Impact of fatty acids on brain circulation, structure and function.

Prostaglandins, Leukotrienes and Essential Fatty Acids ∎ (∎∎∎∎) ∎∎∎–∎∎∎

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Impact of fatty acids on brain circulation, structure and function Roy A.M. Haast, Amanda J. Kiliaan n Department of Anatomy, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands

art ic l e i nf o

Keywords: Mediterranean diet High-fat diet Omega-3 long chain polyunsaturated fatty acids Cerebral circulation Cerebral structure and cerebral function

a b s t r a c t The use of dietary intervention has evolved into a promising approach to prevent the onset and progression of brain diseases. The positive relationship between intake of omega-3 long chain polyunsaturated fatty acids (ω3-LCPUFAs) and decreased onset of disease- and aging-related deterioration of brain health is increasingly endorsed across epidemiological and diet-interventional studies. Promising results are found regarding to the protection of proper brain circulation, structure and functionality in healthy and diseased humans and animal models. These include enhanced cerebral blood flow (CBF), white and gray matter integrity, and improved cognitive functioning, and are possibly mediated through increased neurovascular coupling, neuroprotection and neuronal plasticity, respectively. Contrary, studies investigating diets high in saturated fats provide opposite results, which may eventually lead to irreversible damage. Studies like these are of great importance given the high incidence of obesity caused by the increased and decreased consumption of respectively saturated fats and ω3-LCPUFAs in the Western civilization. This paper will review in vivo research conducted on the effects of ω3-LCPUFAs and saturated fatty acids on integrity (circulation, structure and function) of the young, aging and diseased brain. & 2014 Elsevier Ltd. All rights reserved.

Contents 1. 2.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Circulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Diet effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Fundamental mechanisms. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3. Structure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Diet effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Fundamental mechanisms. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4. Function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Diet effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. Fundamental mechanisms. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction Paleontological studies have shown that feeding habits played a crucial role in the development of the human brain [1]. Differences

n Correspondence to: Department of Anatomy, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Nijmegen Medical Centre, Room M245/0.24, PO Box 9101, 6500 HB Nijmegen, The Netherlands, Geert Grooteplein 21 N, 6525 EZ Nijmegen. Tel.: þ 31 24 3614378; fax: þ31 24 3613789. E-mail address: [email protected] (A.J. Kiliaan).

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in diet among primates affected survival rate and the ability to reproduce, which are both related to brain size and cognitive functioning [2]. It is now known that brain size increased with the development of skills that required proper cognition, such as cooking and access to food and this led to the formation of the modern brain as we know now [3]. An evident example of diet effects on the brain was observed when comparing encephalisation (increasing brain/body-mass ratio) of hominids (early humans) living close to the shore with that of hominids living in-land [4]. A shore-based diet, which included high consumption

0952-3278/$ - see front matter & 2014 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.plefa.2014.01.002

Please cite this article as: R.A.M. Haast, A.J. Kiliaan, Impact of fatty acids on brain circulation, structure and function, Prostaglandins Leukotrienes Essent. Fatty Acids (2014), http://dx.doi.org/10.1016/j.plefa.2014.01.002i

R.A.M. Haast, A.J. Kiliaan / Prostaglandins, Leukotrienes and Essential Fatty Acids ∎ (∎∎∎∎) ∎∎∎–∎∎∎

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of fish, led to extensive encephalisation in this population. This is probably related to the higher consumption of omega-3 fatty acids like docosahexaenoic acid (DHA; 22:6n 3) in this shore-based diet, as DHA is an important brain constituent present in cell membranes but cannot be synthesized efficiently by the human body itself. When we analyze the situation now-a-days, a similar comparison can be made: with on one side a ‘Mediterranean-type diet’ and on the other side a ‘Western-type diet’. The conception of a Mediterranean-type diet (which is rich in long-chain polyunsaturated fatty acids) is derived from the combination of high intake of fruits, vegetables, nuts, cereals, olives and olive oil and more fish; less milk but more cheese; less meat; and moderate amounts of wine [5]. On the other hand, a Western-type diet is the result of increased saturated and trans fatty acids consumption due to introduction of food staples and food-processing procedures after the Industrial Revolution [6]. This difference in diet is reflected in an increased death rate caused by cancer and heart disease in the United States compared to Crete, which are characterized by consuming a Western-type diet and Mediterranean-type diet, respectively [7]. Outcome of cancer and heart disease is clearly affected by different diets and their effect on the cardiovascular system [8]. Cardiovascular risk factors are considered important risk factors for the onset of neurological diseases such as stroke and Alzheimer0 s Disease (AD). The focus of this review will be on the effects of dietary components on the brain as there is abundant data available revealing the effects of specific diet components on brain health and mental functioning [9]. For example, high serum cholesterol levels, possibly via dietary intake of high saturated fat, in midlife increases the risk of AD in later life while a diet low in saturated fat like the Mediterranean diet is inversely related to this [10,11]. Several groups tested the possibilities to slow down the progression of diseases like AD with nutrition-based intervention in animals and humans. Experimental data revealing the influence of diet components on three important indicators of brain health: (1) circulation, (2) structure and (3) function, will be highlighted in the present review. In this context, we will mainly emphasize the effects of omega-3 longchain polyunsaturated fatty acids (ω3-LCPUFAs) on these aspects and compare this with the evidence found concerning the intake of saturated fatty acids. Obtaining more knowledge concerning the aftermaths of malnutrition on the brain is necessary since diseases like obesity, metabolic syndrome and diabetes gain prevalence in modern society.

2. Circulation Due to high demands of energy by the brain and its low capacity to store this energy, the brain is the most highly perfused part of the human body [12]. Proper functioning, including adequate cerebral blood flow (CBF) and vessel reactivity, is necessary to ensure the microenvironment in which brain cells function efficiently. The importance of proper cerebral circulation is reflected in cerebrovascular and neurodegenerative diseases such as atherosclerosis, stroke and AD. Higher cerebral perfusion and the ability to restore blood flow rapidly will lead to a lower amount of cell death after a stroke, resulting in less functional impairment eventually [13]. In addition, more and more evidence points towards a vascular basis of the pathologies observed in AD [14]. For example, AD patients show reduced CBF and cerebrovascular reactivity compared with healthy age-matched control subjects [15,16]. Moreover, Zerbi et al. (2013) showed a reduced microvascular relative cerebral blood volume in the cortical, thalamic and hippocampal brain regions of APPswe/ PS1dE9 Alzheimer mice [17,18]. Sedentary lifestyle characterized by high saturated fat intake is linked to increased onset of dementia

while moderate intake of unsaturated fat is associated with a decreased risk of dementia [10,11], confirming the potential role of diet on underlying pathological mechanisms such as impaired brain circulation. 2.1. Diet effects Indeed, fundamental studies have shown that high-fat intake negatively affects vascular functioning through increased myogenic tone and endothelial dysfunctioning, both important properties in regulating CBF [19–22]. In principle, adequate CBF is regulated via two mechanisms: autoregulation and neurovascular coupling (NVC) [23]. Cerebral autoregulation is responsible for maintaining optimal and stable CBF during normal activities by counteracting changes in arterial pressure through arterial relaxation and constriction (i.e. vascular tone) [24]. Contrary, NVC plays a pivotal role in increasing flow in regions that display increased functional neuronal activity. Experiments with hypercholesterolemic ApoE / mice fed with a high-fat diet (20% fat) showed higher cholesterol plasma levels and impaired endotheliumdependent dilator responses of cerebral arterioles in these animal, compared to normocholesterolemic ApoE / mice [20]. This is presumably caused by increased production of reactive oxygen species (ROS) leading to vascular changes such as impaired regulation of vascular tone [19,22]. Similar differences were also observed in non-transgenic Wistar rats. The high-fat diet (45% fat) significantly attenuated the change in cerebral blood flow after whisker stimulation in these animals. This reduction in cerebral blood flow response may be caused by impaired Kþ-induced vasodilation since this was significantly reduced in the high-fat (45%) diet group compared to rats on control diet (10% fat) rats [21]. Taken together, these differences demonstrate impaired coupling between neuronal and vascular cells due to high dietaryintake of fat. While studies that utilize high-fat diets, containing high levels of saturated and trans fatty acids, indicate impaired neurovascular mechanisms, supplementation with ω3-LCPUFAs like DHA and eicosapentaenoic acid (EPA; 20:5n 3) suggests contrary effects [25–27]. Aged monkeys that were given DHAenriched soymilk for 1 week or for 4 weeks showed significantly increased regional cerebral blood flow (rCBF) in the somatosensory cortex after vibrotactile stimulation compared with the control group that was given soymilk solely [27]. Injection of the DHA and EPA precursor α-linolenic acid (ALA; 18:3n 3) improved local CBF rates in rats by almost 20% compared to the saturated fatty acids palmitate [28,29]. A special diet composed of DHA, EPA and Uridine monophosphate (DEU; all important precursors of membrane components [30]) significantly increased CBF in the cortex and thalamus of APPswe/PS1dE9 Alzheimer mice [17]. In line with these data, increased regional cerebral blood volume (rCBV) was also observed by our group in wildtype mice after treatment for 8 weeks with a DHA and EPA enriched diet [25]. In addition, long-term consumption ( 9 months) of a multi-nutrient (Fortasyn™ Connect; FC) diet by wildtype and ApoE / mice initiated locally increased CBV values. These changes were especially observed in regions close to brain feeding arteries [31]. Compared to the DEU diet, the FC diet included additional nutrients such as choline, phospholipids, vitamins and antioxidants, which are all important co-factors for maintaining neuronal membrane health through the Kennedy Cycle [32]. Human data on modulation of cerebral circulation such as CBV and CBF by dietary components are scarce but available results confirm the detrimental and beneficial effects of high-fat diet and DHA found in animal studies, respectively. To our knowledge, no study is available that showed changes in CBF due to high-fat intake in human in which no metabolic disorder is present. Nevertheless, obese women (mean BMI of 32.7) showed decreased rCBF during



control conditions compared with normal-weight subjects (mean BMI of 22.2) [33]. It remains questionable if this decrease in rCBF is related to high-fat intake in this group of patients as there is no consensus whether high fat intake leads to obesity [34,35]. However, this reduced rCBF may be indirectly related to lower intake of ω3-LCPUFAs, as this led to higher hunger sensations in obese subjects [36]. More convincing human data is available with regard to the effects of DHA on brain circulation. One study showed that rCBF in the prefrontal cortex was significantly enhanced during a cognitive task after 12-weeks daily dietary supplementation with DHA-rich fish oil, in comparison with a placebo [26]. Additionally, position emission tomography (PET) experiments on human that were injected intravenously with labeled DHA showed that the rate of DHA incorporation into the brain is significantly related to rCBF in that region. Despite the fact that regions with high DHA content showed a high rCBF, a causal relationship was not proven [37].

2.2. Fundamental mechanisms There are several proposed mechanisms that may explain the enhanced rCBF in DHA-treated subjects. First, Tsukada et al. (2000) suggested that the observed changes are not the result of global changes in CBF but due to the effect of DHA on the cholinergic system and NVC [27]. They underpinned their suggestion with earlier findings showing that (1) administration of scopolamine, a cholinergic antagonist, abolished the rCBF response to vibrotactile stimulation in the somatosensory cortex in monkeys [38] and (2) DHA increased cerebral choline and acetylcholine levels in rat [39]. Additionally, DHA may enhance CBF through increased activity of nitric oxide synthase (NOS) [40]. Increased NOS activity after DHA supplementation was observed in both piglets and rats [41,42] and may have led to enhanced production of nitric oxide (NO) [43]. NO, like extracellular potassium (K þ), is an important molecular regulator of mechanisms underlying both autoregulation of CBF and NVC [44]. The effects of ω3-LCPUFAs on NVC are further strengthened by the fact that ALA and DHA are found to activate the TREK-1 channel which is an important vasodilatation mediator [28]. Second, sufficient supplementation and implementation of DHA in the membranes of endothelial and neuronal cells may initiate more efficient cerebrovascular responses, e.g. by

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increasing endothelial and neuronal membrane fluidity and improving membrane-bound protein functioning. DHA deficiency (such as in high-fat diets) will lead to opposing effects [45,46]. Third, increased consumption of ω3-LCPUFAs may be effective on a more systemic level by slowing down atherogenesis and improving cardioprotection [8,47,48]. Possible mechanisms that contribute to this latter argument include up-regulation of adiponectin or reduction of proinflammatory cytokines [49]. Contrary, high-fat diets favor conditions that induce atherosclerosis such as increased inflammatory responses and endothelial dysfunction [50]. To briefly summarize, these studies designate a favorable role for ω3-LCPUFAs on cerebral circulation while this seems opposing for high saturated fat intake (although less studied). A schematic overview of all discussed human and animal studies is shown in Table 1. Eventually, changes in CBF following supplementation with ω3-LCPUFAs (e.g. DHA and EPA) or due to an impaired saturated vs. unsaturated fatty acids ratio may be correlated with the observed changes in brain structure and function. Fundamental and epidemiological studies providing evidence for the effect of diet on structure and function will be discussed in the following paragraphs.

3. Structure The hypothesis that diet-induced changes on cerebral circulation may be linked to changes in brain structure is strengthened by a recent study of Chen et al. (2013). They showed a significant relationship between cortical CBF (using arterial spin labeling) and subcortical white-matter integrity (assessed by diffusion tensor imaging; DTI) in healthy human participants [51]. Since diet clearly affects cerebral blood flow based on the data reviewed earlier, potential diet effects are also expected to be translatable towards changes in cerebral structure, such as gray and white matter integrity. As Chen et al. (2013) demonstrated, white and graymatter integrity can be assessed using diffusion tensor imaging (DTI) by constructing three-dimensional ellipsoids based on the direction of water movement in neuronal tissue in each voxel [52]. Differences in the geometry of these ellipsoids, determined by DTI-based parameters like λ1, fractional anisotropy (FA), radial diffusivity (RD) and mean diffusivity (MD), indicate changes such as neuronal loss in gray matter and myelin loss, decreased axonal

Table 1 Summery of in vivo data reporting diet effects on brain circulation, sorted by published date. Negative effects of diet are indicated by gray shading at the bottom. Study [Ref.]

Subject

Model [age]

N

Gender

Diet

Duration supplementation

Parameter

Effect (vs. normal diet)

Tsukada et al. (2000) [27] Blondeau et al. (2007) [28] Hooijmans et al. (2009) [25] Umhau et al. (2009) [37] Jackson et al. (2012) [26] Jansen et al. (2013) [31] Zerbi et al. (2013) [18] Karhunen et al. (1997) [33] Kitayama et al. (2007) [20] Li et al. (2013) [21]

Primates

Macaca mulatta [18 years] Wistar [adult]

8

M

DHA-enriched soy milk

1 and 4 weeks

Stimulus induced ΔrCBF

↑

9

M

ALA (injection intravenously)

30 minutes

CBF

↑

38

M

DHAþ EPA enriched

8 weeks

rCBV

↑

14

M þF

DHA (injection intravenously)

3 minutes

rCBF

↑

65

M þF

DHA

12 weeks

Stimulus induced ΔrCBF

↑

19

FC

9 months

rCBV

↑

27

M M M

DEU

10 months

rCBF

↑

23

F

-

-

rCBF

↓ (vs. non-obese)

18

F

High-fat (20%)

4 6 months

↓

64

M

High-fat (45%)

8 weeks

Endothelium-dependent dilator response Stimulus induced ΔCBF

Rats Mice Human Human Mice Mice Human Mice Rats

C57BL6/J [15 months] Healthy adults [19 – 64 years] Healthy adults [18–29 years] C57BL6/J ApoE-/-[12 months] APPswe/PS1dE9 [12 months] Obese adults [28–56 years] ApoE-/[8 months] Wistar [13 weeks]

↓

DEU, DHA þEPA þUridine monophosphate (UMP); DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; FC, Fortasyn Connect (includes DHA, EPA, UMP, choline, phospholipids, vitamins and antioxidants); rCBF, regional cerebral blood flow; rCBV, regional cerebral volume.



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density and connectivity in white matter [53]. For instance, reduction of the myelin sheath around neuronal axons will lead to lower λ1 and FA values as water is able to diffuse more incoherently. AD patients, that are characterized by extensive hippocampal atrophy and increased white matter lesions (WML) over time, exhibited increased mean diffusivity (MD) in gray matter regions and decreased fractional anisotropy (FA) in white matter regions [54,55]. Similar changes were observed in APPswe/ PS1dE9 mice by our group. Compared to wildtype mice, this transgenic AD mice model exhibited reduced axial diffusivity in several white matter areas including the anterior commissure, splenium of corpus callosum, fornix and increased MD in the dentate gyrus [18,56]. Comparable animal studies confirmed our findings [57,58]. Structural changes of the brain are also present in healthy aging human subjects, without any pathological hallmark [59,60]. Brain atrophy was found to be linearly related to aging, with reduction in gray matter volume already present from the age of 20 and white matter volume from the age of 40 [59]. Decreased FA was detected in aged subjects for both white (especially prefrontal area and related corpus callosum) and gray (thalamus and frontal cortex) matter [60,61].

comparable results [63]. Functional connectivity between brain regions in AD patients was significantly reduced compared to controls. Intervention with this diet improved connectivity in AD patients compared to a placebo-group. However, volumetric assessment of the hippocampus and total brain in mild to moderate AD patients (n ¼108) treated with DHA or a placebo did not show any difference [64]. In healthy aging human subjects, supplementation of DHA, EPA and vitamin E induced augmented microstructural architecture based on increased FA and decreased MD and RD, primarily in the corpus callosum, indicating higher myelination, increased axonal density and reduced fiber tract damage [53]. Moreover, regional (e.g. hippocampus and temporal areas) gray matter volume loss was significantly attenuated ( 0.2%) compared with a placebo group ( 0.6%) during the follow-up period (6-months) [65]. Similar results were also observed by other groups: higher DHA intake in the subject0 s regular diet was associated with a larger gray matter volume of the cingulate cortex [66], larger total brain volume and less white matter hyperintensities (WML) [67]. In contrast, a high trans fat (e.g. linolelaidic acid) diet pattern was associated with less total cerebral brain volume and increased brain atrophy in healthy aging humans [68].

3.1. Diet effects 3.2. Fundamental mechanisms As utilization of dietary intervention with omega-3 LCPUFAs is most promising and profitable for slowing-down progression of diseases like AD or age-related deterioration of brain architecture, almost all available data on brain structure focussed on the beneficial effects of DHA and EPA. White and gray matter disintegrity observed in AD mice was reversed almost completely after dietary intervention with the DEU diet and the multinutrient (FC) diet [18] herewith strengthening the earlier mentioned hypothesis. Voxel-based analysis showed that the FC diet was most effective in diminishing the differences observed between wildtype and transgenic APPswe/PS1dE9 mice, while the DEU diet seemed to be less effective [18]. Moreover, histological staining of brains from APPswe/PS1dE9 mice fed with this same FC diet showed a reduced amount of degenerating neurons in the cortex, which may be equivalent to the reduced cortical MD measured by DTI [62]. Human-based studies on brain health in mild AD patients utilizing the same multi nutrient diet composition using electroencephalography (EEG) instead of DTI, revealed

The beneficial effects of ω3-LCPUFA supplementation on brain structure (e.g. gray and white matter volume and integrity; for a summary see Table 2) are presumably initiated through the neuroprotective properties of these components. As mentioned earlier, increased intake of DHA and EPA is linked to increased membrane fluidity and functionality by adjusting its lipid composition [69]. Via incorporation in neuronal membranes, or in their free form, DHA and EPA may subsequently alter expression of genes promoting neuronal health [70–75]. An important DHAderived mediator involved in brain cell survival is neuroprotectin D1 (NPD1) [72]. NPD1 activates a neuroprotective gene-expression programme, such as Bcl-2, which plays a vital role in antiapoptotic mechanisms. Increased expression of Bcl-2 leads to diminution of ROS and subsequent increased cell survival [74]. Likewise, DHA (and other ω3-LCPUFAs) partly mediates its protective effects by maintaining the PI3-kinase pathway, decreasing pro-apoptotic Bcl-2-associated death promoter (BAD) and

Table 2 Overview of in vivo data reporting diet effects on brain structure, sorted by published date. Negative effects of diet are indicated by gray shading at the bottom. Study [Ref.]

Subject

Model [age]

N

Gender

Diet


Parameter


Tan et al. (2006) [65]

Human

Healthy adults [averege age¼ 67 years]

1575

Mþ F

High red blood cell DHA

–

↑ ↓

Conklin et al. (2007) [64] Quin et al. (2011) [62] Scheltens et al. (2012) [61] Witte et al. (2013) [63]

Human

Healthy adults [average age¼ 45 years] Mild – moderate AD [average age¼ 76 years] Mild AD [51–89 years]

55

Mþ F

High DHA intake

102

Mþ F

DHA

2 24h dietary recall interviews 18 months

Total brain volume White matter hyperintensities Gray matter volume

259

Mþ F

Souvenaida

24 weeks

Zerbi et al. (2013) [18] Bowman et al. (2012) [66]

Human Human Human

Healthy adults [50–75 years]

65

Mþ F

DHAþ EPA þ Vitamin E

26 weeks

Mice

APPswe/PS1dE9 [12 months] Healthy elderly [85–101 years]

27

M

DEU, FC

10 months

104

Mþ F

High plasma trans fat

–

Human

↑

Hippocampal and total brain volume Functional connectivity (EEG)

─

White/gray matter integrity Gray matter volume reduction over time White/gray matter integrity (DTI) Total brain volume

↑ ↓

↑

↑ ↓

AD, Alzheimer0 s disease; DEU, DHAþ EPA þ Uridine monophosphate (UMP); DHA, docosahexaenoic acid; DTI, diffusion tensor imaging; EEG, electroencephalogram; EPA, eicosapentaenoic acid; FC, Fortasyn Connect (includes DHA, EPA, UMP, choline, phospholipids, vitamins and antioxidants). a

Souvenaid (contains Fortasyn Connect; the nutrient combination choline, uridine monophosphate, omega-3 fatty acids, and various antioxidants and B vitamins).



promoting anti-oxidant defense, based on in vivo (mice) and in vitro (Neuro 2 A cells) experiments [71,73]. On the other hand, in vivo DHA depletion resulted in increased cell death [70]. The neuroprotective properties were further strengthened by the fact that injection of ALA up to 6 h after transient occlusion of the middle cerebral artery (MCAO) in mice led to reduced infarct volume [76]. Additive to their vasodilating properties, activation of the K þ channel TREK-1 by ALA and its derivates EPA and DHA may possibly counteract lethal neuronal depolarizations that lead to glutamate excitotoxicity and subsequent stroke-induced neurodegeneration [77]. As also briefly mentioned in the previous section (see the ‘Circulation; Fundamental mechanisms’ section) ω3LCPUFAs may have an anti-inflammatory role. A review by Orr et al. (2013) emphasized the major and detrimental role of inflammation in the outcome of stroke [78]. They highlight evidence that links increased DHA levels in mice to lower innate immune and inflammatory responses which may attenuate neuronal death following MCAO. This may be possibly mediated through NPD1 activated neuroprotective pathways, which was previously found to be inversely related with stroke damage, neurological impairments and cellular markers of neuroinflammation [79]. ω3-LCPUFAs also exert other mechanisms that may maintain, improve and restore neuronal structure. An in vivo study by Salvati et al. (2008) showed that intracerebroventricular EPA injection in rats stimulated the expression of proteolipid proteins and myelin oligodendrocyte glycoprotein, which is suggestive of increased myelogenesis [75]. These observations are in line with the results found in human studies showing stronger myelination after supplementation with DHA, EPA and vitamin E [53]. Moreover, the observed beneficial effects of DHA in AD patients and animal models may be regulated via protection against apoptosis induced by soluble amyloid β (Aβ) oligomers [62]. Neuronal cells pre-treated with DHA showed increased neuronal survival upon Aβ treatment by preventing cytoskeleton perturbations, caspase activation and apoptosis, as well as by promoting extracellular signal-related kinase-related [80] survival pathways [81]. Another pathology increasingly associated with brain aging, neurodegenerative diseases and stroke is mitochondrial dysfunction. Preclinical in vitro and in vivo studies showed improvement of mitochondrial dysfunction in stroke and AD models by DHA and may possibly explain reduced neuronal death after ω3-LCPUFA supplementation [82].

4. Function Cognitive decline is a widely accepted phenomenon associated with normative aging and presumably caused by structural changes in the brain. Structural impairment of the brain, and especially white matter loss and dis-integrity, is significantly associated with poor brain functioning (i.e. cognitive performance). High FA values, and thus proper (white matter) connectivity between brain regions, are most often correlated with high levels of task performance [83–86]. However, in case of a neurodegenerative disease like AD, this normal aging process is disturbed. Compared to healthy aging humans, patients suffering AD, or its preceding stage labeled ‘mild cognitive impairment’ (MCI), are characterized by early cognitive decline. This includes profound impairment of both declarative and non-declarative memory, and reduced capacities for reasoning, abstraction, and language [87]. Many methodologies and paradigms are developed throughout the years to test cognition in human and animals. While DTI provides clues on changes in structural connectivity, functional magnetic resonance imaging (fMRI) and EEG reveal potential changes in functional connectivity between distinct brain regions when performing a specific task. However, also a

5

broad spectrum of neuropsychological questionnaires and tests for humans, and behavioral tests for animals provide insights in the cognitive capabilities of the subject of interest. A relatively large amount of data is available regarding the effects of ω3-LCPUFAs on brain function (i.e. cognition), compared to studies concerning brain circulation or structure. Compelling evidence points towards fundamental roles for DHA and EPA in maintaining brain functioning throughout the pre- and postnatal stage and stretching beyond adulthood [88–90], while high-fat type diets show opposite results [40,91]. The following paragraph will emphasize the important role of diet composition on brain structure by highlighting data found in both human and animal studies. 4.1. Diet effects Increased cognitive development and functionality was associated with increased ω3-LCPUFA intake among several studies involving 17 weeks old to 89 yr old human subjects (see Table 3). As mentioned in the introduction, dietary acquisition of ω3LCPUFAs, like in the shore-based diet, contributed significantly in the development and evolution of the modern brain. This is reflected by the high depositions of DHA in the brain throughout the pre- and postnatal stage. For example, to ensure proper brain development, infants require five times more lipids than adults [69]. The beneficial effects of sufficient ω3-LCPUFAs brain content are already observed from the age of 4 months. Infants that were breastfed or given a DHA þarachidonic acid (AA) supplemented formula showed increased neurodevelopmental performance compared to infants fed a standard formula without DHA or AA [92]. Similar results were obtained in older infants aged 18 months. A randomized controlled trial of early (17 weeks after birth) dietary supply of DHA and AA compared to a control diet showed enhanced cognitive development in term infants (age¼18 months) based on the mental development index (MDI) [93]. Four years old breastfed infants from mothers that were given cod liver oil during their pregnancy scored higher on the mental processing composite of the Kaufmann0 s Assessment Battery for Children (K-ABC) compared to infants from corn oil-fed mothers [94]. In addition, a meta-analysis across four different studies that compared DHA-free formulas with DHA-supplemented formulas in preterm infants supported efficacy of ω-3 LCPUFA intake in early visual system development (e.g. by enhancing visual resolution acuity) at 2 and 4 months [80]. Similar results were also obtained at 1 yr of age [95]. These studies tend to allocate vital properties to ω-3 LCPUFAs on the maturation of cortical functioning in early life. In concordance with this, insufficient intake or supplementation during early life may also participate in the onset of diseases related to impaired brain development such as developmental coordination disorder, dyspraxia and attention deficit/hyperactivity disorder [96]. However, as mentioned earlier, the brain0 s dependency on ω-3 LCPUFAs continues throughout the lifespan. A functional MRI study in boys aged between 8 and 10 yr revealed that DHA supplementation increased functional activation in the dorsolateral prefrontal cortex during the sustained attention task [97]. In addition, similar aged children exhibited better working memory performances after 6-months of ω-3 LCPUFAs supplementation which is consistent with that shown in later life (35–54 yr) [98,99]. Extensive questionnaires on food patterns of 15 yr old Swedish boys (n¼ 3972) revealed that fish consumption of less than once a week was significantly associated with poorer cognitive performance 3 yr later, after adjustment for ethnicity, BMI, physical exercise, parents0 education, place of residence and socioeconomic variables [100]. Enhanced functional integrity after ω-3 supplementation was also observed in another study concerning midlife volunteers (average age¼33 yr). Besides this, reduced reaction


6

Study [Ref.]

N

Gender Diet


Parameter


Agostoni et al. (1995) Human Healthy term infants [85] [4months]

86

–

Breastfeeding

4 months

DQ

↑

Wainwright et al. (1999) [106] Birch et al. (2000) [86]

121

M

DHAþ AA DHAþ AA

13 days

MWM (place and cued)

↑ ─

Human Healthy term infants [18months]

56

Mþ F

DHA

17 weeks

MDI

↑

Makrides et al. (2000) [105]

Human Healthy infants [2years]

68

Mþ F

DHAþ AA DHA

2 years

Visual aquity, MDI and PDI

↑ ─

Auestad et al. (2001) [104] Kaplan et al. (2001) [113] Helland et al. (2003) [87] Kalmijn et al. (2004) [109] Fontani et al. (2005) [82] Freund-Levi et al. (2006) [99]

Human Healthy term infants [14months] Human Healthy adults [61–79years]

404

Mþ F

DHAþ AA DHAþ AA

1 year

Mþ F

50% safflower oil drink

60 minuts

Growth, visual acuity, information processing, general development, ─ language and temperament Trails test and attention ↑

Human Healthy children [4years]

76

Mþ F

Maternal cod liver oil intake 9 months

K-ABC

Human Healthy adults [45–70years]

1613 Mþ F

High ω3-LCPUFA intake

–

Overall cognitive function and speed

↑ (vs. maternal corn oil intake) ↑


33

Mþ F

ω3 LCPUFA-capsules

35 days

Reaction time Go/No-Go and sustained attention test

↓

Human Mild AD [average age¼ 74 years] Human Moderate – severe AD [average age¼74] Human Healthy adults [50–70years]

32

Mþ F

DHAþ EPA

6 months

MMSE

↑

75

Mþ F

DHAþ EPA

6 months

MMSE

─

819

Mþ F

Folic acid

3 years

Cognitive decline

↓

Human Healthy elderly [70–89years] 210

M

Cognitive decline

↓

Human Healthy elderly [ Z 65 years] 302

Mþ F

DHAþ EPA intake in regular – diet DHAþ EPA 26 weeks

Attention, sensorimotor speed, memory and executive function

─

8 weeks

Combined intelligence, verbal performance and visuospatial performance MWM escape latency

↑

M

High fish consumption ( 4 once/week) FC

Dullemeijer et al. (2007) [94] Van Gelder et al. (2007) [83] Van de Rest et al. (2008) [103] Aberg et al. (2009) [93] Hooijmans et al. (2009) [25] McNamara et al. (2010) [90] Muldoon et al. (2010) [91] Yurko-Mauro et al. (2010) [95] Narendran et al. (2012) [92] Scheltens et al. (2012) [61] Jansen et al. (2013) [29] Wiesmann et al. (2013) [101] Wainwright et al. (1999) [106] Kalmijn et al. (2004) [109]

Subject Model [age]

Rats

Long-Evans [6–9weeks]

Human Healthy boys [15years] Mice

3972 M

AβPPswe/PS1dE9 [15months] 17

–

↑

Human Healthy boys [8–10years]

33

M

DHA

8 weeks

Bold signal (fMRI)

↑


280

Mþ F

High DHA serum levels

–

↑

Human Healthy adults [Z 55 years]

485

Mþ F

DHA

24 weeks

Nonverbal reasoning, mental flexibility, working memory and vocabulary Learning and memory function

Human Healthy young adults [18– 25years] Human Mild AD [51–89years]

13

Mþ F

DHAþ EPA

6 months

Working memory

↑

12 and 24 weeks

Memory performance

↑

484

Mþ F

Souvenaid

a

↑

Mice

ApoE-/- [12months]

16

M

FC

9 months

Open field anxiety parameters

↓

Mice

AβPPswe/PS1dE9 [11months] 22

M

FC

9 months

MWM escape latency and search strategy

↑

Rats

Long-Evans [6–9weeks]

M

Saturated fat diet

13 days

Working memory

↓

High cholesterol intake

–

Memory and flexibility

↓


121

1613 Mþ F



Table 3 Overview of in vivo data reporting diet effects on brain function, sorted by published date. Negative effects of diet are indicated by gray shading at the bottom.

Souvenaid (contains Fortasyn Connect; the nutrient combination choline, uridine monophosphate, omega-3 fatty acids, and various antioxidants and B vitamins). a

AA, arachidonic acid; AD, Alzheimer0 s disease; DEU, DHAþ EPA þ Uridine monophosphate (UMP); DHA, docosahexaenoic acid; DQ, developmental quotient; DTI, diffusion tensor imaging; EEG, electroencephalogram; EPA, eicosapentaenoic acid; FC, Fortasyn Connect (includes DHA, EPA, UMP, choline, phospholipids, vitamins and antioxidants); fMRI, functional magnetic resonance imaging; K-ABC, Kaufman assessment battery for children; MDI, mental development index; MMSE, Mini-Mental State Examination; MWM, Morris water maze; Ω3 LCPUFA, omega-2 long-chain polyunsaturated fatty acids; PDI, psychomotor developmental index.

↓ High SF (75%) diet

5 days M 16

Attention, speed and mood

↓ High saturated fat (74%) diet 7 days M 20

Human Sedentary adults [25– 45years] Human Healthy adults [19–28years]

Attention

↓ Spatial learning 21 B6Tg2576 [2months]

Morris et al. (2006) [110] Cao et al. (2007) [121] Edwards et al. (2011) [111] Holloway et al. (2011) [112]

Mice

Mþ F

High saturated and trans fat – intake High fat (16%) fat 25 weeks Human Healthy elderly [ Z 65 years] 3718 Mþ F

Cognitive decline

↑


7

time in the Go/No–Go and sustained attention tests suggested enhanced cognitive capabilities in these subjects [89]. Sufficient supply of ω-3 LCPUFAs by humans from the moment of fertilization towards mid-life is particularly related to proper brain development, whereas in older adults (50–70 yr) and elderly (470 yr), ω-3 LCPUFAs seem to be especially effective in reducing onset of neurological deterioration due to aging or pathologies like MCI and AD. Decreased speed-related cognition was observed in healthy aging 50–70 yr old adults (n ¼819) after three years of follow-up. However, this decline was less in subjects that exhibited higher ω-3 LCPUFAs plasma levels due to intake of folic acid for the duration of the experiment [101]. Yurko-Mauro et al. (2010) reported improved learning and memory in slightly older patients (average age¼70 yr; n ¼485) supplemented with DHA compared to those treated with a placebo [102]. Participants of the Zutphen Elderly Study (n ¼210, aged 70–89 yr) that consumed fish (0–20 g or 420 g fish/day) showed significantly less cognitive decline after a follow-up period of 5 yr, compared to non-consumers [90]. The results showed that intake of EPA þDHA was linearly related to cognitive decline. Based on these studies in healthy aging subjects, nutritional intervention seems promising in limiting functional impairment caused by increased neuronal loss and reduced connectivity in brain pathologies like MCI and AD. Mediterranean-type diets and diet supplementation are indeed found to slow down functional regression of the diseased brain. Higher adherence to a Mediterranean-type diet was associated with a reduced risk for AD across several epidemiological studies [103,104]. Interventions with Mediterranean-type diet components in humans and animals provided similar results. Mild AD patients (n ¼ 484) that received the multi-nutrient Souvenaids diet (containing DHA, EPA, UMP, choline, phospholipids, vitamins and antioxidants) for 12 and 24 weeks responded positively by exhibiting a slightly increased memory performance compared to the control group [63,105]. However, interpretation of these data is difficult as different tests were applied at baseline and the 12- and 24-weeks follow-up. Decreased cognitive decline was also observed for DHA þEPA treated very mild AD patients, but not in moderate to severe AD patients [106]. This may suggest that dietary intervention is most effective before the clinical presence of diseases like AD [107]. Like in humans, aged AβPPswe/PS1dE9 AD mice fed with DHA-enriched diets from the age of 2 months showed enhanced Morris Water Maze (MWM) performance at month 12 and 15, respectively, indicative of increased memory and spatial learning strategies [25,108]. Moreover, anxiety related behavior was significantly attenuated by the same multi nutrient diet in ApoE / mice [31]. An extensive systematic review and meta-analysis regarding the effects of DHA on cognition in AD animals models was recently performed elsewhere [109]. Despite the presence of clear evidence indicating the valuable effects of a Mediterranean-type diet or ω3-LCPUFA supplementation on cerebral functioning, available data is not straight forward as some studies fail to show effects [110–114]. It should be kept in mind that the wide variety of tests that are available, brings along measurements of different aspects of cognition or behavior. Interpretation and comparison of results across different studies need to take this into account. Differences in bioavailability of for example DHA in distinct brain regions may explain conflicting results found across studies that utilize tests that target different neural domains. In addition, possible other confounders like differences in study design (e.g. diet composition, route of administration, treatment duration and/or follow-up period), sociocultural factors (e.g. ethnicity and parents0 education) and stage of disease (e.g. mild vs. moderate to severe AD) may also contribute to these differences between studies [88,115]. Contrary to the Mediterranean diet, the Western-type diet is often associated with cognitive impairment, instead of enhancement [40]. Based on available literature concerning brain functioning, research


8


has focused primarily on the effects of saturated fats. Foodfrequency questionnaires among participants ranging from 45 yr and older showed that high dietary cholesterol intake was significantly associated with accelerated cognitive decline and an increased risk of impaired memory and flexibility [116,117]. In addition, the Women0 s Health Study revealed that high saturated fatty acids intake was associated with worse global cognitive and verbal memory in 6183 aging women ( 445 yr)[114]. A more experimental study, by means of short-term dietary intervention, showed that men (n ¼20, aged 25–45) on a high saturated fat (74%) diet for one week showed significant reduced attention [118]. Similar cognitive changes were also observed after 5 days of intervention with an equally composed diet (75% saturated fat) by Holloway et al. (2011): men aged around 22 yr exhibited impaired attention, speed and mood afterwards [119]. Surprisingly, one study revealed positive effects of a high-fat supplement on cognition in human participants aged 61–79 [120]. Though, this study was characterized by a relatively short intervention period (60 min), which suggests that increased saturated fat intake may become detrimental after a prolonged period of consumption. Pursuant to human data, female Fisher rats on a high-fat (39%) diet showed reduced spatial learning capabilities compared to their counterparts on a low-fat (13%) diet [121]. However, high serum cholesterol levels during midlife was already found to significantly increase the risk for developing MCI and AD in later life [10]. This phenomenon may possibly be caused by long-term high SF intake. Human and animal studies seem to confirm this hypothesis. Several human-based studies showed that high dietary SF intake was associated with an increased incidence of MCI and risk of dementia later in life [122–124]. Moreover, high SF ( 425%) intake vs. low SF (o 7%) intake for 4 weeks significantly increased and decreased Aβ42 in the cerebrospinal fluid (which is a marker of AD), respectively [125]. Increased AD pathologies such as increased Aβ deposition and impaired cognition were also reported in animal studies. Diet-induced hypercholesterolemia in transgenic AD mice led to significantly increased Aβ load, based on deposit number and size [126,127], and learning deficits in these models [128].

[131] which plays a vital role in learning and memory encoding [132]. Increased LTP by DHA was indeed found to enhance performance in the MWM task [133]. The role of ω3-LCPUFAs in brain development and plasticity is strengthened by the fact that cultured immature, adult and aged rat neurons exhibited increased neurite outgrowth after incubation with DHA, EPA and AA, allocating neurotrophic and neuroregenerative properties to these compounds [134,135]. This could be partly regulated trough increased brain derived neurotrophic factor (BDNF) expression upon treatment [136]. DHA-treatment significantly increased expression of BDNF in the hippocampus of rats, which could be the result of increased expression of neuroprotectin D1 [72], enhanced membrane functionality and induction of BNDF activating pathways, reduced oxidative stress [137] or increased energy supply to neurons by enhanced glucose transport across the brood-brain-barrier [138]. Additionally, several studies have characterized cognitive decline in aged-rats and MCI and AD brains by exerting reduced BNDF levels, emphasizing its importance in brain functioning [139,140]. For example, higher BNDF levels are linked to superior memory and executive functioning in humans [65]. In contrast to the valuable effects of a diet based on ω3-LCPUFAs, high fat diets seem to reduce BDNF levels in the hippocampus and prefrontal cortex [141,142], regions involved in cognitive functions like learning, (working) memory, attention and flexibility [143,144]. Moreover, high fat diets may contribute to decreased glucose uptake by the brain, leading to insufficient energy supply and decreased neuronal functionality. Impaired glucose regulation is an important factor in the cognitive decline associated with type-2 diabetes and normal aging. Glucose treatment of rats that were fed a high-fat diet for three months reversed memory impairment while no effect by glucose was observed in rats on a standard diet [145]. An important regulating and limiting factor of glucose uptake by the brain is the blood-brain-barrier (BBB) [146]. So, reduced BBB integrity (e.g. decreased expression of glucose transporter proteins), analogous to reduced CBF, may underlie the impaired glucose homeostasis observed in the rat brain after longterm high-fat diet consumption [147].

4.2. Fundamental mechanisms

5. Conclusion

Cerebral functioning is tightly regulated via plasticity, which is the ability of the brain to adapt to external changes. Synaptogenesis, synaptic functionality, neurite outgrowth and myelination are important mechanisms underlying brain plasticity. These processes, for example, occur at a rapid pace in the infant0 s neural network that is characterized by its hyperplastic growth throughout early life. As indicated above, intake of ω3-LCPUFAs seems to positively affect functioning and mental development of the brain throughout lifespan, while an inverse relationship seems appropriate for saturated fatty acids. Increased cognitive functionality, such as improved learning, memory and attention, by ω3-LCPUFAs may be mediated trough multiple ways. We hypothesized earlier that DHA and EPA incorporation into the neuronal membrane phospholipids may increase neurovascular coupling by increasing membrane fluidity and subsequent modulation of conduction and neurotransmission [46]. However, parallel to this suggestion, high intake or supplementation of DHA and/or EPA may also be beneficial in improving cognition by strengthening functional connectivity via increased synaptic transmission and plasticity. Several studies demonstrated that ω3-LCPUFAs supplementation significantly increased the levels of pre- (e.g. Synapsin I) and postsynaptic (e.g. post-synaptic density) proteins involved in synaptic transmission and long-term potentiation (LTP) [129,130]. Moreover, an 8-week modified feeding schedule implied that increased DHA consumption by rats reversed age-related impairments in LTP

The awareness of food necessity has evolved from the simple means of providing energy and building material to the body into a potential therapeutic mediator to prevent and protect the body against the onset and progression of diseases. An increasing amount of studies demonstrated the beneficial and detrimental effects of distinct dietary components on the healthy and diseased brain. Within this framework, this review highlights important data regarding the effects of ω3-LCPUFAs and saturated fatty acids on brain circulation, structure and function. The importance of these compounds on brain health emerged already during the evolution of the brain in its early stage: different diet patterns by early humans (shore-diet) induced variation in brain development and functionality. Current data extend these paleontological findings: increased intake of, or supplementation with, ω3-LCPUFAs like DHA and EPA was associated with proper brain development in infants, increased cognitive performance in adults and decreased onset of cognitive decline in elderly by neurodegenerative diseases like MCI and AD (Table 3). Animal and in vitro studies have shown that DHA and EPA enhanced neuronal plasticity and LTP, possibly due to increased levels of BDNF, and which may underlie these constructive responses upon increased ω3-LCPUFAs intake. Moreover, enhanced cerebral circulation parameters like CBF and CBV, and structural (e.g. white and gray matter) integrity may contribute to this ameliorated cognition and brain health in general. In



9

References

Fig. 1. Brain health is determined by proper circulation, structure and function. Dietary components like omega 3-long chain polyunsaturated fatty acids (green arrows) and saturated fatty acids (red arrows) seems to affect several important parameters such as cerebral blood flow, and structural and functional connectivity. Dietary manipulation may provide a helpful tool for optimal development in early life and decreased brain deterioration in elderly.

contrast, high saturated fat intake exerts opposing effects and is often associated with decreased cognition, structure and circulation (Fig. 1, Tables 1 and 2). Although the differences seem strikingly across these studies, not all studies were able to show beneficial or detrimental effects by dietary intake, which could partly be explained by existing confounders related to study population and study design. Especially for cognitive testing, it should be taken into account that the wide availability of tests coincide with testing a wide range of neural domains. Therefore, comparison between studies seems difficult as DHA is not equally distributed among brain regions. A better understanding of ω3LCPUFAs metabolism in humans throughout life will lead to a better understanding of whether dietary intervention is more likely to be effective in the situation of long term prevention rather than as a therapeutic. This may explain the lack of evidence that translates the promising results from prospective studies towards more efficient diet-intervention in patients that already show profound brain impairment. Taken together, an increasing amount of studies endorse the promoting and preventive utility of diet on development and healthy and accelerated aging of the brain, respectively. Early treatment of high-risk patients, i.e. before the onset of irreversible neurological damage and clinical symptoms, will ultimately lead to reduced incidence of for example AD. Future (pre-) clinical research should continue to focus on possible correlations between changes in circulation, structure and function due to differences in diet pattern. This will provide a better general insight into the respectively healthy and detrimental effects of dietary components like ω3-LCPUFAs and saturated fatty acids. In addition, such research would strengthen the importance of reducing saturated fat intake and subsequent development of metabolic disorders, like obesity and diabetes.

Acknowledgments The research leading to these results has received funding from the European Community0 s Seventh Framework Programme (FP7/ 2007-2013) under Grant agreement no. 211696.

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