Maralinde R. Abbink

Early-life stress (ES) exposure increases the risk of developing obesity. Breastfeeding can markedly decrease this risk, and it is thought that the physical properties of the lipid droplets in human milk contribute to this benefit. A concept infant milk formula (IMF) has been developed that mimics these physical properties of human milk (Nuturis^®, N-IMF). Previously, we have shown that N-IMF reduces, while ES increases, western-style diet (WSD)-induced fat accumulation in mice. Peripheral and central inflammation are considered to be important for obesity development. We therefore set out to test the effects of ES, Nuturis^® and WSD on adipose tissue inflammatory gene expression and microglia in the arcuate nucleus of the hypothalamus. ES was induced in mice by limiting the nesting and bedding material from postnatal day (P) 2 to P9. Mice were fed a standard IMF (S-IMF) or N-IMF from P16 to P42, followed by a standard diet (STD) or WSD until P230. ES modulated adipose tissue inflammatory gene expression early in life, while N-IMF had lasting effects into adulthood. Centrally, ES led to a higher microglia density and more amoeboid microglia at P9. In adulthood, WSD increased the number of amoeboid microglia, and while ES exposure increased microglia coverage, Nuturis^® reduced the numbers of amoeboid microglia upon the WSD challenge. These results highlight the impact of the early environment on central and peripheral inflammatory profiles, which may be key in the vulnerability to develop metabolic derangements later in life.

Early life stress (ES) increases the risk to develop metabolic and brain disorders in adulthood. Breastfeeding (exclusivity and duration) is associated with improved metabolic and neurocognitive health outcomes, and the physical properties of the dietary lipids may contribute to this. Here, we tested whether early life exposure to dietary lipids mimicking some physical characteristics of breastmilk (i.e., large, phospholipid-coated lipid droplets; Concept Nuturis® infant milk formula (N-IMF)), could protect against ES-induced metabolic and brain abnormalities under standard circumstances, and in response to prolonged Western-style diet (WSD) in adulthood. ES was induced by exposing mice to limited nesting material from postnatal day (P) 2 to P9. From P16 to P42, male offspring were fed a standard IMF (S-IMF) or N-IMF, followed by either standard rodent diet (SD) or WSD until P230. We then assessed body composition development, fat mass, metabolic hormones, hippocampus-dependent cognitive function, and neurogenesis (proliferation and survival). Prolonged WSD resulted in an obesogenic phenotype at P230, which was not modulated by previous ES or N-IMF exposure. Nevertheless, ES and N-IMF modulated the effect of WSD on neurogenesis at P230, without affecting cognitive function, highlighting programming effects of the early life environment on the hippocampal response to later life challenges at a structural level.

Early life stress (ELS) is a potent environmental factor that can confer enduring effects on brain structure and function. Exposure to stress during early life has been linked to a wide range of physiopathological consequences later in life. In particular, ELS has been shown to have lasting effects on neurogenesis in the adult brain, suggesting that ELS is a significant regulator of adult neural stem cell function. Here, we investigated the effect of ELS on the numbers and proliferation of neural stem cells in the hypothalamus of adult mice. We show that ELS has long term negative effects on hypothalamic neural stem cell numbers and on their proliferation. Specifically, ELS reduced the total numbers of PCNA+ cells present in hypothalamic areas surrounding the 3 ^rd ventricle; the numbers of PCNA+/Sox2+/Nestin-GFP+ cells present in the medial eminence at the base of the 3 ^rd ventricle; and the number of β-tanycytes around the ventral 3rd ventricle, without affecting the numbers of α-tanycytes in more dorsal areas. These results suggest that a reduction of proliferation and tanycyte numbers contributes to the effects of ELS on the hypothalamus and its consequent physiological alterations.