Interplaying Role of Epigenetic, Exercise and Nutrition in Metabolic Diseases

It is important to understand the interplay of epigenetic changes, exercise and nutrition associated with the development of obesity and type-2 diabetes because it offers insights into how environment and lifestyle factors can influence gene expression without altering the genetic code. This knowledge can lead to the development of optimal interventions and preventive strategies that could potentially decrease the rising rates of obesity and type-2 diabetes. The purpose of this review is to examine the interplay of epigenetic, exercise and nutrition on inflammation and metabolic diseases including obesity and type-2 diabetes, and to acquaint the clinicians and researchers with the current advancing and evolving field of exercise and epigenetics. The proposed mechanisms involved pertain to the development of insulin resistance in peripheral tissues and type-2 diabetes including inflammation. The benefits with regular exercise include improvement in metabolic health occurring through adaptative mechanisms in the adipose tissue, skeletal muscle, and liver as well as improvement in insulin resistance. Physical activity is defined by providing physiological characteristics of physical fitness that includes aerobic or cardiorespiratory fitness, and muscular strength and muscular endurance via regular aerobic exercise or resistance training. Exercise training encompasses training modality, exercise frequency and duration. We discuss the interplay of epigenetic mechanisms in inflammation that may contribute to the current worldwide obesity and type-2 diabetes. Specifically, epigenetic induces a change in phenotype without changes in genotype and thus the epigenome can modify the genome outcome through several processes that include DNA methylation, post-translational histone modification and gene regulation mediated by non-coding RNA (ncRNA) mechanisms that have been correlated with various metabolic and inflammatory diseases.

The growing prevalence of metabolic diseases, including obesity and type 2 diabetes have reached alarming proportions and is becoming a global economic burden [1]. There exists evidence showing that sedentary behavior or insufficient levels of physical activity are key factors involved in the development of metabolic diseases leading to early mortality [2,3]. Obesity is associated with an individual’s genetic and epigenetic patterns, commonly attributed to environmental factors and associated weight and adipose tissue mass [4,5]. Note that adiposity (i.e., excess fat mass) is influenced by complex interplay between genetics, behavioral developments such as physical activity and dietary habits, and the environment suggesting that epigenetic changes play a key role in weight gain leading to obesity [6]. Therefore, regular exercise as a lifestyle intervention via epigenetic mechanisms should be considered one of the prudent behaviors for obesity prevention because exercise burns calories from triglycerides in white adipose tissue [7]. Understanding the epigenetic changes associated with obesity and type-2 diabetes is vital because it offers insights into how environment and lifestyle factors can influence gene expression without altering the genetic code. This knowledge can lead to the development of optimal interventions and preventive strategies that could potentially decrease the rising rates of obesity and type-2 diabetes.

It has been reported that the beneficial effects of regular exercise include improvements in glucose tolerance, insulin sensitivity, redox health, adaptations to the gut microbiota, and reduced inflammation [8-10]. It is well established that there is a significant association between obesity and the development of insulin resistance in peripheral tissues and type-2 diabetes, and there are proposed mechanisms involved in this process including inflammation, increased levels of free fatty acids in the circulation, and mitochondrial dysfunction [8]. The benefits of regular exercise include improvement in metabolic health occurring primarily through adaptative mechanisms in the adipose tissue, skeletal muscle, and liver as well as improvement in insulin resistance [8]. Therefore, the purpose of this review is to examine the interplay of epigenetic, exercise (or physical activity), and diet on inflammation and metabolic diseases including obesity and type-2 diabetes. Note that we define physical activity by providing physiological characteristics of aerobic activity and cardiorespiratory fitness or VO2max with regular exercise training; introduce exercise training modalities; and discuss the interplaying role of epigenetic mechanisms in inflammation that include DNA methylation, histone modification, and miRNA (microRNA) alterations may contribute to the current worldwide obesity and type-2 diabetes.

Exercise, physical activity and cardiorespiratory endurance

Physical activity is defined as any bodily movement that results in a substantial increase in energy expenditure over Resting Energy Expenditure (REE) [11,12]. Exercise is a mode of physical activity with a structured type of physical activity to perform and a specific location and type of instrument needed to execute the activity [11,12]. For example, walking, jogging, running, weightlifting, dancing, practicing Tai Chi, and playing tennis are examples of exercise modalities. “Light” intensity physical activity is defined as requiring 2.0-2.9 METs of energy expenditure, “moderate” as between 3.0 and < 6 METs, and “vigorous” as equal to or greater than 6 METs [11,13]. MET (metabolic equivalent of task) is a standardized way to describe the absolute intensity of a variety of physical activities, and one MET is equivalent to energy expenditure of 3.5 ml/kg/min of VO2 [11]. Optimal physical activity levels for inducing any health benefits as recommended by the American College of Sports Medicine (ACSM) and U.S. Centers for Disease Control and Prevention (CDC) is that all adults engage in regular physical activity of “moderate intensity” 30 min a day on 5 or more days a week (i.e., equal to or > 150 min a week of moderate-intensity aerobic activity), preferably all days of the week’s [14]. The recommendations also call for all adults to engage in regular “vigorous-intensity” physical activity, 20 min a day on 3 or more days a week (i.e., 75 min a week of vigorous-intensity aerobic activity) [14,15]. These physical activity descriptions highlight the importance of the amount and intensity of physical activity required for attaining health benefits and lowering susceptibility to chronic disease and decreasing premature mortality. Little and associates [16] reported that “low-volume and high-intensity” interval training can improve glucose control and induce adaptations in skeletal muscle that are linked to improved metabolic health in patients with type 2 diabetes [16].

Cardiorespiratory endurance also known as aerobic capacity, is described as the ability of the circulatory and respiratory system to supply oxygen during sustained physical activity. Thus, cardiorespiratory endurance is a physiological characteristic for quantifying the ability of the body to transport oxygen from the lungs via the cardiovascular system to supply circulating oxygen to and be utilized by the working muscles [12,17]. Cardiorespiratory endurance is determined by the highest amount of oxygen (VO2 max) a body can produce during maximal physical exertion and is attributed to cardiovascular efficiency determined by peripheral oxygen uptake by the working muscles (i.e., maximal arteriovenous O2 difference, the “peripheral mechanism”) and cardiac output (i.e., stroke volume and heart rate, the “central mechanism”) [17]. Note that persons regularly engaging in aerobic exercise can enhance cardiovascular and respiratory efficiency, increase muscular oxidative capacity, and lower sympathetic nervous reactivity in response to physical and/or psychological stress [12,17]. Maximal aerobic capacity or VO2max usually lowers with age [13], in patients with cardiovascular or respiratory diseases [12], and in sedentary untrained individuals [12,17]. The other mode of physical exercise is known as resistance training or strength training which refers to any exercise where the skeletal muscles exert a relatively large amount of force to move an object against a resistance (i.e., concentrically or eccentrically), hold an object in place (i.e., isometrically), or isokinetically using an isokinetic machine [18]. These muscular movements can be accomplished by lifting free weights, machine weights, or an isokinetic weight machine and is the most effective method to develop muscle endurance, strength, and power. Thus, resistance training is an essential component of exercise for the young and older adults to systematically develop muscle mass, prevent sarcopenia. It has been reported that muscle strength and power, particularly in the lower extremities, tend to decline after age 40 with an accelerated decline after age 65 [19]. Note that after resistance training modest functional improvements in gait speed, time taken to stand from a chair, standing with closed-eye or opened-eye single leg balance, and walking endurance have been reported for older adults [20,21].

The relationship between epigenetic and inflammatory disorders

Emerging evidence suggests that epigenetic processes affecting gene expression without changes in the nucleotide sequence that may contribute to the pathophysiology of obesity processes [22], endothelial dysfunction, atherosclerosis [23], and type 2 diabetes mellitus [24]. Epigenetics is a mechanism that connects environmental factors to alter gene activity without changing the gene sequence [5]. Specifically, epigenetics refers to the nucleotide triplet base sequence of the DNA code that translates genetic information into a particular peptide chain or protein, and thus epigenetics are chemical tags that regulate the expression pattern of genes [25]. In other words, epigenetic induces a change in phenotype without changes in genotype and thus epigenome can modify the genome outcome through several processes that include DNA methylation, post-translational histone modification and gene regulation mediated by non-coding RNA (ncRNA) mechanisms that have been correlated with various metabolic and inflammatory diseases [2,26]. Research has been documented those epigenetic modifications such as DNA methylation in CpG (cytosine-phosphate-guanine) islands, chromatin remodeling by histone tail modifications, and non-coding RNA (ncRNA) expression occur after environmental stimuli and play a fundamental role in inflammatory gene transcription [27-29]. For example, Nadiger and associates identified association of methylation with type 2 Diabetes Mellitus (T2DM) in blood samples from the lifelines study at 5 CpGs (Cytosine-Phosphate-Guanines) out of the 52 CpGs [24]. Also, DNA methylation has been advocated as a strong candidate biological process for identification of diagnostic and therapeutics for T2DM [24]. Thus, epigenetic signature alterations may exacerbate inflammatory responses and influence the risk of chronic inflammatory disease including obesity, T2DM [30], and heart failure [31]. In addition, researchers have found that ncRNA and long non-coding RNAs (IncRNAs) play crucial roles in gene expression regulation linked to obesity, and in obese individuals’ microRNAs (miRNAs) are elevated which contributes to adipogenesis [30]. Also, increased methylation of CpGs sites in the intron region of apoptosis-associated speck-like protein with a caspase recruitment domain (ASC) is associated with improved outcomes in Heart Failure (HF) [31]. Note that elevated levels of miRNAs (i.e., miR-17-5p, miR-132, miR-21, and miR-221) in obese individuals correlate with higher body mass index and metabolic dysfunction [30]. Thus, silencing these miRNAs reduces adipogenesis and improves metabolic function [30,31]. However, elucidation of the specific epigenetic pathways involved in the modulation of the inflammation mechanism(s) and disease susceptibility remain unknown.

Our understanding of Type 2 Diabetes Mellitus (T2DM) as a complex multifactorial disease is still evolving but some scientists have suggested that the dysregulated secretory function of pancreatic islets and insulin resistance at the target tissues are the main focus of the disease pathogenesis [31]. For example, an inadequate β-cell compensatory mechanism to counteract insulin resistance at the target sites is crucial to the deranged glycemic levels and lipid metabolism [31]. Furthermore, individuals with T2DM vary in their phenotypic features of insulin resistnace and some patients with dysfunctional β-cells [31]. Emerging concepts on the pathogenesis of T2DM is focusing on the role of the interplay between several metabolic pathways involving insulin’s major target tissues, and an inter-organ crosstalk [32]. Clinical researchers believe that dysglycemia is associated with metabolic changes driven by tissue-derived metabolites such as Free-Fatty Acids (FFAs) and amino acids both of which contribute to T2DM onset and play important roles in the inter-organ crosstalk during the development of the disease [32]. Thus, the pathogenesis of T2DM is considered a multifactorial disease in which insulin resistance and elevated FFAs collaborated with hyperglycemia, hyperinsulinemia, fat accumulation, oxidative stress, and inflammation in the liver and other tissues [33]. The second pathogenesis of T2DM is based on the “portal hypothesis” in that there is a direct hepatic exposure to released FFAs and pro-inflammatory adipokines into the portal vein in obesity, resulting in hepatic insulin resistance and the disease manifestation such as diabetes mellitus [34-36]. Note that epigenetic marks are currently regarded as essential mediators of gene-environment interaction in T2DM, and they may reveal possible targets for developing new treatment strategies or preventative approaches for T2DM [34-36]. In summary, epigenetic marks in T2DM are 1) DNA methylation and histone modifications alter gene expression at the transcription level and thus play significant roles in the epigenetics of T2DM, and 2) ncRNAs affects the gene expression at the translation level. In addition, epigenetic marks contribute to the development of T2DM by changing gene expression in response to environmental and lifestyle factors related to diet, exercise, and stress [31]. Table 1 shows the major epigenetic modifications involved in type 2 diabetes mellitus.

It should be noted that combining epigenetic therapy with other treatment modalities may provide novel approaches for preventing and treating type-2 diabetes mellitus. As suggested, the first treatment modality can be lifestyle interventions such as diet and exercise both of which can influence epigenetic modifications and thus improving the effects of epigenetic therapies [31]. For example, a healthy diet and regular exercise can reduce DNA methylation and histone modifications associated with type-2 diabetes mellitus [37]. It has been reported that complementing phytochemicals with the Mediterranean diet and a DNA methylation-based epigenetic intervention can improve glycemic control in type 2 diabetes patients [37]. Another potential novel treatment option is immunotherapy such as targeting pro-inflammatory cytokine is a possible treatment option because chronic low-grade inflammation is associated with the development of type 2 diabetes [31]. The approach is because epigenetic modifications modulate immune cell function and inflammation, and by combining immunotherapy with epigenetic therapy potentially regulates these processes and thus enhancing insulin sensitivity and glycemic control in type 2 diabetes patients [38]. Lastly, combining stem cell-based therapy with epigenetic therapy holds prospects for managing type 2 diabetes, the former regenerates pancreatic β-cells, and the latter may improve stem cells’ therapeutic potential in type 2 diabetes by optimizing their differentiation into functional cells or enhancing their survival through epigenetic modulation approaches [39]. Current reports showed that there are evidence suggesting that targeting the major epigenetic marks such as DNA methylation, histone modifications and ncRNA regulation may provide novel approaches for preventing and treating type 2 diabetes mellitus [31].

Also combining epigenetic therapy with other treatment modalities may be helpful in managing type 2 diabetes. For example, prescribing metformin to DNAMT (DNA methyltransferase) or HDAC (histone deacetylase) inhibitors may synergistically modulate gene expression and enhance insulin sensitivity because metformin affects DNA methylation patterns and histone modifications [40]. The reported mechanisms are that metformin 1) causes hypomethylation of specific genes responsible for glucose metabolism and insulin signaling pathways, 2) can trigger changes in histone modifications resulting in altered gene expression patterns associated with type 2 diabetes mellitus, and 3) activates AMPK (adenosine monophosphate-activated protein kinase) leading to the modulation of epigenetic mechanisms by influencing the activity of DNAMTs, class II HDACs (Histone deacetylases), and HATs (histone acetyltransferases) all of which mediate DNA and histone modifications [38,40]. Thus, the effect of metformin can influence the epigenome and gene expression and thus contribute to the antidiabetic properties of metformin [40,41].

Exercise, epigenetic, obesity and inflammatory disorders

Studies have shown that physical exercise may exert anti-inflammatory effects through epigenetic regulation depending on the type of exercise (i.e., aerobic exercise or resistance training), exercise duration (i.e., short or long-distance such as 5 km, 10 km, half- or full-marathon), body composition, gender, and age [42-44]. For example, in older adults, progressive resistance training muscle-derived microRNAs corrected with thigh lean mass gains [40,45]. Other researchers have shown that the inflammasome which activates inflammatory cytokines that promote cardiac hypertrophy and myocardial apoptosis [46,47]. Note that the inflammasome is composed of a NOD (Nucleotide-binding Oligomerization Domain)-like receptor (NLRP3), apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), and caspase-1 [48-50]. Butts and associates demonstrated in persons with heart failure that exercise intervention is associated with changes in DNA methylation of a key component of the inflammasome, ASC, and that the changes are associated with decreased ASC gene expression [48,51]. Note that this adaptor protein ASC is necessary for inflammation activation of IL-1β and IL-18 [48,51]. For example, Butts and associates (2016) reported that patients with heart failure their ASC miRNA was lower than baseline at 3 months (p =. 004) and 6 months (p =. 002) among those in the aerobic exercise as compared to the control group [31]. Also, in patients with heart failure ASC methylation was positively associated with six-minute walk test at baseline (r =. 517, p < 001), 3 months (r =. 464, p =. 004), and 6 months (r =. 497, p =. 05) [31]. Note that patient’s depression syndrome and poor health status may initiate the positive feedback loop on inflammation associated in heart failure pathology [31]. It has been suggested that ASC methylation was associated with better psychosocial and quality of life status. For example, higher ASC methylation was associated with a decreased risk of hospitalization or death occurring, while ASC expression was associated with an increased risk of a clinical event [31]. Note that inflammation is a key factor contributing to alterations in aerobic capacity, and interleukin-1 cytokines are associated in this process [48,51]. Therefore, it has been suggested that epigenetic regulation of ASC can be further explored as a biological mechanism by which exercise can promote better outcomes in HF [48,51].

In a study of Nishida, et al. [52] who reported that by substituting low-intensity exercise (< 3 METs) with accelerated intensities (from 1 to 3 Mets) for sedentary time were associated with higher methylation of the ASC gene which is a potential biomarker of systemic inflammation. However, Butts and associates found that moderate-intensity aerobic exercise training (determined as peak VO2 of 17.31 ml/kg/min or approximately 5 METs) was positively associated with increased ASC methylation [48]. In another study using interval walking exercise consisted of a 3-min low-intensity at 40% peak VO2, followed by a 3-min high-intensity at > 70% peak VO2 for as many days as possible over a period of 6 months, increased NFKB2 gene promoter methylation, suggesting that this mode of exercise training may epigenetically impact the susceptibility to inflammation [52]. Nishida and associates [52] using either a 6-month aerobic exercise or aerobic exercise plus resistance training in adult women, observed a significant reduction in methylation level at CpG1 and overall CpG in the aerobic exercise group and an increased methylation level at CpG3 in the aerobic plus resistance training group which is associated with changes in visceral fat tissue and weight loss [53]. Other studies have shown that individuals engaging in exercise training experienced increase in DNA methylation and induce specific changes in DNA profiles particularly influencing genes involved in metabolic pathways associated with obesity [54,55]. Note that high level of DNA methylation will subsequently modify histones, resulting in histone methylation at H3K9me3 (histone H3 lysine 9 di-methylation) and H3k27me3 (histone H3 lysine 27 di-methylation) because these regions are where methylation and acetylation mechanisms can occur [54,55]. In addition, histone acetylation decreases leading to the condensation of chromatin from its initial open state to a more compact form and therefore suppressing the expression of certain genes especially those related to obesity [55]. Studies have shown that CpG sites in genes (i.e., NRF1, ADR1B, and PTPRN2) showing differential methylation patterns between obese and non-obese individuals underscoring their potential as biomarkers for obesity risk [56,57]. Note that DNA methylation like the NRF1 gene has the potential to detect obesity in children [53]. Lastialno MP, et al. [30], reported that there are 94 CpG sites that are linked to body mass index and 49 CPG sites that are associated with waist circumference.

Employing a Resistance Training (RT) protocol, O’Bryan KR, et al. [45] utilized untargeted miRNA-seq to examine miRNA in skeletal muscle and serum-derived exosomes of older adults (n = 18, age = 66 ± 1 yr) who underwent three times per week Resistance Training (RT) for 30 wk [e.g., high intensity three times/wk [(HHH, group 1, n = 9) or alternating high-low-high intensity (HLH, group 2, n = 9)], after a standardized 4-week wash in period. The authors found, within each tissue, miRNAs were clustered into modules based on pairwise correlation [45]. When the modules were assessed for association with the magnitude of resistance training-induced thigh lean mass change determined by Dual-Energy X-Ray Absorptiometry (DXA), the authors identified miRNA modules in skeletal muscle associated with thigh lean mass gains irrespective of resistance training dose [45]. The findings point toward potential miRNAs that may be informative biomarkers as potential therapeutic targets as an adjuvant to resistance training to maximize skeletal muscle mass accrual in older adults [45]. Note that this study identified 1) a set of miRNAs correlated with thigh lean mass gains in the older adults and can be served as novel predictive biomarkers correlating with lean mass gains in aging adults, and 2) miRNAs are positively responding to resistance training intervention [45].

Note that acute exercise has been found to decrease global and gene-specific promoter methylation in human skeletal muscle following a dose-dependent response [58]. Furthermore, there are evidence that supports the theory of epigenetic inheritance, where epigenetic germline inheritance of diet-induced obesity and insulin resistance are transferable from parents to offspring’s [59]. Also, Morikawa and associates [60] reported that there may be an immunomodulatory synergistic effect of physical activity and diet via epigenetic modulation.

Exercise-induced adaptations to adipose tissue

Regular exercise has important effects on adipose tissue morphology and function including distinct changes in white adipose tissue and brown adipose tissue. For example, in rodents study exercise training has been shown to decrease white adipocyte size and reduce lipid content, resulting in decreased adiposity [61]. Also, in non-obese and obesity women, it has been reported that during bouts of both endurance exercise and resistance training increase lipolysis and free fatty acid mobilization both of which are important for providing metabolic substrate for increased energy demand during exercise training especially during increased exercise duration [62]. Furthermore, exercise training increases mitochondrial activity and the expression of several important metabolic proteins in white adipose tissue, including Glucose Transporter Type 4 (GLUT4) and PGC1α (peroxisome proliferator-activator ɤ coactivator 1-α) [61]. Note that exercise training even performed over a short period (i.e., 2 weeks), improves adipose tissue metabolism, including increases in glucose uptake in subcutaneous white adipose tissue and visceral white adipose tissue in both healthy and insulin-resistant individuals [64]. Brown adipose tissue, on the other hand, is a metabolically active tissue that metabolizes lipids and carbohydrates to generate heat, and is characterized by a high density of mitochondria, multilocular lipid droplets, and high expression of the thermogenic protein uncoupling protein 1 (UCP1) [65]. Note that study conducted by Barbosa and associates showed that exercise training increased brown adipose tissue activity [66] while others showed that exercise decreased mitochondrial activity in brown adipose tissue [67]. It should be note that in young sedentary men, Martinez-Tellez and associates (2022) observed no evidence of brown adipose activation after 24 weeks of exercise intervention combining resistnace and endurance training [68]. Interestingly, in human study Esteves JV, et al. [69], showed no evidence of exercise-induced beiging of white adipose tissue. It should be note that adipose tissue is directly linked to the detrimental effects of obesity on metabolic health and that regular exercise plays a crucial role in managing these negative effects in the white adipose tissue as well as exerting significant effects on both white and brown adipose tissue that combat the development of obesity and metabolic disease [69]. In terms of the brown adipose tissue, exercise training has an important role in promoting its endocrine function via releasing batokines that can mediate some of the positive effects of exercise [69].

Obesity, exercise, and inflammation

It has been shown in patients with obesity that modulated the overexpression of the inflamma-miR-146a-5p, a biomarker, after 12 weeks of 26 sessions of combined aerobic and endurance exercise training for 90 min each, 2 times a week [70]. This study also showed that after 12 weeks of exercise training plus weight-reduction program increase personalized predictor of the clinical response [70]. Note that for weight-reduction program, acute aerobic exercise response at 75% VO2max for 30 min elicited higher elevation of inflammatory miRNAs in obese patients compared to lean individuals [71]. It has been reported that distinct and specific circulatory inflammatory miRNA (c-inflamma miRs) signatures were observed in plasma samples from active middle-aged male subjects following different doses of acute aerobic exercise (0 h, 24 h, 72 h) 10-km, half-marathon, and full-marathon races [71]. The finding suggests that an epigenetic mechanism controlling the exercise-induced inflammatory cascade, and that a dose-dependent effect of aerobic exercise on systemic inflammation with higher levels detected after 10-km race [71]. Furthermore, acute strenuous exercise consisting of stepping up and down from a step machine unit complete exhaustion resulted in enhanced chronic low-grade inflammation in PBMCs from obese individuals via an imbalance on Histone H4 Acetylation/Histone Deacetylase as compared to lean subjects [73]. Thus, the impact of acute and chronic exercise training on inflammation is dependent on the type, intensity, and clinical settings of the exercise intervention programs.

Nutrition, epigenetic and inflammation

It is important to understand the role of nutrients and dietary bioactive compounds on inflammation status through epigenetic mechanisms, and how these events may influence chronic disease development such as obesity and type-2 diabetes mellitus. It has been shown that abnormal Fatty Acid (FA) levels have long been recognized to participate in metabolic diseases such as diabetes mellitus [72,73]. However, there is scarcity of human studies investigating a link between DNA methylation and fat intake, focusing on specific genes associated with FA metabolism, inflammation, and regulation of circadian rhythms [74,75]. Furthermore, a genome-wide study found that DNA methylation profiles associated with polyunsaturated: saturated FA ratio were related to pathways regulated by the peroxisome proliferator-activated epigenetic effects of diets containing various combinations of specific FAs [76,77]. In addition, Silva-Martinez, et al. [75] reported that Very Low-Density Lipoprotein (VLDL) elicited a global DNA hypermethylation response that is markedly stronger than the one induced by low- or high-density lipoprotein in cultured human THP-1 macrophages, suggesting that FAs might be mediators of the epigenetic responses to VLDL. In terms of cellular disease models, Palmitic Acid (PA) was shown to induce global DNA hypermethylation in primary human myocytes and ex vivo human pancreatic islet cells at a 500 µM and 1 mM dose, respectively, affecting targets such as the PPAR-ɤ coactivator 1A gene [77]. Furthermore, there are anti-inflammatory potential reports on essential fatty acids mediated by epigenetic events. For example, n-3 PUFA (polyunsaturated fatty acids) supplementation was associated with changes in DNA methylation profiles in blood leukocytes related to pathways involved in inflammatory and immune responses [74,75]. The anti-inflammatory effect of oleic acid (OA), a Monounsaturated Fatty Acid (MUFA) was found to be associated with DNA methylation signatures [77]. Furthermore, Silva-Martinez, et al. [75] reported that AA may contribute to influence the epigenome of important metabolic disease, supports and expands current diet-based therapeutic and preventive efforts and conclude that AA-induced methylation profiles were similar to the corresponding profiles described for palmitic acid, atherosclerosis, diabetes, obesity, and autism, but relatively different from OA-induced profiles [77]. In summary, AA and OA exert distinct effects on the DNA methylation.

Furthermore, it has been reported that essential nutrients and added sugar intake could play critical roles in DNA replication, maintenance, and repair together with serving as antioxidant and anti-inflammatory agents [76]. For example, Chiu and associates found that both healthy diet and added sugar intake were independently associated with epigenetic age [76]. Note that epigenetic clocks effectively predict biological age independent of chronical age, and reflect altered gene and protein expression patterns, particularly those resulting from differential DNA methylation at CpG (such as 5’-C-phosphate-G-3’) sites [78,79]. Furthermore, DNA methylation accumulates over time is an indication that the burden of social, behavioral, and environmental forces can have on the body [80-82]. Chiu and associates emphasized that sufficient dietary intakes support genomic stability and preserve health [76]. Importantly, these alterations often result in pathogenic processes such as genomic instability, systemic inflammation, and oxidative stress, all of which are characteristic of aging and chronic disease [80,82,85]. Note that epigenetic clocks reflecting epigenetic age have been developed for a range of age- or disease-related targets [83,85]. Furthermore, epigenetic changes are modifiable and have centered on lifestyle factors including diet such as “epigenetic diet” and “nutriepigenetics” [84,85]. For example, one of the epidemiological studies, the Dietary Approaches to Stop Hypertension [DASH] diet, was a reflective of healthy dietary patterns emphasizing consumption of fruits, vegetables, whole grains, nut and seeds, and legumes [85,86]. Another study is the Mediterranean-style diet which is largely plant-based with emphasis on extra virgin olive oil and seafood [83-85,87]. These dietary patterns are likely effective in preventing and reversing the epigenetic changes and pathogenic processes associated with aging, disease, and health decline [83]. Note that macronutrients and micronutrients play crucial roles in DNA replication, damage prevention, and repair, while nutrient deficiencies and excesses can cause genomic damage to the same degree as physical or chemical exposures [86,87]. It is important to note that promoting diets aligned with chronic disease prevention recommendations and at the same time complete with antioxidant or anti-inflammatory and pro-epigenetic health nutrients while emphasizing low added sugar consumption may support slower cellular aging relative to chronological age [78,88].

miRNAs discoveries and Nobel prizes in medicine or physiology

Dr. Victor Ambros and Dr. Garry Ruvkun discovered a class of molecules called miRNAs that have a crucial role in controlling gene expression [89,90]. They both won the Nobel prize in Physiology or Medicine 2024. Note that both researchers published their first key discoveries in 1993, and they identified two genes called lin-4 (also known as microRNA) and lin-14 involved in the development of the roundworm [89,90]. These two scientists found and characterized miRNAs in the roundworm Caenorhabiditis elegans in 1993 [89,90]. and other researchers discovered hundreds of miRNAs in human genome with some potential applications to treat cancer or prevent heart disease [91]. Dr. Ruvkun and co-workers also discovered the second-known miRNA molecule named let-7, call miR-34 also in roundworms. miR-34 has the potential to slow tumors’ grow in cancer especially in lung cancer. Researchers still unclear how to apply miRNA to provoke a dangerous immune response or how to deliver them to the right target cells in the human body [89,90]. The field of miRNA therapeutics is still in its infancy, but will miRNAs ever be useful as medicines is today’s headline reported in Nature News [91]. Today there are miRNA drugs in development, but delivering RNA molecules to cells has been a key challenge. Currently, clinical researchers are developing miRNA therapies to treat epilepsy, obesity, cancer, and heart illness. For example, one pharmaceutical company in Germany is conducting a phase II clinical trial of a miRNA inhibitor designed to treat heart failure [91]. It is important to note that miRNAs are made naturally by the human body and often affect the activity of many genes. Because of that careful laboratory studies are necessary to ensure that enhancing or suppressing a natural miRNA without unwanted side effects. It is hopeful that the miRNA’s ability to simultaneously affect multiple genes involved in protecting against tumors could help treating certain type of cancers [91]. Noted that it took 30 years for a Nobel Prizes committee to recognize the recovery of miRNA molecules that regulate gene activity in human cells, and hope that making these miRNA molecules to therapeutic medicines may not take longer than 30 years [91]. It should be note that the US Food and Drug Administration (US-FDA) has not approved any miRNA-based drugs for treating human diseases.

Despite the well-established evidence of benefits of exercise training that include decrease white adipocyte size and reduce lipid content, resulting in decreased adiposity, and there has been an increase in mitochondrial activity and the expression of several important metabolic proteins in white adipose tissue, such as Glucose Transporter type 4 (GLUT4) and PGC1α (Peroxisome Proliferator-activator ɤ Coactivator 1-α), and increase lipolysis and free fatty acid mobilization both of which are important for providing metabolic substrate for increased energy demand during exercise training. Furthermore, exercise increases mitochondrial activity and the expression of several important metabolic proteins in white adipose tissue including an increase in glucose uptake in subcutaneous white adipose tissue and visceral white adipose tissue in both healthy and insulin-resistant individuals. The well-established evidence of epigenetic induced changes, including DNA methylation, post-translational histone modification and gene regulation mediated by non-coding RNA (ncRNA) mechanisms, have been correlated with various metabolic and inflammatory diseases including obesity and type-2 diabetes mellitus (T2DM). In addition, researchers have found that ncRNA (non-coding RNA) and long non-coding RNAs (IncRNAs) play crucial roles in gene expression regulation linked to obesity. Obese individuals’ miRNAs are elevated contributing to adipogenesis, however only a few studies have investigated other aspects of exercise-provoked epigenetic responses, such as tissues of the secretory function of pancreatic islets and insulin resistance at the target tissues. Further investigation of exercise-induced epigenetic modulations to elucidate specific epigenetic pathways involved in the modulation of the inflammation mechanism(s) and disease susceptibility are warranted. In addition, our understanding of T2DM as a complex multifactorial disease is still evolving. For example, an inadequate β-cell compensatory mechanism to counteract insulin resistance at the target sites is crucial to the disrupted glycemic levels and lipid metabolism. There is evidence suggesting that targeting the major epigenetic marks such as DNA methylation, histone from an epigenetic perspective modification and ncRNA regulation may provide novel approaches for preventing and treating T2DM. Furthermore, epigenetic regulation of ASC can be explored as a biological mechanism by which exercise can promote better health outcomes in patients that have been diagnosed with heart failure. From an epigenetic perspective elucidating the underlying mechanisms of the novel targets for beneficial effects of exercise will help provide novel targets for treating obesity, T2DM, and heart failure. Ren J, et al. [92] reported that maternal prenatal exercise is an effective intervention for improving metabolic health in offspring, however, the pathways through which exercise work are unclear Note that the gut microbiota mediates the effect of maternal exercise on offspring metabolism, and epigenetic modifications have been proposed to be important molecular mechanisms. In Ren J, et al. [92] recent review, the authors proposed that gut microbiota-metabolites-epigenetic regulation is an important mechanism by which maternal exercise improves offspring metabolism and that may yield novel targets for the early prevention and intervention of metabolic diseases [92]. Furthermore, intergenerational inheritance of exercise-induced inflammation protection and/or metabolic health and its underlying mechanisms as well as development of obesity and T2DM by changing gene expression in response to environmental and lifestyle factors related to diet and exercise should be further investigated. The epigenetic landscape induced by exercise and nutrition in metabolic health and the prevention of obesity and T2DM is still in its infancy. Elucidating the epigenetic mechanisms of the link between exercise, nutrition and metabolic health and inflammatory diseases prevention will advance our understanding of exercise induced metabolic protection to help us to identify novel biomarkers which will direct the development of miRNA therapeutic medicines for treating metabolic diseases including obesity, T2DM, heart failure, and some type of cancers.

The benefits of regular exercise for improvement in metabolic health occurring through adaptative mechanisms in the adipose tissue, skeletal muscle, and liver as well as improvement in insulin resistance which include improvements in glucose tolerance, insulin sensitivity, redox health, and reduced inflammation. There is a significant association between obesity and the development of insulin resistance in peripheral tissues and type-2 diabetes. The proposed mechanisms involved in this process, including inflammation, increased levels of free fatty acids in the circulation, and mitochondrial dysfunction.

Cardiorespiratory endurance is determined by the highest amount of oxygen (VO2 max) a body can produce during maximal physical exertion and is attributed to cardiovascular efficiency determined by peripheral oxygen uptake by the working muscles (i.e., maximal arteriovenous O2 difference, the “peripheral mechanism”) and cardiac output (i.e., stroke volume and heart rate, the “central mechanism”). Persons regularly engaging in aerobic exercise can enhance cardiovascular and respiratory efficiency, increase muscular oxidative capacity, and lower sympathetic nervous reactivity in response to physical and/or psychological stress. The recommended optimal physical activity levels for inducing any health benefits are that all adults engage in regular physical activity of “moderate intensity” 30 min a day on 5 or more days a week. Resistance training is an essential component of exercise for developing muscle mass and preventing sarcopenia. Muscle strength and power, particularly in the lower extremities, tend to decline after age 40 with an accelerated decline after age 65.

Regular exercise has important effects on adipose tissue morphology and function including distinct changes in white adipose tissue and brown adipose tissue. In rodents study exercise training has been shown to decrease white adipocyte size and reduce lipid content, resulting in decreased adiposity. In non-obese and obesity women, it has been reported that during bouts of both endurance exercise and resistance training increase lipolysis and free fatty acid mobilization both of which are important for providing metabolic substrate for increased energy demand during exercise training especially during increased exercise duration. Furthermore, exercise increases mitochondrial activity and the expression of several important metabolic proteins in white adipose tissue, including Glucose Transporter Type 4 (GLUT4) and PGC1α (peroxisome proliferator-activator ɤ coactivator 1-α). Exercise training even performed over a short period (i.e., 2 weeks), improves adipose tissue metabolism, including increases in glucose uptake in subcutaneous white adipose tissue and visceral white adipose tissue in both healthy and insulin-resistant individuals.

Epigenetic induces a change in phenotype without changes in genotype and thus epigenome can modify the genome outcome through several processes that include DNA methylation, post-translational histone modification and gene regulation mediated by non-coding RNA (ncRNA) mechanisms that have been correlated with various metabolic and inflammatory diseases. Furthermore, DNA methylation has been advocated as a strong candidate biological process for identification of diagnostic and therapeutics for type-2 diabetes mellitus (T2DM). Thus, epigenetic signature alterations may exacerbate inflammatory responses and influence the risk of chronic inflammatory disease including obesity and T2DM. Our understanding of T2DM as a complex multifactorial disease is still evolving and some scientists have suggested that the dysregulated secretory function of pancreatic islets and insulin resistance at the target tissues are the main focus of the disease pathogenesis. For example, an inadequate β-cell compensatory mechanism to counteract insulin resistance at the target sites is crucial to the deranged glycemic levels and lipid metabolism.

Current reports showed that there are evidence suggesting that targeting the major epigenetic marks such as DNA methylation, histone modifications and ncRNA regulation may provide novel approaches for preventing and treating type 2 Diabetes Mellitus (T2DM). Also, epigenetic marks contribute to the development of T2DM by changing gene expression in response to environmental and lifestyle factors related to diet, exercise, and stress.

In patients with obesity and non-obesity after 12 weeks, two times a week of 90 min each of combined aerobic and endurance exercise training Russo D, et al. [70] reported that the exercise training plus weight-reduction elicited higher elevation of inflammatory miRNAs with weight-reduction in the obese patients, compared to lean patients. Acute strenuous exercise consisting of stepping exercise to complete exhaustion resulted in enhanced chronic low-grade inflammation in PBMCs from obese individuals via an imbalance on Histone H4 Acetylation/Histone Deacetylase as compared to lean subjects. Thus, the impact of acute and chronic exercise training on inflammation is dependent on the mode and intensity of exercise, as well as clinical settings of the exercise intervention programs.

Abnormal Fatty Acid (FA) levels have long been recognized to participate in metabolic diseases such as diabetes mellitus. There is scarcity of human studies investigating a link between DNA methylation and fat intake, focusing on specific genes associated with FA metabolism, inflammation, and regulation of circadian rhythms. A genome-wide study found that DNA methylation profiles associated with polyunsaturated: saturated FA ratio were related to pathways regulated by the peroxisome proliferator-activated epigenetic effects of diets containing various combinations of specific FAs. Note that Very Low-Density Lipoprotein (VLDL) elicited a global DNA hypermethylation response that is markedly stronger than the one induced by low- or high-density lipoprotein in cultured human THP-1 macrophages, suggesting that FAs might be mediators of the epigenetic responses to VLDL. Also, essential nutrients and added sugar intake could play critical roles in DNA replication, maintenance, and repair together with serving as antioxidant and anti-inflammatory agents.

The field of miRNA therapeutics is still in its infancy. Researchers still unclear how to apply miRNA to provoke a dangerous immune response or how to deliver them to the right target cells in the human body. Today there are miRNA drugs in development, but delivering RNA molecules to cells has been a key challenge. Clinical researchers are developing miRNA therapies to treat epilepsy, obesity, cancer, and heart disease. Currently one pharmaceutical company in Germany is conducting a phase II clinical trial of a miRNA inhibitor designed to treat heart failure.

Authors declare that they have no conflict of interest.

This study was not supported by any internal or external grant.

Michael T.C. Liang and Moustafa Bayoumi Moustafa equally contributed to the article and drafted the first version of the manuscript. MTCL, MBM, NDW, JRR and AA contributed to the overall study design. MTCL, JRR and AA conducted the entire literature search and review. All authors read and approved the final version of the manuscript.

The authors declare that they have no competing interests.

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