Dairy fat blend improves brain DHA and neuroplasticity and regulates corticosterone in mice
Introduction
Breastfeeding is highly recommended by the World Health Organization (WHO), at least for the first six months of life, as it provides young infant the nutrients they need for a healthy growth. Importantly, for brain development, the needs in essential fatty acids from the n-3 and n-6 families are crucial. Because the organism cannot produce these fatty acids, alpha-linolenic acid (ALA) and linoleic acid (LA) have to be provided by the maternal diet. Even though infant formulas follow the recommended guidelines in terms of fat composition for most fatty acids and especially essential fatty acids, they are far from breast milk composition as they are usually prepared using only vegetable oils. Recently, infant formulas prepared with dairy fat have been reintroduced in the panel of commercial infant formulas {Delplanque, 2015 #1305}. Furthermore in an attempt to most adequately mimic the composition of mother's milk, long chain fatty acids (LCPUFA) can be added. Infant formulas containing dairy fats [1] or evaporated milk [2] result in an intermediate LCPUFA status compared to individuals fed with vegetable fat formulas or breast milk. However, the use of lipid formulation does not necessarily take into account brain's need in PUFAs.
Docosahexaenoic acid (DHA; 22:6n-3) and arachidonic acid (ARA; 20:4n-6) are essential PUFAs and key structural components of neuronal membrane phospholipids [3], [4]. DHA and ARA are metabolized from precursors ALA and LA [5] that cannot be synthetized de novo by mammals and have to be provided through the diet. The demand for complex lipids such as DHA is important to form vital cell membrane structures during perinatal period [6] and it accumulates in the brain during the later stages of gestation and lactation via placenta and maternal milk or infant formula [6], [7], [8], [9]. Previous studies have shown that dairy fat-based formula with LA/ALA ratio leads to optimal DHA levels in brain pups [10], [11]. Moreover, dairy products have been shown to have beneficial impact on the bioconversion of ALA in humans or animals [12], [13], [14].
DHA and ARA are necessary for normal brain development and function [15], [16], [17], [18], [19]. DHA promotes neuroplasticity, neurogenesis, synaptogenesis and neuroimmune interactions [16], [20], [21], [22], [23]. Kang et al. [24] recently discovered that the Fat-1 transgenic mouse, which has enriched levels of DHA in the brain because it can convert n-6 to n-3 fatty acids, exhibits increased hippocampal neurogenesis. Neurogenesis is also increased in the hippocampus of aged rats supplemented with DHA [25]. In opposite, Bertrand et al. demonstrated that neurogenesis is decreased in the DHA-deficient embryonic rat brain [26].
PUFA are also powerful immunomodulators and n-3 PUFAs such as DHA and their derivatives (resolvins, neuroprotectins, maresins) exert anti-inflammatory effects and inhibit the production of proinflammatory cytokines [20]. Microglia are the main cellular component of the brain innate immune system and are key players in the regulation and maintenance of central nervous system (CNS) homeostasis [27], [28], [29]. It has been recently demonstrated that microglia play a key role during brain development, especially in neural circuit formation [30], [31], by engulfing and eliminating synapses during development, leading to maturation of the CNS network [30], [31], [32]. Modulation of n-3/n-6 PUFA ratio impacts microglia activity with functional effect during perinatal and adult periods [22], [23].
Numerous studies have shown that, in animal models of nutritional n-3 PUFA deprivation, brain DHA decrease leads to anxiety and depressive-like behaviors [33], [34]. Chronic n-3 PUFA supplementation has beneficial effects on anxiety, cognitive and depressive-like behaviors in animals submitted to stress [35]. Supplementation with n-3 PUFAs has been shown to prevent the disruption of stress axis functionality associated with the development of neuropsychiatric disorders. N-3 PUFA deficiency induces hyperactivity of the hypothalamo-pituitary-adrenal (HPA) axis, reflected by plasma corticosterone elevation whereas dietary n-3 PUFA supplementation induces resilience to the effects of chronic social stress on emotional behaviors, by preventing HPA axis hyperactivity [36].
Providing the adequate amount of n-3 PUFA for optimal DHA accretion in early life is of high importance to promote neuroplasticity. The aim of this study was to evaluate the short and long term impact of partial replacement of vegetable oil in infant formula by dairy fat supplemented or not in DHA and ARA on brain DHA level and neuroplasticity (microglial cells number, neurogenesis) and corticosterone as well as glucocorticoid receptor phosphorylation.
Section snippets
Animals and experimental design
All experiments were conducted according to the INRA Quality Reference System, and to relevant French (Directive 87/148, Ministère de l’Agriculture et de la Pêche) and European (Directive 86/609, November 24th 1986, European Community) legislations. They followed ethic protocols approved by the Région Aquitaine Veterinary Services (Direction Départementale de la Protection des Animaux, approval ID: A33-063-920) and by ethics committee (No. 50120112-A). Every effort was made to minimize
Statistical analysis
All data were expressed as the mean±SEM. A p-value<0.05 was considered as significant. Data were statistically analyzed using a two-way ANOVA comparison factor 1: lipid quality (VL, DL), factor 2: supplementation (ARA+DHA) followed by a Bonferroni post-hoc when interaction was significant.
Effect of lipid quality and DHA+ARA supplementation on fatty acid level in mice cortex at PND14 and PND90
At PND14, the analysis of n-3 PUFA revealed a lipid quality effect (F(1,11)=49.39, p<0.001), a DHA+ARA supplementation effect (F(1,11)=29.20, p<0.001) and an interaction lipid quality×supplementation effect (F(1,11)=6.949, p<0.05). N-6 PUFA changes were the opposite of n-3 PUFA modification and statistical analysis demonstrated a lipid quality effect (F(1,11)=265.4, p<0.001), a DHA+ARA supplementation effect (F(1,11)=17.70, p<0.01) and an interaction lipid quality×supplementation effect
Discussion
The present study demonstrates the importance of dairy lipids for DHA accretion in the developing and adult brain and further demonstrates that the quality of lipids in the diet impacts brain neuroplasticity on both short (PND14) and long (PND90) term.
Here, we first show that dairy lipids in the maternal diet induce an increase in DHA level in the prefrontal cortex of offsprings at PND14 and PND90. These results are in accordance with previous results showing that dairy lipids consumption for 6
Funding
This work was partially funded by Lactalis.
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