Nutri (Epi) Genomics and Metabolic Syndrome
Nutri (Epi) Genomics and Metabolic Syndrome
Nutri (Epi) Genomics and Metabolic Syndrome
Proc Indian Natn Sci Acad 82 No. 5 December 2016 pp. 1425-1436
Printed in India. DOI: 10.16943/ptinsa/2006/48877
Review Article
Nutri (Epi) Genomics and Metabolic Syndrome
NAGA MURALIDHAR MERUGU 1 , RAGHUNATH MANCHALA 2 and RAJENDER RAO
KALASHIKAM1,2*
1Laboratory of Molecular Genetics, National Centre for Laboratory Animal Sciences, National Institute
The metabolic syndrome is a cluster of risk factors such as obesity, insulin-resistance, hypertension, dyslipidemia,
inflammation associated with an increased risk of type 2 diabetes mellitus (T2DM) and cardio vascular diseases (CVD).
Rapid globalization, urbanization and industrialization have spawned epidemics of metabolic syndrome and it has become
one of the major threats among adolescents and children. It is influenced by the interaction of genes, nutrition, environment,
and lifestyle. The technological advances in life sciences have led to the realization that certain nutrients are not only
essential, but also specific quantity of each nutrient is necessary for optimal health. Therefore, it is important to understand
the biological impact of gene–nutrient-disease interactions, which will provide an insight into the pathogenesis and progression
of metabolic syndrome. The present review is focused on the role of gene-nutrient interactions (Nature vs Nurture) towards
the development of metabolic syndrome and associated co-morbidities and its epigenetic regulation.
affect metabolic pathways and homeostatic control individual co-ordinates their response to various dietary
epigenetically, the latter tries to understand how the nutrients (i.e. in the simplest terms: gene → diet
genetic make-up of an individual influences their interactions) (Mutch et al., 2005; Berna et al., 2014).
response to diet. The discovery of these gene-nutrient Further, it also shows why and how people respond
interactions would aid in personalized diets according differently to the same type of nutrient. It has the
to individual’s genotype (Sales et al., 2014). Further, potential to provide scientific evidence for personalized
understanding of gene–nutrient interactions would help dietary recommendations concerning health
in mitigating the symptoms of existing diseases and/ management based on the individual’s genetic makeup.
or to prevent future illnesses, especially in the area of Generally dietary bioactive compounds act on the
non-transmissible chronic diseases (NTCDs), which genome directly or indirectly and alter gene expression.
are currently considered as an important global public Some diet-regulated genes are likely to play a role in
health problem. the onset, progression, and/or severity of metabolic
syndrome. Further, dietary interventions based on
Nutrition, Genomics and Epigenomics knowledge of nutritional requirement, nutritional status
Nutrigenomics is the science of the effect of nutrients and genotype could be used to prevent, mitigate or
and bioactive components on gene expression and cure metabolic syndrome.
helps one understand how diet regulates gene function Epigenetics is defined as the study of changes
(transcription and translation), DNA methylation, in organisms caused by the modification of gene
proteome and metabolome (i.e. in the simplest terms: expression, rather than the alteration of the genetic
diet → gene interactions) which can be studied information itself. Epigenetic regulation is an essential
independently or in an integrated manner, to diagnose process in normal development that occurs all through
health status and/or to understand disease trajectory life. Further, it has been explained as the study of
(Elliott and Johnson, 2007; Gaboon, 2011). Recent external or environmental factors that turn genes on
developments in nutrigenomics has established the and off and affect how cells read genes. The
effects of ingested nutrients and other food excitement about epigenetics is how the gene
components on gene expression and its regulation in expression stably reprogrammed in response to
order to delineate the dietary components having transient external stimuli. It is required to achieve
beneficial or detrimental effects on health. It would stable expression or repression of genes in specific
also determine the individual nutritional requirements cell types or at specific time-points and constitutes
(personalized diet), association between diet and the link between genotype and phenotype. Most
metabolic syndrome which is essential to understand importantly, it could be inherited between generations
the aetiology of type-2 diabetes, obesity and steadily by mitosis and meiosis through cell
cardiovascular disease (CVD). Although humans have differentiation. Epigenetic conditions can illustrate the
99.9% identical gene sequences; 0.1% genetic reason why an organism produces many different cell
variation makes an individual unique from others with types during its development, despite the fact that most
respect to their phenotype, susceptibility to disease or of the cells in a multi-cellular organism share the same
health and their differential responses to nutrients genetic information. Epigenetic change is a regular
(Elliott and Johnson, 2007). Nutritional factors strongly and natural occurrence but can also be influenced by
affect the association of common gene variants with several factors including diet, environment/lifestyle,
multi-factorial chronic conditions. Evidently, major age and disease state. Studies have shown that the
metabolic diseases are closely inter-related, often effects of nutrition/diet could be passed on
through obesity, caused mainly by dysregulation of epigenetically to the offspring add weight to the idea
energy homeostasis. Under certain circumstances, diet that histones act as metabolic sensors, converting
can be a risk factor for some individuals, while in changes in metabolism into stable patterns of gene
others it may be beneficial (Rajoka et al., 2012). On expression. Three important mechanisms involved in
the other hand, nutrigenetics is to elucidate the effect epigenetic regulations include DNA methylation,
of genetic variation on the interaction between diet & histone modifications and non-coding RNA (siRNA/
disease, for example; phenylketonuria (PKU) and miRNAs) associated gene silencing. The interplay
describes how the genetic make-up of a particular and progressive combination of these regulatory
Nutri (EPI) Genomics and Metabolic Syndrome 1427
mechanisms may ‘‘lock’’ the epigenome in specific Interplay of various regulatory mechanisms are
states, thereby determining the fate and physiology expected to have regulatory roles in the inheritance
of a given cell (Katada et al., 2012). Thus, intake of and vulnerability to metabolic diseases i.e., obesity,
dietary methyl-groups (choline, methionine, genistein type 2 diabetes, hypertension and CVD by affecting
and folate) during critical periods of development can the expression(s) of the associated gene(s). Also,
alter promoter DNA and histone (de) methylation/ during specific developmental phases, intrauterine
(de) acetylation, resulting in life-long changes in gene atmosphere can vary the epigenetics of an individual
expression and thereby altering the epigenome and may work as a foundation for the metabolic
towards obesity in adulthood. Further, exposures to disease like obesity and other phenotypes during later
nutritional status (under-nutrition/over-nutrition) that stage of life. For example, variations in birth weight
occur at different developmental stages such as pre- are affected by several factors like in utero and
conception, in utero and early life may result in placental factors, maternal genes and BMI, paternal
epigenetic dysregulation, which put the individuals at genes, smoking, alcohol consumption, drug use, and
a higher risk to develop chronic diseases later in life. exercise during pregnancy etc. In a similar manner,
poor/malnutrition during early and post-natal period
The methylome is the genomic distribution of also affects the mother’s metabolism to acclimatize
methylated DNA sequence present in a cell and is and favour storage of nutrients in mother’s body. A
capable of undergoing modification with respect to study on Pima Indians showed that paternally imprinted
the environment/diet or the developmental stage gene located on chromosome 11 position 80 cM
(Kanherkar et al., 2014). DNA methylation occurs influences birth weight (Lindsy et al., 2002). Similarly,
at the cytosine residues of DNA, especially in CpG in a study on Mexican Americans, quantitative trait
dinucleotides present in regions called CpG islands. loci (QTL) on chromosome 6q, was found to be
DNA methylation is generally associated with reduced associated with birth weight regulation (Arya et al.,
transcriptional activity through decreased binding of 2006). Hence, gene-environment (GXE) interactions
transcription factors and also by attracting methyl CpG play a significant role in the aetiology of obesity,
binding proteins that act as transcriptional repressors. perhaps via modifications in DNA methylation patterns
Over 85% of CpG dinucleotides are spread out in the (Kalashikam et al., 2014). Apart from the well
genome and located in repetitive sequences that are established fact that variations at DNA sequence level,
heavily hypermethylated/transcription - silenced in the the epigenetic incidents also seem to contribute to the
normal cells, a state crucial to the integrity of the development of metabolic diseases and its
chromatin structure of the genome (Zhu and Yao, epidemiology, which is evident from modern day
2007). Further, genetic variation could have an effect sedentary living style.
on promoter DNA methylation percentages and
subsequently on the regulation of gene expression Research studies have shown that during the
(Kalashikam et al., 2014). On the other hand, histones early years of life, monozygotic (MZ) twins are
are globular proteins around which DNA is packaged epigenetically indistinguishable from each other.
to make chromatin. Enzyme modifications, such as Interestingly, with increasing age, remarkable
methylation and acetylation of lysine residues in their differences become noticeable in their overall content
amino termini, lead to the conformational change in and genomic distributions of 5-methylcytosine in DNA
histones. Acetylation leads to increased DNA and histone acetylations. Similarly, diet/environment
accessibility, and methylation can either increase or could have an influence on individual’s BMI and health.
decrease DNA accessibility depending upon the A comparative study of epigenetic metastability of
specific type of methylation and histone modification 6,000 unique genomic regions between matched
(Yasui et al., 2003). DNA methylation and histone monozygotic (MZ) and dizygotic (DZ) twins
modification often work in tandem, as MBPs (methyl demarcated epigenetic differences in both the MZ
– CpG - binding proteins) recruited by DNA and DZ twins (Kaminsky et al., 2009). Molecular
methylation that may exert their effects through mechanisms of heritability may not be limited to
recruitment of histone deacetylases, resulting in differences in DNA sequence only. Indeed, epigenetic
chromatin condensation and transcriptional modifications also act as one of the very important
inactivation. governing factors in unravelling the secrets behind
1428 Naga Muralidhar Merugu et al.
the blue prints of DNA sequence. Latest developments regulation, signal transduction and through alterations
indicate that epigenetic research would add a new in chromatin structure and protein function. All
dimension by explaining inter-individual variations in organisms in the universe, simple or complex, have
body weight. With the use of advanced technologies, the ability to respond to nutrient or nutrient/ hormonal
epigenetic profile of the metabolic diseases like obesity, signals, which regulate gene expression i.e., synthesis
CVD etc associated genes can be discerned and could of mRNA, encoding the enzymes involved in their
be applied in a genome-wide approach. Latest metabolism (Qi and Cho, 2008). Nutrients such as
technological developments and ongoing research on macronutrients (fatty acids, proteins and
epigenetics aspects are continuously uncovering the carbohydrates) and micronutrients (minerals and
role of epigenetics in a variety of human disorders vitamins) along with phytochemicals in food regulate/
and fatal diseases. The renewed interest in epigenetics alter gene expression. Nutrients act as signalling
has led to new findings about the relationship between molecules that activate cellular sensing mechanisms,
epigenetic changes and a host of disorders including which in turn degrade them (nutrients) into metabolites.
various cancers, mental retardation, immunity, Hence, the modifications in gene expression may
neuropsychiatry and paediatrics. Specifically, it is very affect muscle, liver, pancreatic β cells, hypothalamus,
important to explore more about diet and epigenetic adipose tissue etc. The effects of these gene-nutrient
changes and its relation with development of metabolic interactions can be deleterious or protective thereby
diseases. regulating energy homeostasis and metabolic
pathways. Use of high throughput technologies has
To understand the development and or facilitated the collection of important information by
progression of metabolic disease, the present day studying the interaction of bioactive food components
predictors are circumscribed by heritability, with genome at cellular and molecular level.
environmental factors such as diet, lifestyle, and gut Development of metabolic syndrome is practically
microbiome. It is very clear that advances in linked with unbalanced nutrient intakes and generation
nutrigenomics and epigenomics would further the of reactive oxygen (ROS) and nitrogen species
understanding of the complex interplay between (RNS). The nutrients keep the desired balance
genotype, phenotype and environment, which are between total oxidation status and total antioxidant
required for development of personalised nutrition in response of the organism to maintain a balance
the future. Improving diet and other lifestyle between these two variables (Rajoka et al., 2012).
behaviours’ has considerable potential for reducing
the global burden of non-communicable diseases, Metabolic Syndrome (Mets)
especially metabolic diseases and promoting better
health. The metabolic syndrome (MetS) is a clinical entity of
substantial heterogeneity, represented by a cluster of
Gene-nutrient Interaction biochemical and physiological abnormalities
(Goyenechea et al., 2008; Phillips, 2013). The major
Gene-nutrient interactions are complex and hard to risk factors for developing MetS are physical
predict, thus demonstrating the need for highly inactivity, diets rich in fats (particularly saturated fatty
controlled genotypes and environmental conditions that acids) and carbohydrates, contributing to the clinical
allow identification of different regulatory patterns features such as central obesity, insulin resistance,
(Doo and Kim, 2015). Differences in genetic make- inflammation, hypertension and dyslipidaemia.
up or genotype are the factors that determine the Clustering of these risk factors leads to an increased
phenotype; on the other hand nutrient imbalances could risk for the development of type 2 diabetes and
also play a key role (Nature Vs Nurture). Whether cardiovascular disease (Roche et al., 2005; Qing Song
dietary intervention affect the outcome of phenotype et al., 2006; Taylor et al., 2013; Han et al., 2016).
(GXE=P) is determined by the diseased condition Therefore, it is important to understand the biological
known to have genetic and/or environmental impact of gene–nutrient-disease interactions that
components (nutritional) (Perusse and Bouchard, provide an insight into the pathogenesis and
2000). A large number of studies have shown that progression of metabolic syndrome.
nutrients alter gene expression at the level of gene
Nutri (EPI) Genomics and Metabolic Syndrome 1429
and intermediate phenotypes. Calpain 10 (CAPN10) citrus fruits have also been shown to protect against
was the first T2DM susceptibility gene identified T2DM by activating peroxisome proliferator activated
through a genome-wide scan followed by positional receptors (PPARs) in liver and adipose tissue. Studies
cloning (Dedoussis et al., 2007). CAPN10 variants in mice showed that bilberry anthocyanin
have been linked with several MetS phenotypes, supplementation improved insulin sensitivity in T2DM
including hyper triglyceridemia, BMI and by down regulating the expression of gluconeogenic
hypertension. Studies have reported that six genes enzymes and up regulation of peroxisome proliferator
account for majority of the monogenic forms of activated receptor alpha(PPARα), long chain carnitine
diabetes. These are hepatic nuclear factors (HNF- palmitoyltransferse I (L-Cpt-1), Glucose transporter
1α, 4α and 1β), glucokinase (GCK), insulin promoter type 4 (Glut4) and aconitase (Aco) expression in the
factor-1 (IPF-1), and neuro D1 transcription factor liver (Takikawa et al., 2010). The dietary flavones,
(NEUROD1) (Gloyn, 2003). Further, Transcription apigenin and luteolin found in celery, parsley were
factor 7–like 2 (TCF7L2) gene variants (rs7903146 shown to protect the cells from cytokine-induced
SNP ) are specially associated with an increased risk apoptosis by inhibiting inducible nitric oxide synthase
both for T2DM and MetS by causing excess fat and (iNos) expression. The major dietary isoflavones;
glycogen deposition in the liver, glucose intolerance daidzein and genistein, primarily present in soy foods
and hyperlipidaemia (Phillips, 2013). A study reported have been shown to improve glucose tolerance and
that the gene, Two pore segment channel 2(TPCN2) circulating insulin concentration by increasing islet â
plays a role in metabolic regulation, and the single cell proliferation, β cell mass and survival (Kim et al.,
nucleotide polymorphism rs1551305 in TPCN2 is 2007). The genotype and diet interaction studies
associated with type 2 diabetes risk (Fan et al., 2016). showed that peroxisome proliferator-activated
The KCNJ11 gene, a member of the potassium receptor gamma (PPARG) Pro12Ala genotype
channel gene and the common polymorphisms (SNPs) modified the association between total dietary fat
in KCNJ11 gene, such as rs5219, rs5215, rs5210, intake and risk for obesity. The Pro/Pro homozygotes
rs5218, rs886288, and rs2285676 were shown to be of PPARG have been reported to be at increased
involved in diabetes (Haghvirdizadeh, 2015). A study risk for obesity and insulin resistance (Roche et al.,
reported that KCNJ11 SNPs 74 (3p+215), 76 (A190) 2005). Scavenger Receptor Class B Member
and 77 (E23K) showed significant association with 1(SCARB1) genetic variability plays a significant role
T2DM (Dedoussis et al., 2007). FABP (FABP1) is in lipoprotein metabolism. Research findings show that
an abundant cytosolic lipid-binding protein that subjects carrying the A allele in exon 1 at the SCARB1
regulates lipid transport and metabolism. The c.334- gene locus (SCARB1 exon 1, rs4238001) were
135G>A polymorphism (rs2197076) located in the 3 associated with significant increase in insulin
prime un-translated region (UTR) of the FABP1 gene sensitivity after the consumption of a MUFA-rich diet
was associated with the risk of type 2 diabetes and compared to the effect on G/G individuals (Dedoussis
the homeostatic model assessment index (HOMA et al., 2007). The fatty acid (FA)-binding protein 2
index) (Mansego et al., 2012). (FABP2) gene that codes for intestinal FABP
(IFABP), is crucial for fat absorption and transport.
Several studies in humans and animal models Subjects with the Thr54 allele had higher FFA
have shown anti-diabetic effects of dietary flavonoids concentrations than did those who were homozygous
on glucose homeostasis by regulating expression of for the Ala54 allele when consuming a saturated fatty
different genes in pancreas, liver, skeletal muscle and acid (SFA)-rich diet. This suggests a plausible
white adipose that are involved in various cellular mechanism for the FABP2 Ala54/Thr54
pathways. Consumption of anthocyanins, particularly polymorphism-diet interaction for the determination
from blueberries, apples and pears, was consistently of insulin sensitivity and T2D (Dedoussis et al., 2007).
associated with a lower risk of T2DM (Berna et al.,
2014). These compounds were shown to regulate Cardiovascular Disease (CVD)
carbohydrate digestion, insulin secretion, insulin
signalling and glucose uptake in insulin-sensitive CVD can be characterized as a group of multi-
tissues by modulating intracellular pathways. Naringin factorial conditions that include cerebro vascular
and hesperidin, the two major flavanones present in diseases (stroke with transitory ischemic attack),
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