Chapter 12

Environmental factors and Epigenetic modulation of metabolism

Nagaraju Bandaru 1*, Rajeshwar Vodeti2, Ceema Mathew3, Alekhya Ketha4, Shashikala Metri5
1.
Department of Pharmacology, School of Pharmaceutical Sciences (SOPS), Sandip
University, Nashik, and Maharashtra, India.
2.
Department of Pharmaceutics, School of Pharmacy, Anurag University, Hyderabad,
Telangana-500088
3.
Department of Pharmaceutical analysis, Gokaraju Rangaraju College of
Pharmacy, Bachupally, Hyderabad

4.
Department of Pharmaceutical Chemistry, Sree Dattha Institute of Pharmacy, Sheriguda,
Ibrahimpatnam, Hyderabad, India.

5.
Department of Pharmacognosy, Gokaraju Rangaraju College of Pharmacy, Hyderabad,
Telangana, India.

Correspondence:
Dr. Nagaraju Bandaru,
Department of Pharmacology,
School of Pharmaceutical Sciences (SOPS),
Sandip University, Nashik, 422213, Maharashtra, India.
Email: bnrajupharma@[Link].

Abstract

Epigenetics is a crucial component in the regulation of metabolism by contributing to

incorporate genetic predisposition with environmental influences and life-style. This review
emphasizes the interconnectedness of epigenetic modications and metabolic health
pervasively mediated by environment including diet, physical activity, stress and toxicants
on the [Link] process like methylation of DNA, modification of histones and
regulation of Non-coding RNA are featured as master regulators modulating majority of
metabolism-related genes i.e., glucose and lipids. The environmental–epigenome–metabolism
axis has been suggested to describe the manner in which environment leads, via the
epigenome, to control of metabolism. We also provide an overview of discoveries related to
early detection and risk prediction of metabolic diseases employing epigenetic biomarkers,
and the potential interventional use of the epigenetic-based therapy as strategies for obesity,
T2D and CVD prevention. Indeed, lifestyle interventions like exercise, stress management
and sleep also generate favorable epigenetic modifications that can help promote metabolic
health. The destiny of metabolic health will be heavily dependent on precision medicine
strategies employing epigenetic profiling for personalized prevention and treatment.
Nevertheless, issues including the complexity of epigenome, reversibility of epigenetic
modification as well as standardization of diagnostic tools still require consideration. In
general, incorporating epigenetic lessons into clinical practice has great potential for the
development of metabolic health care.

Keywords

Epigenetics, Metabolism, Methylation of DNA, Modification of histones, Non-coding RNA

& Metabolic Disorders,

12. Introduction

12.1 Overview of Epigenetics and Metabolism

Epigenetics is the study of heritable and reversible gene expression modifications that do not
alter the underlying DNA sequence. These modifications may be induced by the external
environment, life style and diseased state without being genetic mutations and are reversible.
Epigenetic modifications occur through Methylation of DNA, Modification of histones &
Non-coding RNA. These processes may affect the manner in which genes are switched on or
off. These adaptations allow an organism to react to changing environmental signals and
maintain homeostasis. Metabolism is the sum of all life sustaining reactions in an organism.
These processes are catabolism of nutrients for energy, anabolism of macromolecules for cell
structure and function, with homeostatic regulation among them [1]. Base metabolic rate is
predominantly determined by our genes, but it is also partly shaped by our environment —
including the food we eat and pollutants we’re exposed to. Genome-environment interaction
is known to modulate metabolic health and disease susceptibility, with the key role played by
epigenetic adaptations. Such a complex relationship between epigenetics and metabolism
complexes, in which epigenetic mechanisms may regulate the expression of metabolic genes
in an environmental specific manner. Such alterations may affect metabolism of glucose and
lipids, energy balance, and possibly have metabolic effects in the long term. These
alterations, importantly, have been proposed to be transmissible to the progeny44–47
indicating that exposure during perinatal programming may cause metabolic health problems
throughout life [2].

12.1.2 Environment–Epigenome–Metabolism Axis

The environment is a major modulator of the epigenome and in specific affects metabolism.
This environment–epigenome–metabolism axis demonstrates how environmental cues,
including diet, stress, toxins and exercise come into play with the epigenome to control
metabolism. The DNA (and histone) modifications due to the effects of external
environmental factors induce an epigenetic change and involve in an encored gene expression
being associated with pro-carcinogen metabolism [3].By way of example, there is abundant
evidence that dietary compounds can profoundly influence epigenetic phenomena. It is also
the case for some nutrients such as folate, B vitamins and polyphenols in diet impact
Methylation of DNA and Modification of histones that can influence metabolic gene
expression. What is more, an unhealthy diet rich in processed food or added sugar may be
prone to epigenetic changes which promote the development of obesity, Type-2 diabetes and
heart diseases. Environmental pollutants and toxins are also capable of modulating the
epigenome, such as it has been shown that exposure to bisphenol A (BPA) or air pollution,
alters epigenetic marks associated with metabolism. Environmental stimuli, such as exercise
can also modulate the epigenome. Exercise can induce epigenetic modifications that enhance
metabolic reprogramming, insulin sensitivity and fat oxidation. Physical activity has been
shown to activate DNA demethylation and histone acetylation in genes linked to energy
metabolism raising the possibility that exercise may have a long-term influence upon
metabolic health through an epigenetic mechanism [4].

Stress effects the environment and it also, influences epigenome and metabolism. Chronic
stress can lead to dysregulation of the HPA axis, causing high cortisol. The environment-
epigenome-metabolism crosstalk illustrates how this relationship is dynamic and
bidirectional. Conversely, metabolic alterations can reciprocally influence epigenetic traits of
genes by sequestration in certain metabolites that increases the stability or activity of histones
and DNA. The feeding state and availability of nutrients might be sensed by the epigenetic
landscape to influence other physiological functions such as Metabolism and its contribution
to homeostasis. This feedback loop, therefore, implicates the intricate axis environment–
epigenome–metabolism and how it is affected by environmental cues to modulate our
metabolic health [5]. Here we are beginning to appreciate that the axis is not only
programming metabolic programmes for the individual but may likely be relevant also over
historical continuity and across generations in population health. A new theme, "epigenetic
inheritance," that is the transmission of ones' phenotypic or functional effects derived from
epigenetic modifications of chromosomes, independent of alteration in DNA sequences, has
developed and can contribute to how environmentally induced metabolic diseases may be
transmitted. Therefore, a holistic understanding of the relationship between environment–
epigenome–metabolism is essential for developing strategies for prevention and cure of
metabolic disorders.

12.2. Molecular Basis of Epigenetic Regulation

12.2.1 Methylation of DNA and Demethylation

This refers to addition of methyl moiety to cytosine residues in CpG dinucleotide resulting in
silencing of gene by inhibition of binding the transcription factors. It is an important process
by which genes are turned on and off, and it can be affected by diet, toxins and stress. For
instance, if nutrients such as folate and B vitamins donate methyl groups to the DNA through
influencing DNA methylation, then diet may affect metabolic health. On the other hand, DNA
demethylation will be either passive (loss of mCs during cell division) or active in case that
methyl groups are enzymatically removed (eg, TET family proteins), often activating genes
that were previously silenced. Perturbations in DNA methylation and demethylation are
associated with several disease states such as obesity and diabetes which indicates a role for
these processes in normal metabolic homeostasis [6].

12.2.2 Histone Modifications

These are the histones, which package DNA into chromatin and whose chemical
modifications such as acetylation, methylation, phosphorylation or ubiquitination modulate
gene expression through remodelling of the chromatin. Acetylation of histones mostly
activates genes by relaxing chromatin, whereas deacetylation represses gene expression.
Histone methylation can activate or repress genes in function of the modified site. For
instance, H3K4 methylation is linked to gene activation, whereas H3K9 methylation
contributes to silencing. These alterations are essential to the regulation of metabolic genes
and can be changed by diet and exercise. For example, butyrate (a product of gut bacteria)
stimulates histone acetylation, and thus improves metabolism, whereas exercise induces
histone modifications that improve insulin sensitivity and metabolic flexibility [7].

12.2.3 Role of Non-Coding RNAs

Non-coding RNAs (ncRNAs) are functional RNA molecules that do not encode proteins but
serve important regulatory roles in gene expression and cellular homeostasis. MicroRNAs
(miRNAs), small interfering RNAs (siRNAs), and piwi-interacting RNAs (piRNAs) are all
post-transcriptional regulators of gene silence that degrade mRNA or block translation. Long
non-coding RNAs (lncRNAs) influence transcriptional and epigenetic regulation by serving
as molecular scaffolds, guides, decoys, or sponges for miRNAs, whereas circular RNAs
(circRNAs) modulate gene networks via stable, closed-loop structures that interact with
proteins or miRNAs. Other ncRNAs, such as small nuclear RNAs (snRNAs) and small
nucleolar RNAs (snoRNAs), are required for RNA processing, notably splicing and chemical
transformation of rRNA. The ncRNAs work together to govern a variety of biological
processes, including development, differentiation, cell cycle control, and genomic integrity,
and their dysregulation has been linked to cancer, neurological disorders, inflammatory
illnesses, and metabolic dysfunctions [8].

12.3. Diet and Nutritional Epigenetics

12.3.1 Macronutrients and Metabolic Regulation

Carbohydrates, proteins and fats are macronutrients in the human diet that provide energy
necessary for cellular life and metabolic homeostasis. Besides fueling metabolism, these
macronutrients modulate gene expression and impact the epigenome in such a way that alters
and coordinates metabolism at the molecular level. Elucidation of the effects of ingestion of
these macronutrients on epigenomic modifications may help to unravel how lifestyle is
connected to metabolic health and disease [9]. These are primarily energy-supplying nutrients
carbohydrates and may involve in insulin signalling system and metabolism of glucose.
Dietary excess of carbohydrates, especially processed sugars and refined foods may cause
imbalances in metabolism that contribute to its degeneration including insulin resistance and
obesity. For example, overexposure to sugar is known to drive alterations in DNA
methylation of glucose metabolism genes regions that regulate insulin resistance and the
development of T2D. Carb Baddie Anytime you eat carb, people probably ain’t make friend
to your epigenome right? Conversely, consumption of complex carbs (like wholegrains) does
seem to associate with a happy looking epigenetic profile— one that could in theory not be
bad for insulin sensitivity & metabolic health [10]. Proteins are required for tissue
restoration and regeneration, but they may also play roles in metabolism control by gene
expression regulation. Amino acids, as precursors of protein and known modulators not only
of protein-synthesis but also gluconeogenesis and lipid metabolism are equally well
documented. The post-translational modifications (acetylation and methylation) regulate
mTOR signaling in histone is a key activator to accelerate metabolism. Particularly,
consumption of leucine had been reported epigenetic modification via this mechanism as
well. Dietary protein might also affect expression of genes linked to body fat deposition and
energy use, which could have an impact on the body composition and metabolic rate. But
taking in too much protein, especially from animal sources such as meat and cheese, can
increase inflammation in the body and that led to elevated risk of certain metabolic diseases
[11]. Lipids (eg, unsaturated fatty acids) are vital for membrane integrity and energy
reserves. Fat intake is a regulator of gene transcription in lipogenesis and adipogenesis. Fatty
acid omega-3 of fatty fish and some plant oils activates not only useful epi(brand) epigenetic
changes that contribute to histone acetylation (which results with the implementation of
unfolded chromatin structure which is providing initiating gene transcription—just as, for
example, for genes encoding anti-inflammatory activities and organization metabolism. These
fats have been demonstrated to modulate DNA methylation and histone modification status of
genes involved in inflammatory response, insulin resistance and adipogenesis. Well, it is well
established that macronutrients and metabolism engage in two-way communication with
substantial consequences for epigenetic stability and metabolic health. Macronutrients and
epigenetics in the development of metabolic diseases such data on macronutrient-epigenetic
interactions in metabolic disorders accentuate diet intervention as a means to prevent or treat
these conditions [12].

12.3.2 Micronutrients and One-Carbon Metabolism

Micronutrients, including vitamins and minerals, regulate metabolic pathways, particularly

one-carbon metabolism. One-carbon metabolism refers to metabolic reactions that transfer
one-carbon units, including DNA methylation, amino acid metabolism, and nucleotide
synthesis. Micronutrients such as folate (vitamin B9), vitamins B6, B12, and choline play a
crucial role in epigenetic regulation in one-carbon metabolism and have been extensively
explored. Folate helps transfer one-carbon units into methyl groups, which is necessary for
DNA methylation. Folate deficiency can interfere with DNA methylation and activate
disease-associated genes, such as those for cancer, CVDs and metabolic diseases [14].
Dietary folate supplements have also been observed to return DNA methylation profiles and
metabolic health in folate deficient individuals. Folate and its association with epigenetics in
immunological pathways are especially important for periods of rapid cell division, such as
during pregnancy where adequate folate levels are critical for the healthy development of a
fetus and reducing the risk along neural tube defects. Vitamins B6 and B12 are also very
important cofactors in one-carbon metabolism, they participate in the enzymatic reactions of
transferring one carbon groups. The vitamins aid in the control of S-adenosylmethionine
(SAM) synthesis, an important methyl donor for DNA methylation and histone
modifications. Both low B6 and low B12 may alter methylation patterns, resulting in
genomic instability and perturbation of metabolic pathways. Studies have demonstrated the
beneficial effects of vitamin B12 on normalisation of DNA methylation and increased insulin
sensitivity, suggesting that it may also play a role in treatment of metabolic disorders such as
type 2 diabetes [15]. Another important micronutrient, choline is required for the formation
of phosphatidylcholine (a major constituent of cell membranes) and in the synthesis and
metabolism of methyl groups used in DNA methylation. Reduced choline levels are
associated with aberrant methylation patterns and altered lipid metabolism that leads to
hepatic lipidosis and other metabolic disorders. Sufficient maternal choline intake during
pregnancy is particularly important, as the consequences of inadequate maternal choline in
offspring on the epigenome and metabolic health are enduring. The role of one-carbon
metabolism and micronutrients in this process is a per se relevant lesson on the influence of
dietary factors in epigenetic regulation of metabolism. If your metabolic system is running
well and is not troubled by the symptoms of these troublesome epigenetically disordering
diseases, perhaps all it takes an excellent dietary source of those valuable vitamins and
minerals [16].

12.3.3 Fasting, Caloric Restriction, and Dietary Patterns

Short, calorie restriction and diversity of diet, are currently regarded as interesting due to
possible effects on metabolic health and longevity. These dietary interventions will regulate
energy balance and may also impact epigenetic modifications and metabolism for optimal
metabolic function that is resistant to disease. Intermittent fasting and sustained calorie
restriction are activating overlapping cellular pathways that promote longevity and metabolic
fitness. These include autophagy, mitochondrial biogenesis and sirtuins, protein deacetylase
enzymes regulating metabolism, stress resistance and lifespan. Fasting-triggered epigenetic
changes (histone deacetylation and DNA methylation) contribute to the drafted of genes
towards energy saving and repair. Research has shown that intermittent fasting can help
increase insulin sensitivity and regulate blood sugar levels, decrease inflammation and lower
obesity and type2 diabetes occurrence risk [17].

Caloric restriction (CR; or reduced caloric intake without malnutrition) is also another
dietary intervention that has been extensively studied in relation to metabolic health and
lifespan. CR has been shown to extend lifespan in multiple species and is associated with
alterations in metabolic parameters including reduced adiposity, cholesterol levels and insulin
sensitivity [18]. It is now postulated that the beneficial effects of CR are mediated through
epigenetic alterations such as various histone post-translational modifications and DNA
methylation, which promote metabolic reprogramming and greater stress resilience. Related
to CR, new compounds so-called caloric restriction mimetics (CRMs) are under investigation
that should mimic effects observed during CR without decreasing food intake. Dietary
regimens as the Mediterranean diet, ketogenic diets, and plant-based diets also modulate
metabolic functions through epigenetics. That diet, the Mediterranean diet — which includes
healthful fats (like olive oil) and plenty of fruits and vegetables, whole grains and very little
meat — has been linked to better metabolic health and a lower risk for many chronic
diseases. This dietary intervention induces beneficial epigenetic changes (histone
modification, DNA methylation of genes involved in inflammation, insulin sensitivity and
lipid metabolism). Diets that are rich in fruits and vegetables, full of fibre, antioxidants and
phytonutrients, also seem to promote healthy epigenetic patterns, many of which influence
the metabolism of glucose and reduce oxidative stress. B The ketogenic diet with high fat,
low carbohydrate intake was proven through assessment of gene expression changes in FA
metabolism and energy utilization inducing weight control and that has potential metabolic
benefits [19].

12.4. Environmental Exposures and Pollutants

12.4.1 Heavy Metals and Endocrine Disruptors

Heavy metals including lead, mercury, cadmium and arsenic are in essence non-degradable
pollutants that can obstruct normal cellular processes like metabolism control through both
direct toxic effects and epigenetic modifications. There are plenty in dirty environments,
industrial centres and dirty foods and drinks with severe hazard to health. The toxicity of
heavy metals seems to be generally connected with their ability to induce ROS formation,
cellular signalling pathways and alter pressure-related epigenetic signatures regulating gene
expression and metabolism [20]. For instance, lead has been shown to interfere with the
activity of enzymes involved in mitochondrial energy generation and calcium efflux
inducing oxidative stress. It might also affect DNA methylation and histone modification,
potentially repressing genes involved in the cellular stress response, immunity and
metabolism. Chronic exposure to lead can retard development, damage the nervous system
and cause metabolic disruptions like high blood pressure and diabetes. Mercury, another
heavy metal, has comparable toxic effects, notably on the nervous system and kidneys.
Effects of mercury exposure [21]. The effect of mercury on gene expression is related to
modification in methylation of DNA & modification of Histones patterns toward genes
involved in detoxification, apoptosis or oxidative stress. Mercury can also block optimal
thyroid function, which is important in regulating your metabolism. Disruptions in the action
of thyroid hormones influence multiple aspects of metabolism which are involved in obesity,
diabetes and thyroid disorders. Endocrine disrupters are chemicals that interfere with the
endocrine system by imitating or blocking hormones. These chemicals may disrupt metabolic
regulation, including by changing hormone levels and signalling. BPA is one of many
endocrine disruptors, like phthalates and some pesticides, commonly found in plastics,
cosmetics, food packaging and agricultural products. Metabolic health can be affected by
these pollutants, which could alter gene expression by changes in epigenetic modifications.
One example is BPA, which has been reported to trigger DNA methylation and histone
modification in genes involved in adipogenesis (fat cell formation), insulin signal pathway,
and fat storage process for the onset of obesity induction as well as type 2 diabetes induction
or cardiovascular diseases initiation [22]. Not only are the influence of heavy metal and
endocrine disruptor on metabolism not confined to their direct chemical effects, but they also
affect the metabolic pathways regulation. These pollutants can result in epigenetic alterations
which are transmitted to successive generations, with significant implications for offspring
exposed in utero or during early life. Therefore, minimizing exposure to these environmental
contaminants is essential for endogenous metabolic health and the prevention of these PAH‐
induced epigenetic legacies in future generations [23].

12.4.2 Air Pollution and Particulate Matter

Although many studies have linked air pollution, mainly PM2. 5), Ozone (O3) and Nitrogen
dioxide (NO2), is a major environmental risk factor for Cardiac, respiratory and metabolic
diseases. These pollutants can be introduced to the body by being inhaled into the deep lung,
where they elicit inflammation, as well as oxidative stress and thus cellular damage that may
rely on epigenetic factors affecting gene expression and metabolism [24]. It has been reported
in a few studies that PM2. 5 may lead to epigenetic modifications in genes implicated in
inflammation, oxidative stress and metabolic regulation (lipid metabolism, insulin
sensitivity). DNA methylation and the modification of histones on genes relevant to immune
function, adipogenesis and glucose metabolism have been observed in subjects exposed to air
pollutants. These epigenetic changes could play a role in obesity, type 2 diabetes and
cardiovascular disorder pathology which are known to be highly environmentally influenced
phenotypes [25]. Apart from PM, other pollutants including ozone and nitrogen dioxide have
also been linked to the metabolic dysfunction. For instance, ozone exposure has been
demonstrated to disrupt insulin signalling through a number of pathways and result in the
development of insulin resistance and impaired glucose homeostasis. Recurrent exposure to
air pollution therefore likely plays a role in the rise of metabolic diseases in urban
populations [26]. The epigenetic impact of air pollution is especially alarming for susceptible
populations such as children, the elderly, and people already suffering from known health
problems. Long-term exposure to air pollution levels have been shown to affect development
and may lead to sustained epigenome changes that render individuals susceptible for
metabolic disease. There is also evidence that exposure to air pollution has transgenerational
effects, with epigenetic changes being passed on from one generation to subsequent
generations. Relevance of the public health intervention to environmental cleanliness
improvement and pollution reduction [27].

12.4.3 Occupational and Chemical Exposures

The exposure to occupational and chemical pollutants may be one of the major risk factors
for environmental pollution on metabolic health and adverse outcomes. Employees in
agriculture, manufacturing, construction and mining are often exposed to toxic chemicals
such as pesticides, aliphatic solvents and heavy metals that can cause harm to metabolism. In
this context, such influences may lead to gene expression changes and metabolic diseases
through epigenetic mechanisms [28].

Pesticides, often used in agriculture to control pests, have been associated with a range of
metabolic health issues. a.a.), Some of these can interfere with endocrine activity by
inhibiting the enzyme acetylcholinesterase, needed for neurotransmission in the brain and
central nervous system or affecting thyroid hormone levels. These endocrine defects can
subsequently result in metabolic derangements, include insulin resistance, obesity and
dyslipidaemia [29]. Industrial solvents, such as benzene, toluene and trichloroethylene can
also jeopardize metabolic health through modulation of gene expression. These chemicals
have been associated to oxidative stress, DNA injury, and modification of histone acetylation
profile. Solvent exposure has also been linked with obesity risk, insulin resistance and liver
injury because they are able to modulate gene expression that affect fat storage,
inflammation and metabolism [30]. Exposure to workplace chemicals in women also has
detrimental effects on the reproductive and perhaps metabolic health for generations of their
offspring. For example, some chemicals such as phthalates and BPA are disruptors of
endocrine function that can result in metabolic disorders. Foetal exposure to these chemicals
can result in an in utero epigenetic template that, during early life stages, predisposes the
offspring to acquire metabolic disorder. Thus, not only those who are young workers would
be affected by occupational exposures, but they can also have putative effects across
generations for the metabolic health. The contribution of occupational and chemical exposure
to epigenetic mediation will prove in favor for more strict environmental protection, for safer
working environments, and for public health intervention to decrease the contact with toxic
substances. It is important to know how these exposures affect metabolic health through
epigenetic mechanisms, for the purposes of implementing preventative strategies and
therapies to counteract the adverse consequences of environmental pollutants(Figure 1&Table
1) [31].
Figure 1: Effect of environmental factors on epigenetic modifications

Table 1: Environmental exposures and their Epigenetic modifications impacting metabolic

health

Environmental Examples Metabolic Health Epigenetic Ref

Exposure Effects Modifications

Heavy Metals Lead, Mercury, Insulin resistance DNA methylation [32]

Cadmium, Arsenic changes in genes
related to
metabolism

Obesity Histone [33]

modification in
genes controlling
glucose and lipid
metabolism

Cardiovascular Altered expression [34]

diseases of genes involved
 in oxidative stress
and inflammation

Neurological [35]
damage (e.g.,
cognitive decline
from lead)

Endocrine Bisphenol A (BPA), Obesity DNA methylation [36]

Disruptors Phthalates, Pesticides of adipogenesis
genes (e.g.,
PPARγ)

Type 2 diabetes Histone [37]

modifications in
genes related to
insulin signaling

Increased fat Disruption of [38]

storage, metabolic thyroid function
syndrome leading to
metabolic
disturbances

Air Pollution and PM2.5, Ozone, Insulin resistance DNA methylation [39]
Particulate Nitrogen Dioxide in genes related to
Matter glucose
metabolism (e.g.,
GLUT4)

Cardiovascular Histone [40]

diseases modifications in
inflammatory
genes and genes
regulating fat
metabolism
 Asthma, COPD Altered gene [41]
expression related
to oxidative stress
response

Occupational Pesticides Obesity, insulin DNA methylation [42]

Exposures (Organophosphates), resistance changes in glucose
Solvents and lipid
metabolism genes

Liver dysfunction Histone acetylation [43]

in genes involved
in fat storage and
inflammation

Reproductive health Altered epigenetic [44]

disruption (e.g., regulation of
infertility, hormone hormonal pathways
imbalances)

Chemical Phthalates, BPA, Development of DNA methylation [45]

Exposures PCB, Dioxins metabolic diseases changes affecting
(obesity, type 2 genes related to
diabetes) adipogenesis and
insulin sensitivity

Dyslipidemia, Histone [46]

cardiovascular modifications
diseases impacting fat
storage and
inflammatory
pathways

Reproductive and Epigenetic [47]

developmental inheritance across
disruptions (e.g., generations
fetal exposure
 leading to long-term
metabolic effects)

12.5. Lifestyle Factors and Epigenetic Modulation

12.5.1 Physical Activity & Exercise

These two are major determinants of a healthy lifestyle, and are also central to the modulation
of physical fitness (direct), as well as metabolic health by means of epigenetic regulation
(indirect). It is well established that exercise training can enhance insulin sensitivity, enhance
fat metabolism, decrease inflammation and improve cardiovascular function mainly through
gene expression modifications (Ahmadizad et al., 2018) and these adaptations are driven by
DNA Methylation, Histone modifications and non-coding RNA regulation [48]. Gene
expression is linked with energy metabolism, mitochondrial biogenesis and muscle
adaptation. For instance, exercise stimulates the peroxisome proliferator-activated receptor
gamma coactivator 1-alpha (PGC-1α), a transcriptional coactivator which controls
mitochondrial function & oxidative metabolism genes. Physical activity can also cause DNA
demethylation and histone acetylation in lipid and glucose metabolism genes to increase FAT
oxidation and ameliorate glyco-homeostasis (Table 2).

In addition, exercise affects expression of ncRNAs (i.e., miRs) that are involved in muscle
hypertrophy, fat deposition and energy homeostasis. For instance, miR-22 is already known
to modulate adipogenesis and the expression of this miRNA changes after exercise indicating
that physical activity may modify gene expression profiles in the adipocyte through an
epigenetic way [49]. Beyond its direct effects on metabolic modulation, exercise exerts major
favorable effect on reducing stress and inflammation which are strongly linked to the
pathogenesis of obesity and type2 diabetes. Hence the beneficial epigenetic modifications
triggered by exercise may have a role not only in improving metabolic health, but also
protect from the impact of stress and poor diet.

12.5.2 Stress, Sleep, and Circadian Rhythm

In conclusion, stress, sleep and circadian systems are interrelated dynamic networks that
impact on healthy metabolism through epigenetic effects. In particular, chronic stress may
have adverse effects on metabolism because it promotes insulin resistance and makes
individuals prone to obesity, cardiovascular diseases. Stress stimulates the HPA axis, resulting
in the release of cortisol—a hormone that’s been associated with glucose regulation, fat
storage and hunger. Persistent stress, resulting in long-term cortisol exposure, may induce
epigenetic modifications promoting a pro-inflammatory hormonal microenvironment and
alterations of gene expression in metabolic cascades [50].

Stress-associated gene demethylation of the glucocorticoid receptor pathway can affect stress
processing in the body, resulting in dysregulated metabolic responses. In addition, chronic
stress may modify the expression of non-coding RNAs, including microRNAs that govern
genes involved into adipogenesis, glucose metabolism and response to stress [51]. Sleep is
also an important modulational factor affecting metabolic health through epigenetic
regulation. The amount, as well as the quality of sleep influences gene regulation associated
with appetite control, glucose metabolism and fat storage. Indeed, circadian rhythm
disturbances (as those that control sleep-wake cycles) are associated with insulin resistance,
obesity and metabolic syndrome. Epigenetic changes to circadian clock genes – such as the
PER and BMAL1 genes – can result in impairments in metabolism. For instance, circadian
rhythm disruptions such as in sleep patterns or during shift work can affect the DNA
methylation and histone acetylation status of genes which are related to energy balance or fat
storage [52].

The interplay between stress, sleep and circadian rhythm underscores the pronounced need
for a healthy life including sufficient sleep, proper strategies to handle stress and an
appropriate regularisation of your ccr. These mechanisms have effects on metabolic health
through epigenetic modifications of metabolism-, inflammation- and energy balance-related
genes [53].

12.5.3 Addiction and Substance Abuse

Addiction and the addictive use of tobacco, alcohol and drugs can substantially affect
metabolic health, promoting obesity, insulin resistance (IR), hepatic disease and
cardiovascular complications. The association between addiction and metabolic
comorbidities is, at least in part, attributed to the influence of substance use on epigenetic
modifications leading to changes in gene expression [54].The addictive component of
tobacco, nicotine is known to modulate the expression of several genes involved in glucose
metabolism and adipogenesis through epigenetic mechanisms. Smoking has previously been
linked to alterations in DNA methylation and histone modifications of genes implicated in
lipid storage, insulin sensitivity and inflammation. These changes may also lead to a high
risk of metabolic diseases such as type 2 diabetes and cardiovascular disease among smokers
[55]. Alcohol is the other predominant cause of metabolic disruption because it influences
liver and lipid metabolism. Alcohol consumption, especially in a chronic manner, induces
hepatic steatosis and insulin resistance and can cause dyslipidemia. Epigenetic effects of
alcohol have been suggested based on DNA methylation and histone acetylation in lipid
metabolism- and stress-responsive genes. A link between alcohol-induced epigenetic changes
with fat and glucose metabolism dys-regulation, resulting in the development of chronic
metabolic disorders has been suggested [56]. Drug abuse, including from illicit drugs cocaine
and opioids, also modifies gene expression through epigenetic reprogramming. For instance,
opioid use has been shown to modify DNA methylation patterns on genes associated with
energy production and fat deposition, resulting in obesity and insulin resistance.

The negative effects of addiction and substance abuse can be heritable, imposed on more
than one generation through changes in genetics. Cross-generational effects of addiction-
related epigenetic changes may implicate long-term consequences on metabolic health over
generations.

Table 2: Lifestyle factors and their epigenetic modifications impacting metabolic health

Lifestyle Examples Metabolic Health Epigenetic Modifications Ref

Factor Effects

Physical Aerobic exercise, Improves insulin [57]

Activity and Resistance sensitivity
DNA demethylation in
Exercise training, Yoga
genes involved in glucose
and fat metabolism (e.g.,
GLUT4)

Reduces Histone acetylation in

inflammation and genes regulating
oxidative stress mitochondrial function and
energy metabolism

Promotes fat Altered expression of

oxidation and microRNAs involved in
improves muscle adaptation and fat
cardiovascular
 health storage (e.g., miR-22)

Enhances muscle
mass and metabolic
flexibility

Stress, Sleep, Chronic stress, Insulin resistance DNA methylation changes [58]
and Sleep deprivation, in genes involved in
Circadian Shift work glucose metabolism (e.g.,
Rhythm glucocorticoid receptor
pathway)

Obesity and Histone modifications

metabolic syndrome affecting circadian clock
genes (e.g., PER, BMAL1)

Increased Altered microRNA

inflammation and expression in genes
cardiovascular risk controlling adipogenesis
and fat storage

Impaired appetite Disrupted Gene expression

regulation and fat involved in sleep-wake
storage cycle and metabolic
regulation

Addiction Tobacco smoking, Insulin resistance DNA methylation in genes [59]

and Alcohol and dyslipidemia related to adipogenesis and
Substance consumption, inflammation (e.g.,
Abuse Drug abuse PPARγ)

Fatty liver disease Histone modifications in

and metabolic genes related to lipid
disorders metabolism and stress
response

Obesity and Altered expression of

cardiovascular microRNAs that regulate
 diseases energy balance and
glucose metabolism

Impaired glucose Epigenetic inheritance of

and fat metabolism metabolic diseases across
generations

12.6. Epigenetic Modulation of Metabolic Disorders

12.6.1 Obesity and Insulin Resistance

Obesity and insulin resistance are closely related metabolic diseases under the influence of a
genetic predisposition associated with environmental factors. Epigenetic alterations,
including DNA methylation and histone modifications, have a key role in the regulation of
energy metabolism-, fat storage- and glucose homeostasis-related genes. For example, in the
gene encoding PPARγ, a master regulator of adipogenesis and lipid metabolism, DNA
methylation can induce fat mass accumulation and predispose individuals to obesity [60].
Environmental factors, including diet, can produce epigenetic changes that influence genes
responsible for appetite regulation and fat storage. Insulin resistance is also mediated by
epigenetic modifications in genes such as IRS1, which interfere with insulin signaling. In
addition, inflammatory response (a contributor to insulin resistance) is intensified by
epigenetic changes at pro-inflammatory genes such as TNF-α, intensifying the disposition
towards metabolic disorders [61].

12.6.2 Type 2 Diabetes

Type 2 diabetes (T2D) is characterized by defective insulin secretion and resistance, in the
pathogenesis of sin which epigenetic changes are involved. DNA methylation is a process
that modulates the expression of genes that are implicated in insulin production, including
the insulin gene and modifications in these patterns result in impaired insulin function.
Histone modification including histone hypo-acetylation at the GCK gene, inhibits glucose
uptake and worsens hyperglycaemia. miRNAs including miR-29, repress genes involved in
insulin secretion, and miR-146a participates in the inflammation associated with T2D. These
epigenetic changes suggest that there is the potential for new therapies that focus on the
epigenome to enhance insulin sensitivity and glucose homeostasis as a therapeutic strategy in
treating T2D [62].
12.6.3 Cardiovascular and Liver Diseases

Cardiovascular and liver disease development, which is commonly associated with metabolic
dysfunction, are to a large extent dependent on epigenetic alterations. These epigenetic
changes in genes associated with the metabolism of lipids, blood pressure regulatory
mechanisms, and inflammation in vasculature have pivotal role in CVDs including
atherosclerosis and hypertension. For instance, DNA methylation of a gene encoding LPL
impact lipid levels (leading to atherosclerosis) and genic histone modifications coding for
inflammation proteins such as MMPs drive CVD development. Similarly in liver, diseases
such as NAFLD and cirrhosis hepatic gene has a link to disturbed DNA methylation of
SREBP-1c which regulates the fatty acid synthesis (Figure 2). Rg1 is found to intervene in
chronic inflammation and oxidative stress, which both play important roles in the
development of liver disease and are modulated by epigenetic modification processes of
genes such as NF-κB and TGF-β. These epigenetic modifications represent targets for therapy
in cardiovascular and liver disease [63].

12.7. Epigenetic Biomarkers and Diagnostics

The application of epigenetic biomarkers has tremendous potential for early detection,
diagnosis and risk stratification of metabolic and chronic diseases. Alterations in the
epigenetic modifications of genes involved in glucose and lipid metabolism, such as PPARγ,
play a role in early development of obesity, type 2 diabetes and cardiovascular diseases.
Additionally, histone modifications and non-coding RNAs -including miR-146a and
MALAT1- are also being proposed as crucial markers for metabolic disorders and cancer
development. With the development of new technology, such as next-generation sequencing,
methylation-specific PCR and CRISPR-based epigenetic editing, the accuracy of the
epigenetic analysis has been largely improved. These tools, along with the application of AI
and machine learning, are elevating the resolution for diagnosis and profiling personalized
risk parameters to intervene early in treatment of chronic diseases [64].

12.8. Therapeutic and Preventive Approaches

12.8.1 Nutraceuticals and Dietary Interventions

Introduction Nutraceuticals, the bioactive components of food products, represents a major

opportunity to alter the epigenome to modulate metabolic health and disease prevention in
obesity, diabetes, cardiovascular disease (CVD) and cancer (1). They are able to modulate
gene expression via epigenetic pathways utrients essential for one-carbon metabolism and
DNA methylation such as folate, vitamins B6 and B12, and zinc play an important role in
regulating gene expression related to metabolic health. Polyphenolic compounds found in
fruit, vegetables and tea, including resveratrol from red wine, regulate histone acetylation and
DNA methylation and may be protective against age-related diseases as well as metabolic
syndrome. Omega-3 fats found in fatty fish, flaxseeds and walnuts are able to affect gene
expression by methylation of DNA and modifications in histones that helps lower
inflammation and the development of chronic diseases. The curcumin in turmeric also exerts
control over histone modifications and further demonstrates prospects on metabolic diseases.
With the help of these nutraceuticals, people can act proactively to naturally modify or
influence the most prominent part of their "epigenome" – allowing disease prevention and
promoting metabolic health [65].

12.8.2 Epigenetic Drugs and Lifestyle Modification

Epidrugs are drugs that alter the epigenome by inhibiting enzymes involved in modifying
DNA (DNMTs), deacetylating histones (HDACs), and methylating histones (HMTs) to
control gene expression. In case of 5-azacytidine, DNMT inhibitors are not only able to
restore incorrect DNA methylation patterns in cancer relevant genes but also have been
tested for diabetes and other metabolic disorders [66]. HDAC inhibitors, such as vorinostat
enhance gene expression by blocking histone deacetylation and represent a potential
treatment for metabolic disorders. HMT inhibitors currently being examined for cancer
treatment may be applied to normalize samplinks in metabolic disorders. Lifestyle alters,
such as exercise, stress and sleep intervention induced favourable epigenetic modifications
which are associated with the improvement of metabolic health. Physical activity helps
stimulate gene expression associated with fat metabolism and insulin sensitivity, while
reducing stress and getting adequate sleep assist in reversing epigenetic changes that make
you more susceptible to metabolic disease. An optimal strategy of epigenetic drugs in
combination with lifestyle interventions may enhance therapy efficiency and risk for disease
prevention [67].

12.8.3 Precision Medicine Approaches

Precision medicine personalizes an individualʼs treatments according to his or her genetic,

epigenetic, environmental, and lifestyle profile as it pertains to the treatment of metabolic
diseases such as diabetes, obesity and cardiovascular diseases. The role of epigenetic
profiling involving DNA methylation, histone modifications and non-coding RNA expression
is invaluable in the identification of high-risk profile patients for such diseases and
assessment of personalized therapy and prevention. Pharmacogenomics applies genetic and
epigenetic information to predict drug response, with the aim of devising effective treatment
plans while avoiding side effects. "Specific nutritional recommendations can be made based
on an individual's epigenetic profile that will further promote metabolic health." By
combining genetic, epigenetic and environmental information together, treatments can work
better to lower risk of disease and promote better general health [68].

12.9. Future Perspectives and Challenges

The epigenetic field has great potential in revealing the etiology of metabolic diseases and in
personalized medicine. Potential targets include the identification of neoteric epigenomic
biomarkers for early detection and diagnosis of diseases such as Obesity, Diabetes Mellitus
and Cardiovascular disease. Since DNMT and HDAC inhibitor therapy have promised to
treat metabolic diseases, personalized epigenetic medicine can individualize intervention
according to each personal epigenetic information [69]. Additionally, environmental
epigenetics will help prevent disease by determining how diet and stress influence the
epigenome. Integrating AI and machine learning with epigenetic information might
contribute to predicative models for personalized medicine. Nevertheless, complicated
matters such as the complexity of the epigenome, that epigenetic changes are reversible,
ethical issues, patient response heterogeneity and non-standardized tests for monitoring
epigenetic markers still remain. These problems will need to be addressed so that epigenetic
tools can fully be utilized in the clinic [70].

2.10. Conclusion

The form of epigenetics is gaining popularity as a framework to elucidate, among others, the
intricate relationship between genetics and metabolic health. Increased public appreciation of
how factors such as diet, stress, toxins or physical activity can alter the epigenome has
inspired an expanding field in the study of epigenetic controls in health and disease.
Epigenetic alterations, such as DNA methylation, histone modification, and non-coding RNA,
have been linked to metabolic illnesses such obesity, insulin resistance, type 2 diabetes, and
cardiovascular disease.

The interplay among environmental exposures, the epigenome and metabolism is dynamic;
lifestyle changes and exposure can modulate gene expression patterns and susceptibility to
develop metabolic diseases. Epigenetic markers represent promising biomarkers for early
detection, personalised interventions and prevention programmes; however, novel challenges
exist including the complexity of the epigenome and its modifications as well as clinical,
non-biased testing. Epigenetic treatments, together with other concepts such as precision
medicine and environmental modulation, could provide new personalized therapeutic
patterns. In the future, nutraceuticals, diet changes and epigenetic therapies could improve
metabolic health beyond current treatment options. Finally, further unraveling the impact of
environmental signals on the epigenome and its crosstalk with metabolic networks will be
very important for identifying new targets to envisage effective therapeutic strategies such as
those based on precision medicine, placing the epigenetic regulation central within future
prevention and precision medicine on metabolism- and chronic disease-related disorders.

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