Authors: Alfonso D. Silva-Ochoa, Erick Velasteguí, Isaac B. Falconí, Valeria I. García-Solorzano, Angie Rendón-Riofrio, Gabriela A. Sanguña-Soliz, Wim Vanden Berghe, Andrea Orellana-Manzano
Categories: Review Article, Diabetes, Epigenetics, Metabolic syndrome, Nutrition, Obesity
Source: Heliyon
Metabolic syndrome is a cluster of conditions that results from the interplay of genetic and environmental factors, which increase the comorbidity risk of obesity, hyperglycemia, dyslipidemia, arterial hypertension, stroke, and cardiovascular disease. In this article, we review various high-impact studies which link epigenetics with metabolic syndrome by comparing each study population, methylation effects, and strengths and weaknesses of each research. We also discuss world statistical data on metabolic syndrome incidence in developing countries where the metabolic syndrome is common condition that has significant public health implications.
Keywords: Nutrition, Epigenetics, Metabolic syndrome, Obesity, Diabetes
Metabolic syndrome is a complex group of conditions typically characterized by insulin resistance, or abdominal obesity, hyperglycemia, dyslipidemia, and arterial hypertension [1], which promotes chronic comorbidity diseases such as type II diabetes, cardiovascular diseases, and cancers or can elicit intergenerational epigenetic alterations in prenatal growth [2].
A low birth weight caused by malnutrition during pregnancy can also increase the risk of metabolic syndrome and cardiovascular disease in the offspring's adulthood, since metabolic rates are imprinted during embryogenesis, poor conditions during this period lead to the fetus acquiring a conservative metabolism that may not match with metabolic rates after birth when a sufficient diet is available [3,4]. Nutrition can also directly influence DNA methylation and development by changing methyl donor concentrations of S-adenosylmethionine [5]. Global hypomethylation has been shown to lead to chromosomal instabilities, such as rearrangements or translocations [6]. On the other hand, hypermethylation of CpG islands can lead to tumor suppressor gene silencing and predispose to cancer [6]. In addition, there are many non-hereditary genetic disorders, such as Prader-Willi syndrome (PWS), Angelman syndrome (AS), Beckwith-Wiedemann syndrome (BWS), Rett syndrome (RTT), and ICF syndrome, which are caused by genetic defects, causing epigenetic dysfunctions [7].
Epigenetics study how lifestyle conditions of individuals chemically modify genetic sequences and gene expression instructions through DNA methylation without changing the genetic code [8,9]. An illustration of the long-term impact of nutrition in epigenetics is the Dutch hunger winter in 1944 during the second world war. The Dutch women, including their neonates, suffered from an extreme undernutrition period of six months during pregnancy. Half a century later, children and grandchildren revealed twice the incidence of cardiovascular diseases, metabolic disorders, or cancer [10].
Malnutrition and starvation can also affect maternal and paternal imprinted genes, even with the programmed demethylation process.
GWAS studies have identified multiple genetic risk factors and structural variants involved in the development of metabolic diseases, a study in overweight children who exceeded adult weight (>80 kg) was found to fail to express leptin, a hormone that regulates the appetite [11]. This phenomenon was due to structural variants and not epigenetic modifications. Other studies revealed that people with two copies of the FTO gene have a higher body weight, around 3 kg more on average. The gene is linked to increased ghrelin levels [12]. Our genetic code is estimated to be responsible for between 40 and 70 % phenotypic variation in metabolic health [13], which environmental lifestyle factors can further modulate via an epigenetic mechanism. By studying how changes in gene expression, influenced by genetic modifications, may contribute to metabolic disorders, potencial advancements in the field could be made.
One of the most studied examples of medical relevance and history in epigenetics and nutrition occurred in 1944 during the “Hongerwinter” in Europe, particularly in the Netherlands. For a year, the German sociopolitical disputes deprived an entire country of food, causing thousands of deaths due to starvation [14]. This “starvation” generated a phenomenon of epigenetic change in those pregnant mothers who survived and transmitted a tendency to obesity to their offspring, particularly those who were already pregnant at the beginning of the famine [53,67]. This is due to the genome during embryogenesis and years later allows us to find a direct correlation between an individual's epigenome and their parents' lifestyle [11].
The Developmental Origins of Health and Disease (DOHaD) theory studies how early experiences and exposures, particularly during prenatal and early childhood, impact future health and disease. Environmental factors during critical development can program the organism, leading to long-term changes in structure, function, and gene expression. Research focuses on maternal nutrition, prenatal stress, chemical exposure, and intrauterine environment quality [68].
Epigenetic modifications are involved in phenotype transmission and predisposition to complex human diseases, including obesity and type 2 diabetes [15]. Methylation patterns can be inherited or influenced by the environment and can be highly stable. Recent studies showed that genetic variation and polymorphisms could also regulate DNA methylation changes in cis/trans via so-called methylation quantitative trait loci (mQTLs) [[16], [17], [18]]. DNA methylation in proximal promoter and enhancer regions has silencing effects on gene transcription. Meanwhile, DNA methylation in the gene body might stimulate transcriptional elongation and contribute to alternative splicing events [19].
Aging has been related to the onset of several chronic diseases due to cumulative epigenetic DNA methylation changes, and therefore, tools that estimate relative epigenetic aging speed have become very valuable as predictors of an individual's health status [20]. The main developed epigenetic clock models are Hannum's, Horvath's, and Weidner's [21]. However, some inconsistencies have been discovered between clock models when predicting the onset of various chronic diseases. This could be due to the model's limitation and tissue specificity indicating that DNA methylation age is not a universal health-disease marker [21]. Nevertheless, DNA methylation age may better estimate biological age than chronological age and may indirectly be a promising marker for health and disease status [22]. Although lifestyle factors, like stress and diet, impact the DNA methylation age, prolonged longitudinal studies in big cohorts of different ethnicities may be required to identify significant effects [21].
Lifelong environmental factors (e.g., salt intake, obesity, alcohol) and genetic factors contribute to the development of hypertension (Table 2). However, it has also been established that stress in utero may ‘program’ the later development of hypertension disease [24]. Angiotensin type 1 receptor (AT1R) plays a vital role in the renin-angiotensin-aldosterone system (RAAS) in blood pressure regulation [23]. A study with rats suggested that age and blood pressure affect CpG methylation in the promoter region of the AT1aR [24]. Systemic low-level inflammation is another common characteristic of older adults that may alter their response to infections [25].
Short-chain fatty acids (SCFAs) are among the main classes of bacterial metabolic products and are mainly synthesized in the colon through bacterial fermentation [54]. SCFAs mainly involve acetate, propionate, and butyrate (Fig. 1). Studies have shown that microbial metabolites, folate, B vitamins, and short-chain fatty acids interact with miRNAs to influence obesity phenotypes [55]. SCFAs generated by gastrointestinal microbiota significantly reduced resting angiotensin-converting enzyme 2 (ACE2) expression in cultured airway epithelial cells [56]. The oral administration of SCFAs in pigs can down-regulate the mRNA expressions of fatty acid synthase (FAS) and sterol regulatory element binding protein 1c and enhance the mRNA expression of carnitine palmitoyltransferase-1α (CPT-1α) in the liver. SCFAs can also decrease FAS, acetyl-CoA carboxylase (ACC), and peroxisome proliferator-activated receptor σ mRNA expressions in longissimus dorsi (add refs). In abdominal fat, SCFAs can reduce FAS and ACC mRNA expressions and increase CPT-1α mRNA expression [57].
Fig. 1 Correlation between the bioactive compounds, diet, and epigenetics modification in metabolic syndrome. The presence or absence of nutrients and bioactive compounds in the diet has been associated with epigenetic modifications in genes that regulate metabolic processes such as CORO7, PCSK, miRNAs, UPC1, and ACE. These genes' influence could lead to the predisposition to develop metabolic disorders and cancer.
Butyrate and propionate, produced in the intestine by the fermentation of dietary fiber, inhibit histone deacetylase enzymes, which increase histone acetylation and gene expression [58]. Butyrate indirectly regulates the activity of critical enzymes such as methylcytosine dioxygenase (TET) and DNA methyltransferase (DNMT1), thus modifying DNA methylation [59]. In addition, it can be oxidized to acetyl-CoA, therefore, it could increase histone acetylation, which occurs when an acetyl group is added to lysine residues in the N-terminal tails of histone proteins [60]. The presence or absence of nutrients and bioactive compounds in the diet is related to epigenetic modifications in genes that regulate metabolic processes such as CORO7, PCSK, miRNAs, UPC1, and ACE (Fig. 1). These genes' influence could lead to the predisposition to develop metabolic disorders and cancer.
During glycolysis, acetyl-CoA is derived from the catabolism of carbohydrates, lipids, and proteins in the mitochondria. Once formed, acetyl-CoA donates acetyl groups giving way to histone acetylation. This modification creates a more relaxed and open histone configuration, leading to the binding of transcription factors and RNA polymerase, increasing gene transcription levels [61].
The metabolite S-adenosylmethionine (SAM) is an essential methyldonor in cell differentiation and survival, regulating key metabolic pathways, including methylation and polyamine synthesis [62,63]. The excess of SAM catabolizes adenine and methylthioadenosine, which behave as toxic methylation inhibitors [63]. Table 1 provides some of the epigenetic studies performed in pacients with metabolic syndrome, methylation being specifically examined, the MetS component investigated, as well as the associated advantages and disadvantages of these studies.
The “thrifty gene” hypothesis suggested that people predisposed to obesity and type 2 diabetes might belong to a human subgroup more adapted to storing nutrients, increasing their chances of surviving during a famine [35]. Over the past six decades, extensive GWAS studies have established an undeniable relationship between an individual's metabolic disorder and genetic makeup [36]. Evaluating the global incidence of metabolic syndrome presents a complex challenge due to the diverse social and economic factors that impact the nutritional status of populations. Enclosed below is a listing of countries and their corresponding MetS prevalence index. Table 2 summarizes the global statistics in various metabolic syndrome categories and age groups, along with a brief description of each study approach.
The correlation between the economic level and the prevalence of Metabolic Syndrome in the listed countries is robust. It has been observed that areas with lower incomes are at a higher risk of developing the cluster of symptoms associated with this disorder (Table 2). This provides insight into the dietary habits of each region. Interestingly, while developed countries have a higher incidence of obesity, less developed regions and countries are at a greater risk of Metabolic Syndrome.
Increasing evidence indicates that non-DNA sequence-based epigenetic information can be inherited across several generations in organisms ranging from yeast to plants to humans. This raises the possibility of heritable ‘epimutations’ contributing to heritable phenotypic variation and, thus, to evolution [64]. Transgenerational epigenetic changes induced by hypoxia can result in permanent changes early in fetal development [66]. For instance, polyphenols can inhibit endothelial dysfunction when considering dyslipidemias at the molecular level because they reduce oxidative stress and increase Nitric Oxide (NO) production [65]. Dietary polyphenols are key in modulating epigenetic-sensitive mechanisms involved in vascular endothelium homeostasis. An example is revestratol, a polyphenol usually found in diets via fruits and vegetables. Revestratol influences the activity of histone-modifying enzymes and DNA methyltransferases, contributing to epigenetic modifications [69].
Interestingly, a pleiotropic SNP (rs964184) harbored in the ZPR1 zinc finger (ZNF259) gene resulted in cis-associated with the expression of the proprotein convertase subtilisin/kexin type 7 (PCSK7) gene promoting the interindividual variation in LDL-C, HDL-C, and TAG plasma levels suggesting a novel therapeutic target, Table 1. Despite the increasing knowledge on lipidome-related molecular perturbations at early and late stages of life and how the infant can keep dysregulated epigenetics marks established during that time and alter their lipid metabolism [70], current risk assessment and pharmacological management of dyslipidemias are not satisfying [66].
Recent research has indicated that the ACE gene could notably impact METS, mainly when regulating blood pressure during exercise and releasing Nitric Oxide (NO), Table 1. It has been discovered that the insertion/deletion polymorphism (rs4646994) of this gene has a strong correlation with a reduction in NO release, lower hypertension rates, and increased levels of angiotensin-converting enzyme [46].
Research on the Saudi population has found that the UCP1 gene plays a significant role in energy metabolism and is linked to obesity, Table 1. Two variations, known as rs1800592 and rs3811791, have been associated with moderate obesity and affect the availability of functional proteins, impacting oxidative phosphorylation and energy expenditure [47].
Proprotein Convertase Subtilisin/Kexin Type 1 (PCSK1 or PC1/3) has been associated with obesity, body mass index, birth weight, and proinsulin levels [50]. Rare mutations in PCSK1 have also been implicated in early monogenic obesity. Null mutations in the PCSK1 gene can cause morbid obesity, hypoadrenalism, hypogonadism, bowel dysfunction, hyperphagia, impaired proinsulin-insulin ratio, postprandial hypoglycemia, and diabetes insipidus [48]. A deficiency in PC1/3 activity has severe gastrointestinal consequences from birth, including recurrent watery diarrhea, weight loss, dehydration, and metabolic acidosis. In addition, they resulted in hospitalization and parenteral nutrition, Table 1.
In certain instances, children may pass away during their early years. Although intestinal biopsies indicate no visible abnormalities, there is a notable failure to absorb fats and amino acids. Despite the intestine's structural soundness and preserved villous architecture, this lack of absorption is severe [49].
The human gene Coronin7 (CORO7 or CRN7) acts as a POD1 analog and regulates metabolic balance and body weight by controlling the central feeding circuits, CpG islands near the CORO7 promoters exhibit lower methylation in overweight children, leading to higher CORO7 expression [50]. In contrast, in rats, reduced food intake resulted in decreased expression of this gene, which is associated with decreased appetite stimulation [50]. The relationship between dietary patterns and the expression of CORO7 was observed in regions of the brain responsible for regulating energy balance, such as the hypothalamus, which is particularly sensitive to feeding behaviors [51].
Susceptibility to metabolic disorder, in part, is determined by an individual's genome configuration, which hosts MetS risk alleles and/or SNPs.
New studies have also identified the significant complementary contribution of environmental lifestyle factors, which further propagate MetS risk via epigenetic DNA methylation silencing mechanisms. However, further research is required to untangle the genetic-epigenetic crosstalk in MetS. The high costs of investigating allelic variants and an individual's epigenome in big cohort studies pose a logistic socioeconomic challenge in developing countries with an increased incidence of malnutrition. New, cost-effective 4th-generation sequencing technologies may create new opportunities for the combined identification of allelic variants in long sequences and methylated cytokines in epigenetics without bisulfite conversion [52].
Population (epi)genetics studies can provide valuable insights into metabolic disorders, their prevalence, and their potential impact on future generations. By identifying epigenetic variants within a population, public health and prevention systems can be tailored to improve the quality of life and reduce the costs associated with treating metabolic disorders. Given the unique nutritional needs and epigenetic effects of different countries and demographics, conducting these studies within each population is essential.
All authors listed have significantly contributed to this article's development and writing.
Data included in article/supp. Material/referenced in article.
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
The authors thank VLIR-UOS and ESPOL University.
Alfonso D. Silva-Ochoa, Email: adsilva@espol.edu.ec.
Erick Velasteguí, Email: erick.velastegui@epn.edu.ec.
Isaac B. Falconí, Email: ifalconi@espol.edu.ec.
Valeria I. García-Solorzano, Email: vagasolo@espol.edu.ec.
Angie Rendón-Riofrio, Email: avrendon@espol.edu.ec.
Gabriela A. Sanguña-Soliz, Email: gsanguna@espol.edu.ec.
Wim Vanden Berghe, Email: wim.vandenberghe@uantwerpen.be.
Andrea Orellana-Manzano, Email: akorella@espol.edu.ec.
Data included in article/supp. Material/referenced in article.