic adaptations are not yet fully understood. Specifically, it remains unclear whether the gestation or the lactation is the more vulnerable period to modify offspring metabolic flexibility. We investigated in a rodent model of intrauterine growth restriction (IUGR) induced by maternal protein restriction (R) during gestation which time window of maternal undernutrition (gestation, lactation or gestation-lactation) has more impact on the male offspring metabolomics phenotype. Plasma metabolome and hepatic lipidome of offspring were characterized through suckling period and at adulthood using liquid chromatography-high-resolution mass spectrometry. Multivariate analysis of these fingerprints highlighted a persistent metabolomics signature in rats suckled by R dams, with a clear-cut discrimination from offspring fed by control (C) dams. Pups submitted to a nutritional switch at birth presented a metabolomics signature clearly distinct from that of pups nursed by dams maintained on a consistent perinatal diet. Control rats suckled by R dams presented transiently higher branched-chain amino acid (BCAA) oxidation during lactation besides increased fatty acid (FA) ß-oxidation, associated with preserved insulin sensitivity and lesser fat accretion that persisted throughout their life. In contrast, IUGR rats displayed permanently impaired ß-oxidation, associated to increased glucose or BCAA oxidation at adulthood, depending on the fact that pups experienced slow postnatal or catch-up growth, as suckled by R or C dams, respectively. Taken together, these findings provide evidence for a significant contribution of the lactation period in metabolic programming.

Perinatal protein restriction affects milk free amino acid and fatty acid profile in lactating rats: potential role on pup growth and metabolic status.

Perinatal undernutrition affects not only fetal and neonatal growth but also adult health outcome, as suggested by the metabolic imprinting concept. Although maternal milk is the only channel through which nutrients are transferred from mother to offspring during the postnatal period, the impact of maternal undernutrition on milk composition is poorly understood. The present study investigates, in a rat model of nutritional programming, the effects of feeding an isocaloric, low-protein diet throughout gestation and lactation on milk composition and its possible consequences on offspring's growth and metabolic status. We used an integrated methodological approach that combined targeted analyses of macronutrients, free amino acid and fatty acid content throughout lactation, with an untargeted mass-spectrometric-based metabolomic phenotyping. Whereas perinatal dietary protein restriction failed to alter milk protein content, it dramatically decreased the concentration of most free amino acids at the end of lactation. Interestingly, a decrease of several amino acids involved in insulin secretion or gluconeogenesis was observed, suggesting that maternal protein restriction during the perinatal period may impact the insulinotrophic effect of milk, which may, in turn, account for the slower growth of the suckled male offspring. Besides, the decrease in sulfur amino acids may alter redox status in the offspring. Maternal undernutrition was also associated with an increase in milk total fatty acid content, with modifications in their pattern. Altogether, our results show that milk composition is clearly influenced by maternal diet and suggest that alterations in milk composition may play a role in offspring growth and metabolic programming.