Influence of maternal nutritional conditions and milk bioactive compounds on metabolic programming of the offspring

Abstract

Introduction. Lactation represents a critical programming window during which breastfeeding, compared to infant formula feeding, protects the offspring from developing obesity later in life. This developmental stage results of interest in the identification of measures for obesity prevention. Breast milk provides a source of bioactive compounds with potential programming effects that could be responsible, at least in part, for such protective role. However, milk composition can be influenced by maternal metabolic status and/or diet during the perinatal period and, consequently, affect offspring health. A better understanding of both the role of milk-derived bioactive compounds on infant health and the impact of maternal nutrition on milk composition is of interest to make dietary recommendations that promote optimal growth and development from early stages of life. Research content. The first objective of this Thesis has been to identify milk bioactive compounds with potential programming effects in the offspring, and to assess their effects when administered orally to suckling rats at physiological doses on later metabolic health. We have described important changes in the milk metabolite profile of 20% calorie-restricted lactating rats, which is a model associated with a healthier phenotype in adult offspring. Among them, and considering its biological function, increased levels of myo-inositol in milk of calorie-restricted lactating rats have been highlighted as of potential interest in relation to the beneficial effects of this maternal dietary condition in offspring. In this sense, we have shown that myo-inositol supplementation at physiological doses during suckling improves metabolic health and prevents the development of insulin resistance and hypertriglyceridemia programmed in male rats by mild/moderate gestational calorie restriction, particularly when coping with an obesogenic environment in adulthood. These effects of myo-inositol during suckling in mild/moderate gestational calorie-restricted rats could be explained by the reversal of early alterations in hypothalamic structure and function, partially comparable to leptin effects. The second objective of the Thesis has focused on assessing the impact of maternal Western diet consumption throughout the perinatal period on offspring health, as well as the potential effects of improving maternal diet during lactation. We have shown that the offspring of diet-induced obese rats displays rapid postnatal growth-up, along with hyperleptinemia and higher circulating glucose levels at weaning, and alterations in the plasma lipidome and metabolome at late lactation. In adulthood, especially when exposed to an obesogenic environment after weaning, these animals show higher body weight increased fasting triglycerides, leptin, and insulin levels, and greater HOMA-IR than their controls. These alterations have been attributed, at least partly, to alterations in the macronutrient content, metabolic hormone levels, and lipidomic and metabolomic profiles in milk of Western diet-induced obese dams. Of note, we have also evidenced that the improvement of maternal diet during lactation, despite these animals maintained excess body fat, prevents large part of the aforementioned alterations associated to the exposure to an obesogenic environment during the perinatal period, both in milk and plasma of the offspring. In addition, we have described that alterations in the expression levels of specific miRNAs and of anti- and pro-inflammatory factors in mammary gland of Western diet-induced obese rats may also be preventable by dietary improvement during lactation. Altogether, these results highlight the importance of maternal diet during lactation, rather than obesity per se, on mammary gland function and milk composition, and, consequently on the metabolic health programming in the offspring. Moreover, our results show that maternal Western diet consumption throughout the perinatal period, coupled with subsequent obesogenic diet after weaning, weakens the beneficial effects of leptin ingested during suckling. In contrast, maternal diet improvement during lactation is capable to offset such attenuation of leptin effects, particularly in males. This reinforces the relevance of a balanced maternal diet during lactation. In this sense, we have identified a set of potential biomarkers whose levels may be indicative of maternal obesogenic diet throughout the perinatal period, particularly stachydrine, N-acetylornithine and trimethylamine N-oxide in maternal milk, and stachydrine, ergothioneine and acylcarnitine C12:1 in plasma of the offspring at late lactation. Conclusion. In conclusion, the present doctoral Thesis provides new evidences on the impact of maternal nutritional conditions and milk bioactive compounds on metabolic programming. These findings, if extrapolated to humans, may be of interest for their potential application into improved infant formula and to make specific recommendations to improve breast milk quality, which, in turn, may help preventing adverse programming effects on offspring, particularly in women with overweight or obesity