Open access peer-reviewed chapter

The Role of Over-Nutrition and Obesity in Multiple Sclerosis

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Ema Kantorová, Egon Kurča, Daniel Čierny, Dušan Dobrota and Štefan Sivák

Submitted: 26 January 2016 Reviewed: 28 April 2016 Published: 08 September 2016

DOI: 10.5772/63992

From the Edited Volume

Trending Topics in Multiple Sclerosis

Edited by Alina Gonzalez-Quevedo

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Abstract

In countries with high standard of living, lowered risk of infectious diseases is parallel to increased incidence of autoimmune diseases. One of the autoimmune disorders, multiple sclerosis, affects genetically susceptible individuals. Genetic susceptibility is supposed to interact with lifestyle and environmental factors in developing autoimmunity in MS. From this point of view, epigenetics provides the bridge between the external environment and the internal genetic system. In MS, environmental burden can modulate gene expression by epigenetic modification of chromatin components, microRNAs or by subtle changes in DNA methylation. Our paper focuses on describing the epigenetic mechanisms linking environmental factors with pathogenesis of multiple sclerosis. We summarise current knowledge about the role of over-nutrition and obesity as epigenetic factors in multiple sclerosis.

Keywords

  • multiple sclerosis
  • epigenetics
  • early life environmental factors
  • obesity
  • microRNA
  • DNA methylation
  • histone acetylation

1. Introduction

The genomewide association study (GWAS) conducted by International Multiple Sclerosis Genetics Consortium has identified genes conferring susceptibility to multiple sclerosis (MS) [1]. Many of these genes play a role in the immune system with a prominent role for major histocompatibility complex (MHC) class II molecules in particularly defined HLA-DRB1 alleles. GWAS found complete concordance between the rs 3135388A SNP and the HLA-DRB1*1501 genotype [1].

In most cohorts, especially in Caucasian population, genetic burden for MS has been found to be associated with gene clusters in chromosome 6p21.3 [2]. Evident genetic heterogeneity of MS makes identification of single candidate gene impossible. This highlights the role of molecular markers rather than MS-susceptibility genes in indicating the disease status [3]. As the genetic background determines only about 26–30% of the risk of developing MS [4, 5], other factors have been considered to determine heterogeneity of clinical course and MS symptoms [6].

Epigenetics is defined as heritable changes in gene expression that are not due to any alteration in the primary DNA sequence. The changes are responsible for organisation and reading of genetic information [7]. The term epigenetics has evolved to define mechanisms underlying phenotype plasticity due to environmental influences, parent-of-origin effects, gene-dosage control, imprinting, and X-chromosome inactivation. At the molecular level, epigenetics includes modification of DNA base pairs, post-translational modification of histones, and the effects of non-coding RNAs [8]. Moreover, it was found that epigenetic alterations accumulate in time; consequently they can exert their effect on expressed genes longitudinally [9].

Our paper focuses on describing the epigenetic mechanisms linking environmental factors with pathogenesis of multiple sclerosis. We summarise current knowledge about roles of over-nutrition and obesity as epigenetic factors in multiple sclerosis.

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1.1. Molecular epigenetic mechanisms

In human DNA, cytosines in the CpG dinucleotide are commonly methylated, and methylation is well-balanced. DNA methylation is involved in normal development and sustaining of cellular homeostasis and functions in adult organisms (particularly for X-chromosome inactivation in females, genomic imprinting, silencing of repetitive DNA elements, regulation of chromatin structure, and control of gene expression). CpG sites are concentrated in short regions of the genome [7, 10, 13]. Another common mechanism that regulates chromatin structure inside a cell involves histone modification. In general, histone acetylation and phosphorylation act as activators of gene expression, whereas histone deacetylation, biotinylation and sumoylation inhibit gene expression [10, 12]. Other described mechanisms of epigenetic regulation of gene function are mediated by miRNAs. They are small non-coding RNAs, 16–29 nucleotides-long, that function primarily as negative gene regulators at the post-transcriptional level. Recently, novel microRNAs (miR) have been identified to be human-specific as well as tissue-specific [7, 11].

Different authors have suggested that epigenetic mechanisms could be directly controlled by metabolic and dietary constituents, metabolic state, or endocrine unbalances [10, 40].

1.2. Early life period and potential epigenetic risks

Recently, studies on humans have indicated that adaptive changes made by foetus in response to intrauterine environment result in permanent changes in early life programming [1416].

Currently, there are no prospective systematic studies conducted in humans that would evaluate the association of selective environmental factors and risk of MS in humans. However, many environmental factors have been described to be potential epigenetic regulators of MS development [16, 17, 18]. Some of the metabolic and toxic epigenetic factors are listed and included in Table 1.

  1. - lower levels of maternal vitamin D and lower exposure to UV light in childhood

  2. - nutritional factors + obesity

  3. - exposure to glucocorticoids, metabolic trigger

  4. - smoking

  5. - epigenetics of endocannabinoid system

  6. - maternal psychosocial stress

Potential epigenetic factor Mechanism of action Clinical and immunological consequences References number
Lower maternal vitamin
D Decreased vitamin
D in MS patients
blocking of NF for
activated T-cells,
sequestration of
Runt-related TF-1
FokI gene polymorphism
(rs10735810)
Vitamin-D-mediated
trans-repression of
the CYP27B1 p450 27B1
gene methylation of CpG
sites IL-17 gene expression by
blocking of NF,
necessary for activating
Th-1 cells TF and by
HDAC Vitamin-D mediated
suppression of IL-12
via HDAC
1,25(OH)2D3 inhibits
the production of
IFNγ, IL2
and IL12, expansion
of dependent Th-1
cells, modification
of dendritic cells
58% reduced risk of
MS for each 400
IU/day evolution
of MS, sex-differences
[1925]
Lower UV exposure Similar to vitamin D
deficiency
Increase of TNFα
and IL-10-impaired
antigen-presenting cell
function, and antigen
-specific Th-cell tolerance,
decreased Th-regulatory
cells region of
birth and low
maternal exposure
to UV radiation
in the first trimester
are independently
associated with subsequent
risk of MS
in offspring
[26, 27]
Higher maternal
pre-pregnancy BMI
Oxidative stress, lower
vitamin D exposure,
over-expression of
miR-145,146,155,
cluster 17-92 on immune
cells Over-expression of
Notch1 signalling pathways
on oligodendrocytes,
impaired neural stem
differentiation
No significant relation
of weight gain during
pregnancy and MS risk
when increased
pre-pregnancy BMI
(OR: 0.39; 0.18–0.85)
[18, 2831]
Glucocorticoids hyperglycaemia/
diabetes
Reduction of GLUT, dysfunction
of cell membrane, impaired DNA
methylation of central myelin and genes
important in regulating
cortisol levels
Blockage of the HPA
axis increased
risk to MS in
offspring
[3234]
Parental smoking,
passive inhalation
Methyl group
deficiency, loss
of histone H3K9
and H4K20 methylation
24–50% increased
risk of MS in women
exposed to parental
or passive smoking
[18, 30, 31, 35]
Cannabis consumption Endocannabionoids influence
gametogenesis, DNA
modulation of
reproductive cells,
dysregulation of
glutamatergic gene
expression, findings that
would be predictive
of impaired synaptic
plasticity
Trans-generational effect
to next generation, potential
modulatory effect to
mesolimbic reward-related
subregion of
the striatum, risk
of MS and neurodegenerative
disorders
[34, 36]
Lower choline in diet Impaired DNA methylation
of PAD2 promotor, encoding
oligodendrocyte activity,
developmental
type of myelin
Increased inflammatory
cytokines: IL-6 and TNFα
Increased risk of MS
[37, 38]
Psychosocial stress in
pregnancy,
inappropriate
maternal immune activation
due to stress, maternal
separation and obesity
Increased DNA
methylation of endocannabionoid
receptor-1
Increased IL-6,
IL-1, IL-10, increased
CD4 and B lymphocytes, decreased
Th-regulatory cells,
increased permeability of
BBB, altered the
HPA axis in infants,
risk of immune deregulations
[32, 38, 39]

Table 1.

The list of potential epigenetic risk factors.

Abbreviations: NF = nuclear factor, TF = transcriptional factor, 1.25(OH)2D3 = 1.25-dihydroxycholecalciferol, FokI = polymorphism of vitamin D receptor, IFNγ = interferon gamma, TNFα = tumour necrosis factor alfa, IL-1,-2,-6,-10,-12,-17 = interleukine 1,-2,-6,-10,-12,-17, Th-1 = autoaggresive T lymphocytes, CYP27B1 p450 27B1 = cytochrome P450 family 27 subfamily B polypeptide 1, CpG = cytosine guanine islands - regions of DNA, HDAC = histone deacetylase, UV = ultraviolet, MS = multiple sclerosis, BMI = body mass index, HPA = hypothalamo-pituitary-adrenal, miR = microRNA, GLUT = glucocorticoid transporters, PAD2 = peptidylarginine deiminase 2, CD4 = Th lymphocytes - helpers, BBB = blood-brain barrier.


1.3. Obesity, nutritional factors and multiple sclerosis

Over the last decade, obesity appears to be a new component of the complex mosaic of autoimmunity [41], suggesting that starvation leads to immunosuppression [42] and that over-nutrition or obesity promotes autoimmunity [8, 41, 43].

Maternal obesity in pre-pregnancy period [measured by body mass index (BMI)], correlated with higher risk of developing MS in children [18], suggests that obesity is a prenatal risk factor. Maternal obesogenic environment is considered to be an epigenetic modulator [40, 43, 44].

Trans-generational epigenetic effects have been supported by nutritional studies that identified a link between food supply during childhood and MS mortality in grandchildren [45, 46]. Although not clearly defined in MS, intergenerational epigenetic effects could explain why the HLA DRB 1*15 frequency is significantly lower in the first-generation affected females, whereas it remains unchanged across the two generations in affected males [46].

Although in one of the retrospective studies, maternal obesity in pre-pregnancy period was associated with risk of MS in children [18], other studies analysed the association of body configuration in adolescence with risk of MS. They found a correlation between higher BMI in adolescence and subsequent development of MS [28, 29, 47], whereas the interaction of obesity and carriage of HLA DRB 1*15 genotype was identified [48]. Munger et al. [28] found that a higher BMI at ages 7–13 years was associated with a significant 1.61–1.95-fold increased risk of MS only among girls. Similarly, another study [49] identified a higher risk of paediatric MS and clinically isolated syndrome (encompassing optic neuritis and transverse myelitis) in extremely obese adolescent girls (BMI ≥ 35 kg/m2) with an OR = 2.57. In age-adjusted analyses, women with a BMI ≥ 30 kg/m2 at an age of 18 had a greater than twofold risk of developing MS as compared to women with a BMI between 18.5 and 20.9 kg/m2. A higher percentage of women who were obese (BMI ≥ 30 kg/m2) at an age of 18 were smokers at baseline as compared to women with lower BMI [29]. However, body weight at age ≥ 30 was not associated with risk of MS [28], indicating that postnatal life period and adolescence are most important for future development of MS. Other authors did not prove the relationship between obesity and MS in adult patients with ongoing MS symptoms [50, 51]. Moreover, Emamgholipour and colleagues presented a study demonstrating a decreased adipose tissue mass in patients with definite MS compared with healthy individuals (18% MS versus 22.6% in controls) [52]. The negative correlation of MS severity and adipose tissue mass was supposed to result from increased lipolysis and loss of metabolic plasticity.

During over-nutrition, immune cells are increasingly activated and accumulated in adipose tissue, but pro-inflammatory cytokines and chemokines, released from immune cells can also affect other organs [53]. Obesity is associated with accumulation of macrophages, changed from anti-inflammatory M2 to pro-inflammatory M1 phenotype [53]. Obesity selectively promotes an expansion of the Th17 T-cell sub-lineage, producing progressively more IL-17 than lean subjects. IL-6-dependent Th17 expansion is a clinically prominent element in obesity [53]. The results of a small clinical study concurred with the previous investigations. These authors demonstrated stimulation of pro-inflammatory pathways through elevated IL-17 in serum of obese women [54].

Moreover, inflammatory peptides, originated from enlarged adipocytes, have a tendency to change the activity of the HPA axis via hypothalamic receptors [34, 71] and consequently modulate immune responses [58]. Obesity induced by high-fat diet increases blood-brain barrier (BBB) permeability [56] and leads to accumulation of lipids in brain tissue [60, 61], stimulating innate immunity responses. Over-nutrition was correlated with increased number of activated brain microglial cells and oligodendrocytes [61].

MS is one of the autoimmune disorders of the central nervous system (CNS) with not fully known aetiology [6]. Immunological assessments of MS patients have supported the concept of MS as the disorder driven by myelin-specific Th1 helper cells [6], and/or Th17 cells [52]. They were found to migrate into CNS, where they cause demyelination and axonal loss and subsequent neurological disability in MS [6]. Currently, it is known that both innate and adaptive immune processes contribute to MS pathogenesis [42]. Additionally, there is evidence indicating that MS has a neurodegenerative component since neuronal and axonal loss occurs even in the absence of overt inflammation [56]. However, interactions between infiltrating immune cells and resident cells of the CNS require co-stimulatory and additive factors that determine both disease evolution and clinical outcome of MS patients [57]. However, neuroinflammation cross-talk can have either beneficial or destructive consequences [57], depending on the environmental influences interacting with genetic risks. In MS, environmental exposures might occur long before the disease becomes clinically evident. In addition, the onset of the disease is unknown. Changes in gene expression driven by epigenetic mechanisms play an important role in the predisposition to future disease development [17, 61].

1.4. Epigenetic links between over-nutrition or obesity and multiple sclerosis

1.4.1. Micro RNA

Until today many studies have demonstrated that miR have multiple functions in negative gene 4 regulation and play important roles in neurological disorders, and it seems possible that 5 several epigenetic mechanisms have multiple targets [62].

Interestingly, while obesity increases the expression of the miR-143–145 cluster in adipose tissue/adipocytes via increasing over-expression of tumour necrosis factor alpha (TNFα) secretion and lipolysis [62], recent research has shown miR-145 to be expressed dramatically in peripheral blood mononuclear cells (PBMCs) from patients with MS [63]. Other miR-142-3p, miR-146a, miR-155 and miR-326 were also aberrantly expressed in the PBMCs of MS patients [64].

Obesity-induced over-expression of miR-155, miR-107, and miR-146-5p led to release of pro-inflammatory cytokines, adaptive and innate immune activation [65, 66], while miR-155 and miR-326 were up-regulated in both PBMCs and brain white matter lesions [67].

It has also been found that miR-146a increases IL-17 expression and miR-155 promotes Th1 and Th17 cells [65], determining severity of the disease course [64]. Th17 cell–associated miR-326 expression was highly correlated with disease severity in patients with MS. In vivo silencing of miR-326 resulted in fewer Th17 cells [65]. Moreover, a recent research has revealed that miR-155 over-expression could be implemented into acute BBB dysfunction, as miR-155 was increased at the neurovascular unit in MS lesions when compared to levels in MS normal-appearing white matter [68]. Pro-inflammatory cytokines, such as interferon gamma (IFNγ) and TNFα were able to up-regulate miR-155 in human cells. The findings indicate contribution of miR-155 to cytokine-induced disruption of the brain endothelium via cell-to-cell and cell-to-matrix interactions, leading to an increased permeability of BBB which is typical for MS [68]. Similarly, another study confirmed increased expression of miR-155 on astrocytes in acute MS demyelinated lesions [69], while miR-155-deficient macrophages had a decreased inflammatory potential, and miR-155 inhibited adipogenesis in adipocytes [62].

Pro-inflammatory cytokines, namely IFNγ, secreted from auto-reactive Th-1 lymphocytes in not only MS patients [67] but also in obese individuals [53, 71] could be responsible for up-regulation of miR-155 and dysfunction of BBB.

Another possible cross-link between obesity and MS might be the expression of the miR-17-92 cluster, which was found down-regulated in B lymphocytes of MS patients [72] and also in blood and adipocytes in obese individuals [62]. The immunogenetic study by Steiner and colleagues proposed that miR-17-92 family members potentiate T helper cell proliferation, whereas miR-29 family members specifically inhibited IFNγ [73].

Further studies are needed to investigate whether obesity-induced over-expression of specific miR and release of pro-inflammatory cytokines in periphery could trigger autoimmune reaction against brain structures in sensitive life periods. We hypothesise that maternal over-nutrition or high-fat diet in childhood might stimulate over-expression of miR-145, -146, -155 in several sites including adipocytes and peripheral blood cells. This allows inflammatory cells to release cytokines and cross the BBB and attack myelin in brain white matter.

Reported down-regulation of the cluster miR-17-92 in Th cells both in obese subjects and MS patients [62, 72] supports the theory of common immune pathways, and indirectly supports the role of over-nutrition in autoimmunity and development of MS.

1.4.2. DNA methylation

One of the epigenetic mechanisms, methylation of myelin basic protein (MBP), is important for maintaining protein stability. In MS patients, methylation of MBP was reported to be higher than in healthy controls [74, 75], and some isoforms of MBP (such as the early developmental ones) are implicated in de- and re-myelination attempts during MS [74]. Since the myelin sheath has been described to be developmentally immature due to impaired myelin synthesis via oligodendrocyte failure [76], a post-translational pathogenetic mechanism has been proposed. A recent research confirmed the previous hypothesis, whereas re-expression of the developmental pathway was found to restrict oligodendrocyte maturation [77]. The authors showed that over-expression of Notch1 within and around active MS plaques lacking re-myelination was associated with immature oligodendrocyte phenotype and up-regulation of transforming growth factor beta1 in perivascular extracelullar matrix [77]. It is of interest that animal studies proved maternal high-fat diet to be a potent epigenetic regulator of the Notch signalling pathway that impairs hippocampal development in the offspring. Notch signalling was involved in molecular mechanisms of neurogenesis, whereas over-expression of Notch1 in neural stem cells caused inhibition of the proliferation of neural progenitors [78]. Although in humans the relationship between high-fat diet and inhibition of neural progenitors has not been confirmed yet, we hypothesised that nutritional factors could exert the effect via the same mechanism.

Myelin structure can be altered when an alternative pathway for the reversal of arginine methylation involves the conversion of an arginine in either histone H3 or H4 to a citrulline. This is termed deimination because the methyl group is removed along with the imine group of arginine and is accelerated by peptidylarginine deiminase 4 (PAD4). Converting citrulline back to arginine has not yet been described [7, 10]. It was found that deimination of MBP-bound arginyl residues makes them more susceptible to myelin-associated proteases [75]. The accompanying loss of positive charge compromises the ability of MBP to interact with the lipid bilayer. The conversion of arginine to citrulline in brain is carried out by an enzyme peptidylarginine deiminase 2 (PAD2). The amount of PAD2 in brain was increased in MS normal-appearing white matter. The mechanism responsible for this increase involved hypomethylation of the promoter region in the PAD2 gene in MS [79]. The triggering factor is not fully known. However, the methylation process requires Vitamin B12, which transfers its methyl group to homocysteine via synthesis of methionine, which is then converted to S-adenosylmethionine, the methyl donor in all biological methylation reactions [79]. Cholin, methionine and 5-methyl tetrahydrofolate are major sources of methyl groups in humans [10, 38]. Moreover, they have an importance in suppression of inflammatory processes. Individuals whose diet was rich in choline and betaine had the lowest levels of several inflammatory markers, including C-reactive protein, homocysteine, IL-6 and TNFα [37]. Among the most concentrated sources of dietary choline are fish and fish-caviar, liver, eggs and wheat germ [37]. On the other hand, vulnerability of myelin sheath is caused by disturbed lipid metabolism, while the uptake of external lipids may also play a role in the formation and disturbances of myelin membranes. The pathogenic mechanisms are known from research of neurodegenerative brain disorders [81, 82].

1.4.3. Histone acetylation

Histone acetylation is another epigenetic mechanism involved in the pathogenesis of MS. Histone deacetylases (HDACs) are responsible for the removal of the acetyl group from histones, with resulting ability to influence expression of genes encoded by DNA linked to the histone molecule. HDACs are also able to modify a large variety of non-histone proteins whose activity depends on their acetylation status, such as transcription factors, chaperone proteins, signal transduction mediators, structural proteins, and inflammation mediators [83].

Sirtuin-1 (SIRT1), a member of the HDAC class III family of proteins, can induce chromatin silencing through the deacetylation of histones and can modulate cell survival by regulating the transcriptional activities [84]. It was recently reported that SIRT1 was expressed by a significant number of cells in both acute and chronic active lesions in brains of MS patients. Authors found SIRT1 to co-locate with CD4, CD68, oligodendrocytes and glial fibrillar acidic protein (GFAP) cells in MS plaques, when statistically significant decrease in SIRT1 expression correlated with that of histone H3 lysine 9 acetylation (H3K9ac) and methylation (H3K9me2) [84].

HDAC9 has a key role in the development and differentiation of many types of cells, including regulatory Th cells. Dysfunction of Th cells in MS suggests that HDAC9 may act as an epigenetic switch in effector Th cell-mediated systemic autoimmunity [85]. Genetic variability in HDAC9, along with variants in HDAC11, SIRT4 and SIRT5, has also been shown to influence brain volume in MS patients, as assessed using neuroimaging methods [86].

A growing number of the dietary HDAC reported in the literature are generated as metabolites during the course of digestion [83]. Dietary constituents are formed by the metabolism of some vegetables and fruits, olive oil and nuts. Broccoli, cabbage, Brussel sprouts, cauliflower, kale, Savoy cabbage, citruses, grapes, berries and apples contain many HDAC regulators [83]. For example, resveratrol, naturally occurring compound found in grapes, wine and eucalyptus, is a potent activator of sirtuins (class III HDACs) and in particular, SIRT1 [83]. Thus, regular consumption of foods rich in this compound can have protective effect.

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2. Conclusion

Until now, a lot of potential epigenetic mechanisms in MS have not been discovered, and also the hypotheses linking nutritional factors and obesity or nutritional compounds have not been proved by prospective epidemiological studies. The relationship among diet, obesity and genetic risk of MS has been studied only occasionally. The included studies were usually focused on a role of vitamin D. Further studies based on both genetic-epigenetic factors and environmental triggers could bring new information about how to determine the MS risk factors more precisely and much earlier in life. Although at present, there is no particular preventive strategy in MS, new findings could help us to work out dietary interventions and other alternative non-conventional therapies.

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Acknowledgments

This work was supported by Project APVV 14-0088.2014.

References

  1. 1. Risk Alleles for Multiple sclerosis identified by a genomewide study. The International Multiple Sclerosis Genetics Consortium. N Engl J Med 2007; 357: 851-862.
  2. 2. Olerup O, Hillert J. HLA class II-associated genetic susceptibility in multiple sclerosis: a critical evaluation. Tissue Antigens 1991; 38(1): 1-15.
  3. 3. Bomprezzi R, Ringnér M, Kim S, et al. Gene expression profile in multiple sclerosis patients and healthy controls: identifying pathways relevant to disease. Hum Mol Gen 2003; 12(17): 2191-2199.
  4. 4. Ebers GC, Bulman DE, Sadovnick AD, et al. A population-based study of multiple sclerosis in twins. N Engl J Med 1986; 315(26): 1638-1642.
  5. 5. Ebers GC, Sadovnick AD, Dyment DA, et al. Parent-of-origin effect in multiple sclerosis: observations in half-siblings. Lancet 2004; 363: 1773-1774.
  6. 6. Weiner HC. Multiple sclerosis is an inflammatory T-cell- mediated autoimmune disease. Arch Neurol 2004; 61(10): 1613-1615.
  7. 7. Chango A, Pogribny IP. Considering maternal dietary modulators for epigenetic regulation and programming of the fetal epigenome. Nutrients 2015; 7: 2748-2770.
  8. 8. Hyunh JL, Casaccia P. Epigenetic mechanisms in multiple sclerosis: implications for pathogenesis and treatment. Lancet Neurol 2013;12(2): 195-206.
  9. 9. van den Elsen PJ, van Eggermond MC, Puentes F, van der Valk P, Baker D, Amor S. The epigenetics of multiple sclerosis and other related disorders. Mult Scler Relat Disord. 2014 Mar;3(2): 163-75. doi: 10.1016/j.msard. 2013.08.007.
  10. 10. Millagro FI, Campión J, Martinez JA. Dietary and metabolic compounds affecting chromatin dynamics/remodelling. In: Handbook of Epigenetics: The New Molecular and Medical Genetics. Trygve Tollefsbol 1st ed. Elsevier Inc; 2011. p. 302-307.
  11. 11. Londin E, Loher P, Telonis AG, et al. Analysis of 13 cell types reveals evidence for the expression of numerous novel primate- and tissue-specific microRNAs. Proc Natl Acad Sci U S A 2015; 112: E1106-E1115.
  12. 12. Kouzarides T. Chromatin modifications and their function. Cell 2007; 128: 693-705.
  13. 13. Butler JS, Koutelou E, Schibler AC, Dent SY. Histone-modifying enzymes: regulators of developmental decisions and drivers of human disease. Epigenomics 2012; 4: 163-177.
  14. 14. Tarantal A, Berglund L. Obesity and lifespan health-importance of the fetal environment. Nutrients 2014; 6(4): 1725-1736.
  15. 15. Martínez JA, Cordero P, Campión J, Milagro FI. Interplay of early-life nutritional programming on obesity, inflammation, and epigenetic outcomes. Proc Nutr Soc 2012; 6: 1-8.
  16. 16. Laker RC, Wlodek ME, Connelly JJ, Yan ZE. Epigenetic origins of metabolic disease: the impact of the maternal condition to the offspring epigenome and later health consequences. Food Sci Hum Wellness 2013; 2: 1-11.
  17. 17. Gardener H, Munger KL, Chitnis T, et al. Prenatal and perinatal factors and risk of multiple sclerosis. Epidemiology 2009; 20(4): 611-618.
  18. 18. Munger KL, Chitnis T, Ascherio A. Body size and risk of MS in two cohorts of US women. Neurology 2009; 73(19): 1543-1550.
  19. 19. Munger KL, Bentzen J, Laursen B, et al. Childhood body mass index and multiple sclerosis risk: a long-term cohort study. Mult Scler J 2013; 19(10):1323-1329.
  20. 20. Ascherio A, Munger KL. Environmental risk factors for multiple sclerosis Part II: noninfectious factors. Ann Neurol 2007; 61(6):504-513.
  21. 21. Ascherio A, Munger KL, Lunemann JD. The initiation and prevention of multiple sclerosis. Nat Rev Neurol 2012; 8: 602-612.
  22. 22. Reynolds RM. Glucocorticoid excess and the developmental origins of disease: two decades of testing the hypothesis-2012 Curt Richter Award Winner. Psychoneuroendocrinology 2013; 38(1): 1-11.
  23. 23. Mirzaei F, Michels KB, Munger K, et al. Gestational vitamin D and the risk of multiple sclerosis in the offspring. Ann Neurol 2011; 70(1): 30-40.
  24. 24. Staples J, Ponsonby AL, Lim L. Low maternal exposure to ultraviolet radiation in pregnancy, month of birth, and risk of multiple sclerosis in offspring: longitudinal analysis. BMJ 2010; 340: 1640.
  25. 25. Coussons-Read ME, Okumn ML, Nettles CD. Psychosocial stress increases inflammatory markers and alters cytokine production across pregnancy. Brain Behav Immun 2007; 21(3): 343-350.
  26. 26. Marquez AH, O’Connor TG, Roth Ch, et al. The influence of maternal prenatal and early childhood nutrition and maternal prenatal stress on offspring immune system development and neurodevelopmental disorders. Front Neurosci 2013; 7: 120.
  27. 27. Ponsonby AL, McMichael A, van der Mei I. Ultraviolet radiation and autoimmune disease: insights from epidemiological research. Toxicology 2002; 181-182: 71-78.
  28. 28. Karatsoreos IN, Thaler JP, Borgland S, et al. Food for thought: hormonal, experiential, and neural influences on feeding and obesity. J Neurosci 2013; 33(45): 17610-17616.
  29. 29. Zeisel SH, da Costa K-A. Choline: an essential nutrient for public health. Nutr Rev 2009; 11: 615-623.
  30. 30. Nijland PG, Moolenar RJ, van der Pol SMA, et al. Differential expression of glucose-metabolizing enzymes in multiple sclerosis lesions. Acta Neuropathol Commun 2015; 3:79.
  31. 31. Hewagama A, Richardson B. The genetics and epigenetics of autoimmune diseases. J Autoimmun 2009; 33: 3-11.
  32. 32. Ramagopalan SV, Maugeri NJ, Handunnetthi L, et al. Expression of the multiple sclerosis-associated MHC class II allele HLA-DRB1*1501 is regulated by vitamin D. PLoS Genet 2009; 5(2): e1000369. doi:10.1371/journal.pgen.1000369
  33. 33. Čierny D, Michalik J, Kurča E, et al. FokI vitamin D receptor gene polymorphism in association with multiple sclerosis risk and disability progression in Slovaks. Neurol Res 2015; 37(4): 301-308.
  34. 34. Kim MS, Kondo T, Takada I, et al. DNA demethylation in hormone-induced transcriptional derepression. Nature 2009; 461(7266): 1007-1012.
  35. 35. Saccone D, Asani F, Bronman L. Regulation of the vitamin D receptor gene by environment, genetics and epigenetics. Gene 2015; 561(2): 271-280.
  36. 36. Niculescu MD, Zeisel SH. Diet, methyl donors and DNA methylation: interactions between dietary folate, methionine and choline. J Nutr 2002; 132: 2333S-2335S.
  37. 37. Versini M, Jeandel P-Y, Rosenthal E, Shoenfeld Y. Obesity in autoimmune diseases: not a passive bystander. Autoimmun Rev 2014; 13(9): 981-1000. Doi: http://dx.doi.org/10.1016/j.autrev.2014.07.001
  38. 38. Bhat R, Steinman L. Innate and adaptive autoimmunity directed to the central nervous system. Neuron 2009; 64(1): 123-132.
  39. 39. Riccio P. The molecular basis of nutritional intervention in multiple sclerosis: a narrative review. Complement Ther Med 2011; 19: 228-237.
  40. 40. Sookoian S, Gianotii TF, Burgueňo AL. Fetal metabolic programming and epigenetic modifications: a systemic biology approach. Pediatr Res 2013; 73: 531-542.
  41. 41. Pembrey ME, Bygren LO, Kaati G, et al. Sex-specific, male-line transgenerational responses in humans. Eur J Hum Genet 2006; 14(2): 159-166.
  42. 42. Chao MJ, Ramagopolan SV, Herrera BM, et al. Epigenetics in multiple sclerosis susceptibility: difference in transgenerational risk localizes to the major histocompatibility complex. Hum Mol Gen 2009; 18 (2): 261-266.
  43. 43. Hedström AK, Baarnhielm M, Olsson T, Alfredsson L. Exposure to environmental tobacco smoke is associated with increased risk for multiple sclerosis. Mult Scler 2011; 17:788-793.
  44. 44. Hedström AK, Olsson T, Alfredsson L. High body mass index before age 20 is associated with increased risk for multiple sclerosis in both men and women. Mult Scler 2012; 18(9): 1334-1336.
  45. 45. Hedström AK, Bomfim IL, Barcellos L, et al. Interaction between adolescent obesity and HLA risk genes in the etiology of multiple sclerosis. Neurology 2014; 82(10): 865-872.
  46. 46. Langer-Gould A, Beaber BE.Childhood obesity and risk of pediatric multiple sclerosis and clinically isolated syndrome. Neurology 2013; 80(6): 548-552.
  47. 47. Sioka C, Fotopoulos A, Georgiou A, et al. Body composition in ambulatory patients with multiple sclerosis. J Clin Densitom 2011; 14: 465-470.
  48. 48. Lambert CP, Lee Archer R, Evans WJ. Body composition in ambulatory women with multiple sclerosis. Arch Phys Med Rehabil 2002; 83:1559-1561.
  49. 49. Emamgholipour S, Eshaghi SM, Hossein-Nezhad A, et al. Adipocytokine profile, cytokine levels and Foxp3 expression in multiple sclerosis: a possible link to susceptibility and clinical course of disease. PLoS ONE 2013; 8(10): e76555.
  50. 50. Lumeng CN, Saltiel AR. Inflammatory links between obesity and metabolic disease. J Clin Invest 2011; 121(6): 2111-2117.
  51. 51. Sumarac-Dumanovic M, Stevanovic D, Ljubic A, Jorga J, Simic M, Stamenkovic-Pejkovic D, Starcevic V, Trajkovic V, Micic D. Increased activity of interleukin-23/interleukin-17 proinflammatory axis in obese women. Int J Obes (Lond). 2009 Jan;33(1):151-6. doi: 10.1038/ijo.2008.216.
  52. 52. Brucklackner-Waldert V, Sturner K, Kolster M, et al. Phenotypical and functional characterization of T helper 17 cells in multiple sclerosis. Brain 2009; 132: 3329-3341.
  53. 53. Lassmann H. Multiple sclerosis: is there neurodegeneration independent from inflammation? J Neurol Sci 2007; 259: 3-6.
  54. 54. Kerchensteiner M, Hohlfeld R. Multiple sclerosis: neuro-immune cross-talk in acute and progressive stages of the disease. In: Kilpatrick T, Ransohoff RM, Wesselingh S. (eds.) Inflammatory Disease of the Central Nervous System. Cambridge University Press; 2010.
  55. 55. Michelson D, Stone L, Galliven N, et al. Multiple sclerosis is associated with alterations of hypothalamo-pituitary-adrenal axis functions. J Clin Endocrinol Metab 1994; 79(3): 848-853.
  56. 56. Minagar A, Alexander SJ. Blood-brain barrier disruption in multiple sclerosis. Mult Scler J 2003; 9 (6): 540-549.
  57. 57. Haltia LT, Viljanen A, Parkkola R, et al. Brain white matter expansion in human obesity and the recovering effect of dieting, J Clin Endocrinol Metab 2007; 92(8): 3278-3284.
  58. 58. Thaler JP, Yi Chun-Xia, Schur EA, et al. Obesity is associated with hypothalamic injury in rodents and humans. J Clin Invest 2012; 122(1): 153-162.
  59. 59. Deiulius JA. MicroRNAs as regulators of metabolic disease: pathophysiologic significance and emerging role as biomarkers and therapeutics. Int J Obes 2016; 40: 88-101.
  60. 60. Sondergaard HB, Hesse D, Krakauer M, et al. Differential microRNA expression in blood in multiple sclerosis. Mult Scler 2013; 19:1849-1857.
  61. 61. Waschbisch A, Atiya M, Linker RA, et al. Glatiramer acetate treatment normalizes deregulated microRNA expression in relapsing remitting multiple sclerosis. PloS One 2011; 6: e24604.
  62. 62. Du C, Liu C, Kang J, et al. MicroRNA miR-326 regulates Th-17 differentiation and is associated with the pathogenesis of multiple sclerosis. Nat Immunol 2009; 10: 1252-1259.
  63. 63. Liu S, Yang Y, Wu J. TNFα-induced up-regulation of miR-155 inhibits adipogenesis by down-regulating early adipogenic transcription factors. Biochem Biophys Res Commun 2011; 414: 618-624.
  64. 64. Ma X, Zhou J, Zhong Y, et al. Expression, regulation and function of MicroRNAs in multiple sclerosis. Int J Med Sci 2014; 11(8): 810-818.
  65. 65. Lopez-Ramirez MA, Wu D, Pryce G, et al. MicroRNA-155 negatively affects blood-brain barrier function during neuroinflammation. FASEB J 2014; 28(6): 2551-2565.
  66. 66. Junker A, Krumbholz M, Eisele S, et al. MicroRNA profiling of multiple sclerosis lesions identifies modulators of the regulatory protein CD47. Brain 2009; 132(Pt12): 3342-3352.
  67. 67. Olsson T, Zhi WW, Hôjeberg B, et al. Autoreactive T lymphocytes in multiple sclerosis determined by antigen-induced secretion of interferon-gamma. J Clin Invest 1990; 86(3): 981-985.
  68. 68. Levine TB, Levine AB. Metabolic Syndrome and Cardiovascular Disease. 1st ed. Philadelphia: Elsevier Inc.; 2006, p. 121-137.
  69. 69. Sievers C, Hoffmann F, Fontoura P, et al. Effect of natalizumab on microRNA expression in B-lymphocytes of relapsing-remitting multiple sclerosis patients. Mult Scler 2010; 16: 197-352.
  70. 70. Steiner DF, Thomas MF, Hu JK, et al. MicroRNA-29 regulates T-box transcription factors and interferon-gamma production in helper T cells. Immunity 2011; 35: 169-181.
  71. 71. Harauz G, Ishiyama N, Hill CM, et al. Myelin basic protein - diverse conformational states of an intrinsically unstructured protein and its roles in myelin assembly and multiple sclerosis. Micron 2004; 35: 503-542.
  72. 72. Kim MS, Pak YK, Jang PG, et al. Role of hypothalamic Foxo1 in the regulation of food intake and energy homeostasis. Nat Neurosci 2006; 9: 901-906. doi:10.1038/ nn1731
  73. 73. Moscarelo MA, Wood DD, Ackerley C, et al. Myelin in multiple sclerosis is developmentally immature. J Clin Invest 1994; 94:146-154.
  74. 74. John GR. Multiple sclerosis: re-expression of a developmental pathway that restricts oligodendrocyte maturation. Nat Med 2002; 8: 1115-1121.
  75. 75. Mendes-da Silva C, Lemes SF, Baliani T da S, et al. Increased expression of Hes 5 protein in Notch signaling pathway in the hippocampus of mice offspring of dams fed a high-fat diet during pregnancy and suckling. Int J Dev Neurosci 2015; 40: 35-42.
  76. 76. Moscarello MA, Mastronardi FG, Wood DD. The role of citrullinated proteins suggests a novel mechanism in the pathogenesis of multiple sclerosis. Neurochem Res 2007; 32: 251-256.
  77. 77. Mastronardi FG, Noor A, Wood DD. Peptidyl argininedeiminase 2 CpG island in multiple sclerosis white matter is hypomethylated. J Neurosci Res 2007, 85: 2006-2016.
  78. 78. Chrast R, Saher G, Nave K-A, et al. Lipid metabolism in myelinating glial cells: lessons from human inherited disorders and mouse models. J Lipid Res 2011; 52: 419-434.
  79. 79. Bourre JM, Pascal G, Durand G, et al. Alteration in the fatty acid composition of rat brain cells (neurons, astrocytes, and oligodendrocytes) and of subcellular fraction (myelin and synaptosomes) induced by a diet devoid of n-3 fatty acids. J Neurochem 1984; 43: 342-348.
  80. 80. Bassett SA, Barnett MPG. The role of dietary histone deacetylases (HDACs) inhibitors in health and disease. Nutrients 2014; 6: 4273-4301.
  81. 81. Yan K, Cao Q, Reilly CM, et al. Histone deacetylase 9 deficiency protects against effector T cell-mediated systemic autoimmunity. J Biol Chem 2011; 286: 28833-28843.
  82. 82. Inkster B, Strijbis EMM, Vounou M, et al. Histone deacetylase gene variants predict brain volume changes in multiple sclerosis. Neurobiol Aging 2013; 34: 238-247.
  83. 83. Tegla CA, Azimzadeh P, Adrian-Albescu M, et al. SIRT1 is decreased during relapses in patient with multiple sclerosis. Exp Mol Pathol 2014; 96(2): 139-148.
  84. 84. D’Addario C, Di Francesco A, Pucci M, et al. Epigenetic mechanisms and endocannabinoid signalling. FEBS J 2013; 280: 905-917.
  85. 85. Gynther P, Toropainen S, Matilainen JM, et al. Mechanism of 1alpha,25-dihydroxyvitamin D(3)-dependent repression of interleukin-12B. Biochim Biophys Acta 2011;1813: 810-818.
  86. 86. Joshi S, Pantalena LC, Liu XK, et al. 1,25- Dihydroxyvitamin D (3) ameliorates Th17 autoimmunity via transcriptional modulation of interleukin-17A. Mol Cell Biol 2011; 31: 3653-3669.

Written By

Ema Kantorová, Egon Kurča, Daniel Čierny, Dušan Dobrota and Štefan Sivák

Submitted: 26 January 2016 Reviewed: 28 April 2016 Published: 08 September 2016