Dairy fat blend improves brain DHA and neuroplasticity and regulates corticosterone in mice

https://doi.org/10.1016/j.plefa.2016.03.013Get rights and content

Highlights

  • The importance of dairy lipids for DHA accretion in the developing and adult brain.

  • The quality of lipids in the diet impacts brain neuroplasticity (neurogenesis, neurotrophic factor, microglia number) on short and long term.

  • That the quality of lipids in the diet impacts HPA axis on both short and long term.

Abstract

Mimicking the breast milk lipid composition appears to be necessary for infant formula to cover the brain’s needs in n-3 PUFA. In this study, we evaluated the impact of partial replacement of vegetable oil (VL) in infant formula by dairy fat (DL) on docosahexaenoic acid (DHA) brain level, neuroplasticity and corticosterone in mice. Mice were fed with balanced VL or balanced DL diets enriched or not in DHA and arachidonic acid (ARA) from the first day of gestation. Brain DHA level, microglia number, neurogenesis, corticosterone and glucocorticoid receptor expression were measured in the offsprings. DL diet increased DHA and neuroplasticity in the brain of mice at postnatal day (PND) 14 and at adulthood compared to VL. At PND14, ARA and DHA supplementation increased DHA in VL but not in DL mice brain. Importantly, DHA and ARA supplementation further improved neurogenesis and decreased corticosterone level in DL mice at adulthood. In conclusion, dairy lipids improve brain DHA level and neuroplasticity.

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.

References (70)

  • E. Kawakita et al.

    Docosahexaenoic acid promotes neurogenesis in vitro and in vivo

    Neuroscience

    (2006)
  • P. Coti Bertrand et al.

    Maternal dietary (n-3) fatty acid deficiency alters neurogenesis in the embryonic rat brain

    J. Nutr.

    (2006)
  • C. Madore et al.

    Nutritional n-3 PUFAs deficiency during perinatal periods alters brain innate immune system and neuronal plasticity-associated genes

    Brain Behav. Immun.

    (2014)
  • J.C. DeMar et al.

    One generation of n-3 polyunsaturated fatty acid deprivation increases depression and aggression test scores in rats

    J. Lipid Res.

    (2006)
  • A.C. Ferraz et al.

    Chronic omega-3 fatty acids supplementation promotes beneficial effects on anxiety, cognitive and depressive-like behaviors in rats subjected to a restraint stress protocol

    Behav. Brain Res.

    (2011)
  • A.L. Lepinay et al.

    Perinatal high-fat diet increases hippocampal vulnerability to the adverse effects of subsequent high-fat feeding

    Psychoneuroendocrinology

    (2015)
  • J. Folch et al.

    A simple method for the isolation and purification of total lipides from animal tissues

    J. Biol. Chem.

    (1957)
  • W.R. Morrison et al.

    Preparation of fatty acid methyl esters and dimethylacetals from lipids with boron fluoride--methanol

    J. Lipid Res.

    (1964)
  • C. Madore et al.

    Early morphofunctional plasticity of microglia in response to acute lipopolysaccharide

    Brain Behav. Immun.

    (2013)
  • A.-L. Dinel et al.

    Lipopolysaccharide-induced brain activation of the indoleamine 2,3-dioxygenase and depressive-like behavior are impaired in a mouse model of metabolic syndrome

    Psychoneuroendocrinology

    (2014)
  • V. Rolland et al.

    Body weight, body composition, and energy metabolism in lean and obese Zucker rats fed soybean oil or butter

    Am. J. Clin. Nutr.

    (2002)
  • H. Bendixen et al.

    Effect of 3 modified fats and a conventional fat on appetite, energy intake, energy expenditure, and substrate oxidation in healthy men

    Am. J. Clin. Nutr.

    (2002)
  • I. Carrie et al.

    Specific phospholipid fatty acid composition of brain regions in mice. Effects of n-3 polyunsaturated fatty acid deficiency and phospholipid supplementation

    J. Lipid Res.

    (2000)
  • I. Marteinsdottir et al.

    Changes in dietary fatty acids alter phospholipid fatty acid composition in selected regions of rat brain

    Prog. Neuropsychopharmacol. Biol. Psychiatry

    (1998)
  • K. Teffer et al.

    Human prefrontal cortex: evolution, development, and pathology

    Prog. Brain Res.

    (2012)
  • L.G. Robson et al.

    Omega-3 polyunsaturated fatty acids increase the neurite outgrowth of rat sensory neurones throughout development and in aged animals

    Neurobiol. Aging

    (2010)
  • K. Gharami et al.

    Essential role of docosahexaenoic acid towards development of a smarter brain

    Neurochem. Int.

    (2015)
  • G. Bertrand et al.

    Predictive value of sequential maternal anti-HPA-1a antibody concentrations for the severity of fetal alloimmune thrombocytopenia

    J. Thromb. Haemost.

    (2006)
  • M.V. Schmidt et al.

    The postnatal development of the hypothalamic-pituitary-adrenal axis in the mouse

    Int. J. Dev. Neurosci.

    (2003)
  • C.D. Walker

    Nutritional aspects modulating brain development and the responses to stress in early neonatal life

    Prog. Neuropsychopharmacol. Biol. Psychiatry

    (2005)
  • T.A. Sanders et al.

    A comparison of the influence of breast-feeding and bottle-feeding on the fatty acid composition of the erythrocytes

    Br. J. Nutr.

    (1979)
  • M.L. Courage et al.

    Visual acuity development and fatty acid composition of erythrocytes in full-term infants fed breast milk, commercial formula, or evaporated milk

    J. Dev. Behav. Pediatr.

    (1998)
  • I. Carrie et al.

    Diets containing long-chain n-3 polyunsaturated fatty acids affect behaviour differently during development than ageing in mice

    Br. J. Nutr.

    (2000)
  • T. Moriguchi et al.

    Recovery of brain docosahexaenoate leads to recovery of spatial task performance

    J. Neurochem.

    (2003)
  • A.J. Sinclair

    Long-chain polyunsaturated fatty acids in the mammalian brain

    Proc. Nutr. Soc.

    (1975)
  • Cited by (18)

    • Perinatal Nutrition and Programmed Risk for Neuropsychiatric Disorders: A Focus on Animal Models

      2019, Biological Psychiatry
      Citation Excerpt :

      Evidence from the perinatal period demonstrates that these neural processes, as well as hippocampal development and microglia activation, are already disrupted before weaning (120–125). Preweaning examinations additionally show that dietary PUFAs impact hippocampal neuroplasticity via impaired endocannabinoid signaling and glucocorticoid inhibition (126,127). This literature suggests that the timing of altered brain lipid availability during critical periods of development could contribute to neurobehavioral impairments later in life.

    • Maternal dairy fat diet does not influence neurotrophin levels and cognitive performance in the rat offspring at adult age

      2018, International Journal of Developmental Neuroscience
      Citation Excerpt :

      In the present study high dairy fat diet contained 0.54% ALA and we found no change in the levels of DHA in the brain of the offspring. However, a recent study examining the effect of feeding dairy lipid diets containing 2.2% ALA to pregnant mice from d0 of gestation report increase in brain DHA levels in offspring on postnatal d14 and attribute the increase in DHA to the presence of short and medium chain fatty acids present in dairy lipids which prevent the oxidation of ALA and favor the conversion of ALA to DHA (Dinel et al., 2016). Our findings suggest that a low amount of ALA in the diet does not increase its conversion to DHA.

    • Impact of Lactobacillus fermentum and dairy lipids in the maternal diet on the fatty acid composition of pups' brain and peripheral tissues

      2016, Prostaglandins Leukotrienes and Essential Fatty Acids
      Citation Excerpt :

      The present study demonstrates the importance of the quality of the lipids in the mother's diet that influenced the maternal milk composition for pups’ DHA accretion. Previous study demonstrated that dietary lipid quality impacts brain neuroplasticity on both short (PND14) and long (PND90) term [49]. Even if the supplementation of probiotics in the deficient diet of mothers during the perinatal period did not restore the DHA level observed in the VL group, it led to a higher DHA level in the brain and peripheral tissue of P14 pups than without supplementation.

    View all citing articles on Scopus
    View full text