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Breast milk bioactives in metabolic programming: novel ingredients for the prevention of obesity-related alterations and exploration of underlying mechanisms

Year: 2026
Type: dissertation
Abstract: [eng] Introduction: Maternal nutrition during pregnancy and lactation has a profound impact on the long-term metabolic health of the offspring. Both undernutrition and overnutrition during these periods are associated with increased risk of obesity, insulin resistance, and metabolic disorders later in life. Lactation, in particular, represents a critical window of metabolic plasticity during which early-life trajectories can still be modified. In this context, bioactive compounds naturally present in breast milk offer a promising opportunity to counteract adverse metabolic programming. This thesis evaluates whether supplementation during suckling with selected breast milk-derived bioactive compounds (myo-inositol, leptin, and betaine) can modulate early metabolic programming and mitigate the effects of two perinatal nutritional insults: maternal caloric restriction and maternal exposure to a Western-style obesogenic diet. To this end, rat models of altered maternal nutrition were used, including a condition where the maternal diet was normalized during lactation. Research Content:To investigate this hypothesis, two rat models of maternal nutritional imbalance were used. In the first model, early gestational caloric restriction was applied to examine how maternal undernutrition affects the offspring’s adult metabolomic profile and whether myo-inositol supplementation during lactation could counteract these effects. Maternal caloric restriction induced significant, sex-specific alterations in circulating metabolites, suggesting pro-inflammatory states, oxidative stress, and impaired liver function, particularly in males. Myo-inositol supplementation during the suckling period normalized many of these disruptions, especially those related to hepatic and carbohydrate metabolism in males, while in females, whose metabolomic alterations were less pronounced, the supplementation largely restored the affected metabolites. In the second model, dams were exposed to a Western-style diet from one month before gestation until the end of lactation. Leptin supplementation during the suckling period improved long-term metabolic outcomes, although its effectiveness depended on maternal diet, offspring sex, and post-weaning nutrition. Leptin modulated central pathways involved in energy homeostasis, including those related to Bdnf and Npy/Agrp genes. It reduced the increased energy efficiency and fat deposition associated with a maternal Western diet. Offspring exposed to this maternal diet exhibited persistent, sex-specific metabolomic alterations, with orotic acid and arginine emerging as discriminating markers in males and females, respectively. Leptin supplementation modulated these metabolic signatures, suggesting increased metabolic flexibility, and normalization of the maternal diet during lactation reversed many of the alterations induced by Western diet exposure. Betaine supplementation in the same Western diet model produced contrasting, sex-dependent effects. In females, it improved circulating lipid profiles, whereas in males it led to increased adiposity and elevated insulin and leptin levels. At the hypothalamic level, changes in the expression of Drd2 and Fgfr1 pointed to sex-specific modulation of FGF21-related pathways. Maternal Western diet also altered the breast milk miRNA profile, consistently downregulating several miRNAs, particularly miR-223-3p, miR-32-5p, let-7i-5p, miR-140-5p, miR-29a-3p, and miR-29c-3p, while specific predicted targets were upregulated in both brown and white adipose tissues of the offspring, especially those involved in thermogenesis and browning. Betaine supplementation showed partial protective effects in females by slightly enhancing thermogenic capacity. Conclusion: This thesis demonstrates that supplementation with specific milk-derived bioactive compounds during the suckling period (myo-inositol, leptin, and betaine) can mitigate or partially reverse adverse metabolic programming induced by suboptimal maternal nutrition. The effectiveness of these interventions depends on the interplay between maternal diet, metabolic status, and offspring sex. Overall, the results highlight lactation as a critical window for implementing targeted nutritional strategies aimed at improving long-term metabolic health.
Language: English
Field: Medicine
Open Access status: green
OpenAlex ID: W7139709203
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