Obesity is a rapidly increasing epidemic disease worldwide. Nearly 39% of adults (aged 18 years and over) are overweight (BMI 25–30 kg/m2) and 13% suffer from obesity (BMI >30 kg/m2) and from comorbidities (1). At least 2.8 million people worldwide die each year as a result of being overweight or obese. High body weight increases blood pressure, cholesterol, triglycerides and insulin resistance, resulting in a higher risk for coronary heart disease, ischemic stroke and type 2 diabetes mellitus, as well as an increased risk for cancer (2). However, obesity is not only attributable to a genetic-driven imbalance between energy uptake and energy expenditure, although many genetic loci have been identified. Rather, an interplay between many systems is implicated, such as unbalanced energy uptake, gene mutations, an aberrant gut microbiota and epigenetics (3, 4). In recent years, many efforts have been undertaken to study epigenetic mechanisms and their influence on genes and their expression (5), as well as environmental factors, including nutrition and the developmental origins of obesity.
Epigenetic modifications are stable heritable patterns of gene expression occurring without changes in the DNA sequence. They include interacting components at the transcriptional level (DNA methylation and histone modifications) and at the posttranscriptional level – RNA interference (5–12) – which are modified by internal factors (e.g. inherited mutations, metabolic pathways, neuroendocrine balance, hormonal activities) and external factors (e.g. nutrients, bioactive food components, medication, tobacco, radiation, infectious organisms, stress) (7). The term ‘obesogens’, reviewed by Skinner et al. (2011), describes all the environmental factors and dietary, pharmaceutical and industrial compounds that have a potential role in the development of obesity or metabolic disease in the offspring by affecting the number of fat cells, or the size of fat cells, the hormones influencing appetite, satiety, food preferences and energy metabolism (13). Chemical pesticides in food and water, e.g. dicholorodiphenyldichloroethylene (14), bisphenol A (15), diethylstilbestrol (16), pharmaceuticals such as the diabetes drug Avandia® (rosigliatazone), are already linked to weight gain. Mechanisms of dietary factors modifying epigenetic marks are under study (17). In this context, nutrients and other food components, e.g. the soy phytoestrogen genistein (18) and monosodium glutamate (19), are among the factors that have been associated with epigenetic modifications in obesity. Most of the epigenetic modifying enzymes require nutrients or their metabolites as substrates or cofactors, thus dietary composition and bioactive nutrients are of current research interest. In addition, intergenerational, transgenerational and prenatal effects must be taken into account. Caloric restriction of parents and also grandparents is already known to increase the risk of metabolic disorders in offspring reaching adulthood (20). Whereas, a high-fat diet either strongly influences epigenetic modifications to induce metabolic stress, resulting in obesity, insulin resistance, diabetes and cardiovascular disease (21). Thus, previous generations are suggested to increase the risk of obesity or type 2 diabetes for their offspring through genetic and/or epigenetic mechanisms. Although there is no possibility to modify the genetic basis, we can change our epigenome: e.g. a healthy diet and exercise are suggested as sufficient to change the epigenome (22). More information is available on the evidence of specific nutrients (e.g. folate, butyrate, secondary plant metabolites) in obesity-mediated inflammation and oxidative stress, as well as other metabolic syndrome-related diseases including type 2 diabetes, atherosclerosis and hypertension (23). Methyl donors like folate and SAM (S-Adenosylmethionin) alter the methylation of the DNA and histones. Curcumin, genistein, epigallocatechin gallate (EGCG), resveratrol and equol inhibit DNMT (DNA methyltransferase) activity (24–27). Dietary components such as butyrate, sulforaphane, resveratrol and diallyl sulfide inhibit histone deacetylases (HDAC) and curcumin inhibits histone acetyltransferase (HAT) activities (7). However, a precise breakdown of these activities is not possible as the effects depend on the nutrients’ structure, nutrient interaction and interaction with other lifestyle factors (7). In addition, epigenetic patterns occur as a result of developmental and regenerative processes, with tissue specificity reflecting the temporary gene expression (28). The epigenetic pattern is the result of the interdependent interactions of methylation, miRNAs and histone modifications (29). Methylation in a promoter or other regulatory region of a gene is usually associated with repressed gene transcription (29) by blocking transcription factor binding (30), whereas DNA demethylation (hypomethylation) is suggested to induce gene activation. In the case of histone acetylation combined with an open chromatin structure and transcriptional activation, a high level of acetylation combined with rapid deacetylation has been indicated as an important factor (31).
In the present review we focus on nutrients, diets and habits influencing intergenerational, transgenerational, prenatal and postnatal epigenetics (Table 1); on evidence of epigenetic modifiers in adulthood (Table 2); and on animal models for the study of obesity, as the understanding of epigenetic patterns in metabolic syndrome might provide invaluable evidence for prevention, diagnosis and development of future therapeutic interventions.
Evidence for intergenerational and transgenerational inheritance
Epigenetic modifications are already accepted to have a critical role in the regulation of gene expression, but in general a deletion and re-establishment in each generation has been suggested. After fertilization, the global DNA methylation is thought to be reduced to ±10% (32); the occurrence of histone modifications is unknown. These phenomena make the offspring susceptible to parents’ or even grandparents’ behaviors, extending their responsibility over generations (33). The grandmother’s nutrition might be recurring to influence cardiovascular disease, type 2 diabetes, or hypertension in adulthood of the offspring because of transmission in utero, although little is known about imprint establishment or deletion down the male line (34). However, most of the studies only include the F0–F2 generation, but not the F3 generation, although the term ‘transgenerational inheritance’ refers to the F3 generation and up as the F1 and F2 generations are exposed in utero of the F0 generation as a fetus or as the germline of a fetus. Thus, the F1 and the F2 generation are suggested to be described as ‘intergenerational epigenetic inheritance’ and only the F3 generation and up shall be considered as ‘transgenerational inheritance’ (Figure 1) (35).
The most prominent human study was of the Dutch famine of 1944, in which starvation in one generation affected the health of their grandchildren. Painter et al. (2008) did not observe intergenerational inheritance after prenatal exposure to famine on metabolic disease rate nor on birth weight. This F1 generation was associated with higher F2 neonatal adiposity and poor health in adulthood (20). Data collected in the Överkalix parish in northern Sweden in 1890, 1905 and 1920 and continuing until death or 1995 are one of the first picking up the epigenetic hypothesis, suggesting that overeating during the child’s slow growth period (before prepubertal peak in growth velocity) was an important factor in the offspring’s risk of death from cardiovascular diseases and diabetes. Reduced dietary availability during the father’s slow growth period lowered the risk for cardiovascular diseases. Excessive food intake of the paternal grandfather during their slow growth period induced higher diabetes prevalence and shortened the life-span, whereas food scarcity extended the life-span (36).
In mice an impaired glucose tolerance in the F1 and F2 generation has been shown to be associated with the paternal over-nutrition in the F0 generation (37). Paternal exposed F0 generation to a high-fat diet also induced the epigenome of sperm via increased acetylation and differential microRNA content in further generations (38). A low-protein diet in the F0 generation also transmitted changes in DNA methylation in liver cell loci (e.g. involved in lipid metabolism) via the paternal line (39).
Due to transmission via the maternal line, a high-fat diet showed adverse effects in the F2 generation compared to F1, namely higher cardiovascular risk (40). F1 males exposed to maternal high-fat diet in the F0 generation transmit impaired glucose tolerance to the F3 generation (41). Under-nutrition in the maternal line decreased beta cell mass in the F1 as well as the F2 generation (42) and showed impaired glucose/insulin metabolism (43). In comparison a female protein restriction showed effects on glucose and insulin metabolism (44–46), adiposity (46), DNA methylation in the liver (47), pancreatic islet mass (48) and cardiovascular effects (49, 50).
Studies of transgenerational inheritance in the F3 generation are variable, with conflicting results as well as difficulties in interpretation when further interventions are applied to F1 generations. An increased insulin/glucose ratio persisted in the F3 generation due to protein restriction during pregnancy even though a decreased insulin/glucose ratio compared to controls was observed in the F1 generation (51). Protein restriction in the F0 generation, with normal diet due to generations F1–F3, produced an F3 generation with reduced basal insulin levels and decreased pancreatic beta cell mass (48). Others showed only effects from the F0–F2 generation with no persistence in F3 (50–52). In contrast, experiments on rats with persistent high-fat diet exposure over three generations showed epigenetic changes in all exposed generations. However, a reprogramming in each generation cannot be excluded (53).
Exposure of the F0 generation to potent endocrine disruptors (vinclozolin and methoxychlor; fungicides and pesticides) induced alterations of DNA methylation patterns in the male gametes persisting in the F3 generation (54). Little evidence exists about transgenerational effects of histone modifications (55) or of miRNAs. Additionally, the majority of environmental factors and exposures interact with somatic cells and tissues and thus are critical for adult-onset diseases rather than for their offspring. Only the maternal transgenerational epigenetic inheritance includes effects of the intrauterine environment, of the age of pregnancy, somatic epigenetics and mitochondrial programming (35). For the further research it is of interest to acquire knowledge about the exact mechanism of epigenetic inheritance and to identify molecular patterns that are either transmitted or deleted between the generations. However, the epigenetic memory might fill the gap of missing genetic heritability for complex diseases such as obesity, schizophrenia, but also longevity.
Evidence of prenatal epigenetic influences
It is well known that the prenatal period is crucial in the establishment of the epigenome (21, 56–58). One of the most critical processes during pregnancy is the establishment of imprinted genes. Caloric availability as well as metabolic status of the mother during this period can influence the programming of imprinted genes and the development of metabolic disease and obesity in the offspring (59). The earlier discussed risk factors such as parental obesity or malnourishment as well as obesogen exposure have compelling connections to changes in the epigenetic environment of the embryo leading to an increased risk for obesity and metabolic disease in the offspring (57).
The agouti viable yellow mouse (Avy) model, in which coat color variation is correlated with epigenetic patterns and whose heavily overweight phenotype facilitates diabetes development, has been one of the first models employed for investigating the impacts of nutritional and environmental influences on the fetal epigenome. The Avy genotype is characterized by the presence of a transposon upstream of the agouti gene promoter that predisposes hyperphagia in obese mice. In this model, expression and DNA methylation of the agouti gene are correlated with the coat color when supplementing the mother during pregnancy with a promethylation cocktail (methionine, choline, folic acid and vitamin B12). The administration of these substances increases the methylation of the upstream IAP (intracisternal A-particle) transposable element, which in turn leads to the reactivation of the agouti gene altering the coat color and suppressing an obese phenotype in their offspring (60–62). Dolinoy et al. (2006) have shown that maternal supplementation with genistein (250 mg/kg) during pregnancy protected offspring against obesity in agouti mice (27). Mouse models have shown that the increase in maternal energy-dense diet (high-fat, high-sugar) leads to increased expression and hypomethylation in the promoter region of central signaling molecules such as dopamine reuptake transporter (DAT), μ-opioid receptor (MOR), preproenkephalin(PENK) and leptin in the offspring, correlating with an increase in obesity (55). A study on rats has also shown that HFD during the pregnancy causes changes in the DNA methylation in the imprinted gene agouti related protein homolog (AgRP) in the hypothalamic arcuate nucleus (ARC), which plays a role in the regulation of energy balance leading to an increased obesity risk (63). Furthermore the development of gestational diabetes mellitus contributes to increased insulin in the embryo in response to increased intrauterine glucose levels. This induces hypermethylation of the insulin-like growth factor 2 (IGF2) promoter region leading to down-regulation of this gene and impaired insulin secretion, making the offspring more susceptible to obesity and metabolic syndrome (64).
Other contributors to the obesity epidemic are obesogens that influence the establishment of an epigenetic equilibrium during the pregnancy. Some of these have already been well studied: TBT (tributyltin hydride) is implicated in the disruption of endocrine signaling and leads to an increased adipocyte differentiation, especially in the mesenchymal stem cell compartment through epigenetic imprinting in vitro and an increase in adipose tissue mass in a mouse model (56). Mice treated with high levels of phytoestrogens during pregnancy gave birth to offspring more susceptible to estrogen exposure upon which they showed sex-specific changes in the methylation of the Acta1 promoter region (65). Another obesogen is BPA (bisphenol A), which in pregnant agouti mice decreases CpG methylation on an IAP retrotransposon upstream of the Agouti gene in the offspring. This effect could be reversed upon supplementation with methyl donors or a phytoestrogen to the diet (66). Supplementation of vitamin B12 and folate in physiological amounts in sheep during gestation leads to an increase in body weight and insulin resistance in adult offspring and this is closely associated with an increase in genome wide DNA methylation, most notably in male subjects (67).
Infants have an innate sense of satiation and hunger; thus aberrations during the embryogenesis are suggested as crucial in the development of childhood obesity and also to play a role in the development of adult obesity and metabolic disease (68). This can be explained through an increase of caloric availability, decreasing the competition for energy during pregnancy and in turn favoring the development of adipocytes and β-cells over other cell types, leading to increased birth weight and infant obesity. This tendency for heightened birth weight is further increased due to the rise in frequency of cesarean sections, which eliminates the evolutionary disadvantage of oversized newborns during birth (58). DNA methylation has been established as one of the best epigenetic marker for the prediction of the development of obesity. In particular, aberrations in the early establishment of imprinted genes seem to predict quite accurately the development of metabolic syndrome in the offspring of obese parents (69). On the one hand there is a clear link between maternal obesity and its effects on childhood obesity, but on the other hand malnourishment of the mother during the pregnancy also favors obesity (70). One of the best-studied examples of the effects of malnutrition during gestation on the offspring is the Dutch Hunger Winter. This study investigated the events during the famine of 1944–1945 in the Netherlands and showed a compelling link between decreased caloric intake and the subsequent increase in metabolic disease and obesity in the following generation (71). A more recent example is a study of the effects of decreased nutrient intake during a famine in Gambia (72). It suggests a correlation between the reduction of caloric intake during preconception and the phenotype of the offspring. This malnourishment leads to a reduction in methylation in two imprinted genes in a sex-specific manner, namely the insulin-like growth factor 2 receptor (IGF2R) in female offspring and the Gon-Two Like (TRP subfamily) (GTL2-2) in male offspring. These two genes have important roles in the regulation of blood glucose levels and in growth, respectively (73). This link between maternal caloric intake and child development can be explained by the ‘thrifty phenotype hypothesis’, which states that there is a connection between poor growth in utero and in infancy and an increased risk to develop metabolic disease and obesity later in life if metabolic homeostasis is disrupted due to high caloric abundance (33). Studies in humans on exposure to obesogenic substances showed an increased obesity risk. One example is prenatal exposure to polycyclic aromatic hydrocarbon (PAH), which increased the incidence of obesity in the offspring. It also increased the expression of peroxisome proliferative activated gamma (PPAR γ), CCAAT/enhancer binding protein alpha (C/EBPα), cytochrome C oxidase assembly factor (Cox2), Fas cell surface death receptor (FAS) and adiponectin and resulted in lower DNA methylation of PPAR γ (74). In addition, BPA was found to increase the expression of FABP4 and CD36, which play an important role in lipid metabolism while at the same time downregulating PCSK, a gene influencing insulin production indicating that the exposure to BPA deregulates the metabolism, which increases the risk to develop metabolic syndrome later on in life (75).
Evidence of epigenetic modifiers in humans
A growing number of studies have investigated DNA methylation in different DNA regions associated not only with obesity but also with weight loss interventions. A recent study published by Dick et al. (2014) investigated 485,000 CpG-sites with the Infinium Human Methylation 450 array (Illumina, USA) (76). Whole blood samples of 479 individuals and two replication cohorts with a total of 2128 participants were analyzed. Analysis between BMI and the methylation state of the investigated CpG-sites showed positive correlations in all three cohorts between three CpG-sites in the first intron of the hypoxia-inducible factor 3α (HIF3A)-gene and the BMI of the study participants. Although the increased methylation state might only be a consequence of the increased BMI rather than a cause, or it is possible that other confounding factors might influence the BMI and the methylation state of the identified CpG-sites. A comparison of obese and lean study groups is missing (76).
A study performed with the same array platform by (77) compared differentially methylated CpG-sites (based on mean statistics) and differentially variable CpG-sites (based on variance statistics) in blood samples of 48 obese and lean youths. They found that the CpG methylation in obese participants was more variable than in the lean controls. Furthermore, they showed that the differentially variable CpG-sites as well as the differentially methylated CpG-sites could predict the obesity status of another sample set (78). Feinberg et al. (2010) analyzed 4.5 million CpG-sites in whole blood of 74 individuals at two time points 11 years apart. Four CpG-sites were identified that correlate with BMI in the same strength and direction at both sampling time points. These methylation sites were in or near the genes peptidase M20 domain containing 1 (PM20D1), matrix metallopeptidase 9 (MMP9), cGMP dependent protein kinase type 1 (PRKG1) and replication factor C subunit 5 (RFC5). In total, they identified variably methylated regions in or near 13 genes that correlated with the BMI at both investigated time points and many of which have been described to be involved in obesity or diabetes in earlier studies (79).
Yeon Kyung Na et al. (2014) investigated the methylation status of the Alu elements as a marker for global methylation in blood of 244 Korean women. A U-shaped distribution of methylation levels has been identified, with overweight women (BMI 25–30 kg/m2) having the lowest methylation levels and lean (BMI<25 kg/m2) and obese (BMI>30 kg/m2) individuals showing higher methylation levels. These interesting results need further investigation to elucidate the underlying mechanisms. The authors also draw comparison with the U-shaped association between BMI and overall mortality, which is lowest in a BMI range between 22 and 26 kg/m2 and a biphasic dose-response-model for toxins but they did not suggest an explanation for their result. They excluded cofounders such as age, smoking and alcohol consumption but maybe effects of physical activity or inflammatory processes are responsible for the U-shaped methylation curve (80).
Despite differences in the methylation level of CpG-sites between overweight or obese and lean individuals, several studies published in recent years have investigated the changes of methylation during weight reduction. The results of these studies showed either methylation changes occurring during the weight loss or differences in the baseline methylation levels between individuals who successfully lose weight and those who do not. Campion et al. (2009) suggested the methylation of distinct CpG-sites in the promoter region of the tumor necrosis factor alpha (TNF-α) gene as a predictive biomarker for weight loss response in a caloric restricted diet (81). Moleres et al. (2013) investigated blood samples of 107 overweight individuals undergoing a 10-week weight loss intervention. Differences in the methylation level of five regions between low and high responders before the start of the intervention were identified. These CpG-sites were located near or in the genes aquaporin 9 (AQP9), dual specificity phosphatase 22 (DUSP22), homeodomain interacting protein kinase 3 (HIPK3), troponin T type 1 (TNNT1) and troponin I type 3 (TNNI3) (82). Another study indicated 1034 differentially methylated CpG-sites between high and low responders to weight loss before the start of the intervention. After 8 weeks of caloric restriction the methylation level of 15 CpG-sites was still significantly different. Detailed analyses revealed CpG-sites on the genes ATPase class V type 10A (ATP10A) and CD44 as a possible biomarker for weight loss prediction (83). A small number of studies have focused on changes in DNA methylation during weight loss after bariatric surgery. For example, the statistic distance between promoter methylation of 11 obese and 16 normal-weight patients was reduced 6 months after a Roux-En Y gastric bypass surgery compared to distance before the intervention. Furthermore, 51 promoters were differentially methylated before and 6 months after the surgery. However, if these results were adjusted for weight loss and fasting plasma glucose only one promoter methylation was still significant different. The authors suggest that the surgery-induced changes in weight and fasting glucose may be responsible for the changes in DNA methylation (84).
Histone modifications have not been studied extensively in humans in association with obesity as DNA methylation because more complex methods and more sample materials are required. The role of histone modifications, especially methylation and acetylation, in adipogenesis and adipocyte differentiation has been mainly investigated in mouse models (85, 86).
In contrast to histone modifications, recent studies have investigated miRNAs in association with obesity. The miRNA pattern in the plasma of obese men and patients with surgery-induced weight loss indicated significant differences in 18 miRNAs between obese and lean individuals. The miRNAs miR-126, miR-140-5p, miR-142-3p and miR-222 were increased in plasma from obese men, whereas miR-15a, miR-21, miR-122, miR-125b, miR-130b, miR-193a-5p, miR-221, miR423-5p, miR-483-5p, miR-520c-3p, miR-532-5p, miR-590-5p, miR-625 and miR-625 were decreased. After surgery-induced weight loss the plasma level of 14 miRNAs had changed significantly after 1 year (87). Further, gender-specific differences in the miRNA profile of obese individuals were shown and miR-125a-3p was more highly expressed in men than in women. The higher levels of miR-125-3p in adipose tissue correlated with the expression of insulin-signaling related genes (88).
Data from mouse and cell-culture studies suggest an important role of diverse miRNAs in the differentiation of adipocytes and thus in adipogenesis and a variety of differences in epigenetic modifications between obese and lean individuals and changes during weight loss have been indicated.
Animal models of epigenetic modifiers in obesity
The main dietary strategies considered in the study of epigenetic changes are high-fat diets and energy-restricted or low-protein diets in animal models and also diets supplemented with specific nutrients including micronutrients and other food components (bioactive compounds) (89). The study of diet-induced obesity requires the development of animal models that reproduce the characteristics of this disease in humans (90). The main advantage of the use of experimental animals is the ability to control potential confounding factors (91). In this context, the consumption of high-calorie diets have an increased percentage of energy from fat often accompanied by a high fructose, trans fatty acids and cholesterol, inducing obesity and insulin resistance (92).
Moreover, the effects of chronic caloric restriction are to increase maximal life-span and to prevent some chronic diseases such as type 2 diabetes, cardiovascular diseases, among others (93). Caloric restriction induces epigenetic modifications leading to the development of obesity in adulthood (94). For example, caloric restriction induces epigenetic changes in the GLUT4 promoter in adipose tissue of mice previously fed a high-fat diet (95). Zhang et al. (2010) determined that caloric restriction during the periconceptional period in both normal-weight and overweight ewes, resulted in hypomethylation of IGF/H19 DMR in adrenal gland (96). Furthermore, there is evidenced that caloric restriction mediates its beneficial effects by modulating chromatin function and increasing genomic stability through reversing DNA methylation and increasing global histone deacetylases activity (97).
Accordingly low-protein diets are used most often as a model for maternal malnutrition. In this context, there are some studies that provide evidence for the influence of maternal protein malnutrition on the development of obesity and obesity-related diseases due to epigenetic changes (5). Thus, a maternal low-protein diet has been associated with epigenetic changes in the promoters of glucocorticoid receptor (98) and induced methylation changes in the hepatic PPAR α promoter of the offspring (99). Likewise Sohi et al. (2011) reported changes in liver histone methylation status in the offspring after a maternal protein-restricted diet (100). Adult mice showed increased hepatic cholesterol/lipid biosynthesis caused by epigenetic changes in PPAR α after a low-protein diet (39).
High-fat diet-induced obesity shows phenotype characteristics such as increased weight and alterations in lipid and carbohydrate profile (101). In obese rats fed a high-fat diet, a CpG island in the leptin promoter was hypermethylated and was associated with low circulating leptin levels (92). Another study showed evidence of epigenetic changes in key genes regulating energy metabolism in white adipose tissue after chronic high-fat diet intake in male Wistar rats (102). Adult mice showed epigenetic changes in opoid receptor mu subunit gene (Oprm1) that participate in the central regulation of food intake and the development of obesity after the transition to a high-fat diet (103). Likewise Vucetic et al. (2011) observed histone modification in Oprm1 after high-fat diet in mice that resulted in altered food behavior (104). In addition, rats fed with high-fat diet showed beta cell dysfunction in islet cells (105). Likewise, chronic high-fat diet altered patterns of DNA methylation of genes associated with appetite and this epigenetic alterations participate on the development of obesity (103).
Specific nutrients have also been associated with epigenetic modification in obesity. Two major mechanisms by which nutritional factors and diet may affect DNA methylation are (i) changes in the availability of methyl donors and (ii) changes in the activity of the enzymes involved in the process of DNA methylation (methyltransferases). Nutrients involved in this mechanism are methyl donors and micronutrients that act as cofactors for the enzymes involved in the one-carbon metabolism, including folic acid, vitamin B6, vitamin B12, zinc, choline and methionine (89).
Several mouse and rat models deficient in methionine and choline exhibit increased expression of genes related to inflammation such as interleukins and TNFα, whereas there is a decline in plasma levels of triglycerides and cholesterol (106). Moreover, male C57BL/6J mice were fed a lipogenic methyl-deficient diet and showed epigenetic alterations in hepatic steatosis (107). Additionally, Uthus et al. (2006) showed the effects of selenium deficiency on methyl metabolism (108).
However, other nutrients and bioactive compounds may affect the one-carbon metabolism indirectly (21). Likewise, among other modifications, histones undergo acetylation, phosphorylation and methylation. In this context, a number of nutrients and bioactive compounds have also been correlated with changes in the methylation of histones (109). Obesity has been repeatedly associated with epigenetic alterations. Therefore, in order to induce obesity in an animal model to study epigenetic mechanisms, the combination of high-calorie diets supplemented with or lacking nutrients and non-nutrient substances have been developed.
In addition to the studies conducted in rodents, there are other species such as primates and birds that have also been used to study the influence of nutrition on DNA methylation pattern, confirming its role in energy homeostasis (110, 111). Su et al. (2009) evaluated the effects of betaine on fatty liver disease in Landes geese and observed a hypermethylation of the S14α gene (110). Two recent studies showed that Drosophila is also a valid model for studies of epigenetic changes and the influence on obesity, underlining the mechanisms involved (112, 113). Matzkin et al. (2013) found evidence that parental diet can influence progeny metabolism in Drosophila (113) and Buescher et al. (2013) focused on effects of a high-sugar diet fed to adult females (112).
It is evident that the environment interacts with the genome to influence human health and disease. However, the question remains of whether the altered epigenetic markers in obesity are a cause or a consequence of weight gain. On the one hand, overweight and obesity develops mostly because of high caloric intake and/or low physical activity and it seems plausible that this altered lifestyle impacts epigenetics modifications. On the other hand not all individuals following an ‘obese’ lifestyle become obese. Thus, epigenetic modifications that already may have been shaped in utero or even transgenerational increase the susceptibility to gain weight under distinct conditions and may explain the missing heritability of obesity. Thus, epigenetics have shifted the paradigm in the understanding of complex diseases including metabolic syndrome. Different epigenetic patterns provide not only information about mechanisms but also prospects for interventions in prevention and therapy.
Competing interests: The authors declare that they have no actual or potential competing interests that might be perceived as influencing the results or interpretation of a reported study.
List of abbreviations
- ATP10 A
- PPAR γ
agouti viable yellow
agouti related protein homolog
ATPase class V type 10A
CCAAT/Enhancer Binding Protein alpha
cytochrome c oxidase assembly factor
dopamine reuptake transporter
dual specificity phosphatase 22
Fas cell surface death receptor
gestational diabetes mellitus
Gon-Two Like (TRP subfamily)
hypoxia-inducible factor 3-alpha
homeodomain interacting protein kinase 3
insulin-like growth factor 2
insulin-like growth factor 2 receptor
matrix metallopeptidase 9
mesenchymal stem cell
polycyclic aromatic hydrocarbon
peptidase M20 domain containing 1
peroxisome proliferative activated gamma
cGMP dependent protein kinase type 1
replication factor C subunit 5
tumor necrosis factor alpha
troponin T type 1
troponin I type 3.
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Published Online: 2015-06-10
Published in Print: 2015-06-01