Exposure to early‐life stress (ES) is associated with cognitive and metabolic deficits in adulthood. The role of early nutrition in programming these long‐term effects is largely unknown. We focused on essential ω‐3 and ω‐6 long‐chain polyunsaturated fatty acids (LCPUFA) and investigated whether ES affects central and peripheral FA profiles, as well as if and how an early diet with increased availability of ω‐3 LCPUFA (via lowering ω‐6/ω‐3 ratio) protects against ES‐induced impairments. ES exposure [limited nesting and bedding paradigm from postnatal day (P)2 to P9] altered central and peripheral FA profiles in mice. An early diet with low ω‐6/ω‐3 ratio from P2 to P42 notably prevented the ES‐induced cognitive impairments, and the alterations in hippocampal newborn cell survival and in CD68+ microglia, without affecting the ES‐induced metabolic alterations. Other markers for hippocampal plasticity, apoptosis, and maternal care were unaffected by ES or diet. Our findings highlight the importance of early dietary lipid quality for later cognition in ES‐exposed populations.—Yam, K.‐Y., Schipper, L., Reemst, K., Ruigrok, S. R., Abbink, M. R., Hoeijmakers, L., Naninck, E. F. G., Zarekiani, P., Oosting, A., Van der Beek, E. M., Lucassen, P. J., Korosi, A. Increasing availability of ω‐3 fatty acid in the early‐life diet prevents the early‐life stress‐induced cognitive impairments without affecting metabolic alterations. FASEB J. 33, 5729–5740 (2019). http://www.fasebj.org
Early-life stress (ES) increases the vulnerability to develop psychopathologies and cognitive decline in adulthood. Interestingly, this is often comorbid with metabolic disorders, such as obesity. However, it is unclear whether ES leads to lasting metabolic changes and to what extent this is associated with the ES-induced cognitive impairments. Here, we used an established chronic ES mouse model (from postnatal day (P) 2 to P9) to investigate the short- and long-term effects of ES exposure on parameters of the adipose tissue and the leptin system (i.e. circulating levels and gene expression of leptin and its receptor) in both sexes. Immediately following ES, the offspring exhibited reductions in white adipose tissue (WAT) mass, plasma leptin levels and in leptin mRNA expression in WAT. Furthermore, ES exposure led to increased brown adipose tissue and browning of WAT, which was evident by a drastic increase in uncoupling protein 1 mRNA expression in the inguinal WAT at P9. Notably, the ES-induced reductions in WAT mass, plasma leptin and leptin expression in WAT were sustained into adulthood and were accompanied by changes in body fat distribution, such as a higher ratio between mesenteric WAT and other WATs. Interestingly, while ES exposure increased leptin receptor mRNA expression in the choroid plexus, it was unaltered in the hippocampus. This suggests an adaptation to maintain central leptin homeostasis following ES exposure. In addition, chronic ES exposure resulted in the well-established cognitive impairment in object recognition performance during adulthood, which correlated positively with reductions in WAT mass observed in male, but not in female mice. Finally, to assess if ES leads to a different metabolic phenotype in a moderate obesogenic environment, we measured body fat accumulation of control and ES-exposed mice in response to a moderate western-style diet (WSD) that was provided during adulthood. ES-exposed mice subjected to WSD exhibit a higher increase in adiposity when compared to controls, suggesting that ES exposure might result in a higher vulnerability to develop obesity in a moderate obesogenic environment. To conclude, chronic ES exposure alters parameters of the adipose tissue, leads to central adaptations in leptin regulation and results in higher fat accumulations when exposed to a WSD challenge later in life. A better understanding of these metabolic effects induced by ES might open up new avenues for therapeutic (e.g. nutritional) interventions.
Background: In addition to contemporary lifestyle factors that contribute to the increased obesity prevalence worldwide, early nutrition is associated with sustained effects on later life obesity. We hypothesized that physical properties of dietary lipids contribute to this nutritional programming. We developed a concept infant formula (IMF) with large, phospholipidcoated lipid droplets (Nuturis; Danone Research, Paris, France) and investigated its programming effect on metabolic phenotype later in life. Methods: Male c57Bl/6j mice were fed a control formula (control IMF) or Nuturis (concept IMF) diet between postnatal day (PN)16 and PN42. all mice were subsequently fed a Western-style diet (WsD) until PN126. Body composition was monitored repeatedly by dual-energy X-ray absorptiometry between PN42 and PN126. results: concept IMF slightly increased lean body mass as compared with control IMF at PN42 but did not affect fat mass. Upon 84 d of WsD feeding, the concept IMF group showed reduced fat accumulation as compared with control IMF. In addition, fasting plasma leptin, resistin, glucose, and lipids were significantly lower in the concept IMF group. conclusion: Large phospholipid-coated lipid droplets in young mice reduced fat accumulation and improved metabolic profile in adulthood. These data emphasize that physical properties of early dietary lipids contribute to metabolic programming.
Obese individuals have more (hyperplastic) and larger (hypertrophic) adipocytes in their white adipose tissue (WAT) than normal-weight individuals. The difference in cell number emerges early in childhood, suggesting that this is a critical period for being susceptible to obesity. Breast-feeding has been shown to be protective against obesity, and we have previously shown in mice that the physical structure of lipids in human milk may contribute to this protective effect. In the present study, we investigated how differences in the physical structure of lipids in the early diet may modulate adipose tissue development. Male mice were fed a diet containing control infant milk formula (Control IMF; Danone Research) or Nuturis w (Concept IMF with large phospholipid-coated lipid droplets; Danone Research) from postnatal day (PN)16 to 42. Subsequently, mice were challenged with a moderate Western-style diet (WSD) until PN98, and body composition was monitored by dual-energy X-ray absorptiometry. Epididymal WAT was analysed for adipocyte size, number and gene expression of metabolic transcription factors. Early Concept IMF exposure reduced fat accumulation during the WSD challenge by 30 % compared with the Control IMF. It reduced adipocyte size without affecting adipocyte number in adult mice. The Concept IMF decreased the expression of PPARg, CCAAT/enhancer-binding protein and retinoid X receptor a in WAT in adulthood, key regulators of metabolic activity. In conclusion, Concept IMF exposure in early life reduced susceptibility to obesity in adult life, by preventing adipocyte hypertrophia upon adult dietary challenge without affecting adipogenesis. These data emphasise the importance of the physical properties of dietary lipids in early life in obesity risk later in life.
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