Epigenetics in obesity: Mechanisms and advances in therapies based on natural products

Abstract

Obesity is a major risk factor for morbidity and mortality because it has a close relationship to metabolic illnesses, such as diabetes, cardiovascular diseases, and some types of cancer. With no drugs available, the mainstay of obesity management remains lifestyle changes with exercise and dietary modifications. In light of the tremendous disease burden and unmet therapeutics, fresh perspectives on pathophysiology and drug discovery are needed. The development of epigenetics provides a compelling justification for how environmental, lifestyle, and other risk factors contribute to the pathogenesis of obesity. Furthermore, epigenetic dysregulations can be restored, and it has been reported that certain natural products obtained from plants, such as tea polyphenols, ellagic acid, urolithins, curcumin, genistein, isothiocyanates, and citrus isoflavonoids, were shown to inhibit weight gain. These substances have great antioxidant potential and are of great interest because they can also modify epigenetic mechanisms. Therefore, understanding epigenetic modifications to target the primary cause of obesity and the epigenetic mechanisms of anti‐obesity effects with certain phytochemicals can prove rational strategies to prevent the disease and develop novel therapeutic interventions. Thus, the current review aimed to summarize the epigenetic mechanisms and advances in therapies for obesity based on natural products to provide evidence for the development of several potential anti‐obesity drug targets.

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Abbreviations

ALT

alanine aminotransferase

BMI

body mass index

DNMTs

DNA methyltransferases

HAT

histone acetyltransferase

miRNAs

MicroRNAs

RISC

RNA‐induced silencing complex

SAM

S‐adenosyl‐l‐methionine

SCFAs

short‐chain fatty acids

WHO

World Health Organization

1. INTRODUCTION

Obesity is a complex multifactorial disease defined as having more body fat than is optimally healthy. Traditionally, a body mass index (BMI) of >30 kg/m² has been used to define obesity, and overweight or preobesity is defined as a BMI of 25 kg/m² or higher. ¹ According to a recent study from the World Health Organization (WHO), more than 2 billion adults worldwide are overweight, and over 650 million adults are obese. ² In addition, a survey of the national population shows that 34.3% of adults are overweight and 16.4% of adults are obese. ³ The most noteworthy is that obesity is a driver of a wide range of chronic cardiometabolic diseases, including type 2 diabetes and cardiovascular disease, along with numerous non‐metabolic co‐morbidities such as several types of cancer. ⁴ The recent COVID‐19 pandemic revealed that individuals living with obesity were at increased risk of severe illness and hospitalization. ⁵ Altogether, obesity has become a heavy burden on human society, and there is a great need to elucidate the mechanisms of obesity and develop new treatments.

The causes of obesity are multifaceted and include the interactions of genetic, hormonal, and environmental variables. Interindividual variations in the development of obesity are caused by genetic predisposition. However, the etiology of obesity is largely influenced by environmental variables, such as lifestyle, eating habits, and other environmental factors, rather than genetic pathways. ¹ , ⁴ Recently, extensive evidence has indicated that epigenetic regulation is critical to the development and progression of obesity. ⁶ Epigenetics is regarded as various covalent modifications of nucleic acids and histone proteins which regulate gene function and expression and the chromatin structure cooperatively. ⁷ Epigenetic regulation can occur at various levels, including through DNA methylation, histone modifications, chromatin remodeling, and noncoding RNA (ncRNA) modulation. ⁶ , ⁷ Epigenetics is essential for multiple aspects of vital cell processes, including cell growth, differentiation, proliferation, and membrane transport. ⁸ Notably, several epigenetic alterations have been confirmed to have appreciable potential as candidate clinical biomarkers and targets of therapy for patients with obesity since they are highly connected with metabolic syndrome‐related gene expression profiles and frequently arise early in illnesses. ⁹ Additionally, epigenetic modifications to genes and proteins may function as fresh therapeutic targets in clinical situations because epigenetic control is reversible and dynamically modified. ¹⁰ Therefore, studying the epigenetic regulation mechanism of obesity is of great significance for a deep understanding of the development and progression of metabolic diseases and for developing new safe and effective drugs to diagnose, prevent, and treat human diseases related to metabolism. ¹¹

Since evidence has supported the general idea that obesity is closely related to epigenetics, researchers worldwide have become more interested in searching for bioactive natural products derived from medicinal plants or dietary herbs that contribute to epigenetic regulation in obesity. ¹² Recently, a number of studies have been conducted showing that some natural products have potential use in the management of obesity due to their strong antioxidant and anti‐inflammatory properties, and their side effects are negligible. ¹³ , ¹⁴ Numerous studies have been conducted in the past few years with the goal of understanding the regulatory mechanisms of these natural compounds, which may aid in the prevention and treatment of obesity. ¹⁵ , ¹⁶ This study provides an overview of recent research on obesity treatment using natural products from an epigenetic perspective and helps to fully understand the epigenetic mechanism of obesity and develop natural products that can be applied in clinical practice in the future.

2. PATHOGENESIS AND PATHOPHYSIOLOGY OF OBESITY

Many studies have reported that the development of obesity mainly depends on the balance between excess food intake and caloric utilization, but there is a complex interplay between underlying genetic and environmental factors, availability of healthcare systems, and socioeconomic status. ¹⁷

2.1. Food intake and energy homeostasis

There is substantial debate over the main causes of obesity. The underlying physiological principle that fat storage is caused by an energy imbalance between caloric intake and caloric expenditure forms the basis of current medical recommendations on how to control obesity. Increased access to stimulating foods has led to an increase in energy, which has contributed significantly to the obesity epidemic. ¹⁸ Diet has a significant impact on a patient's ability to maintain balance; in addition, a number of other social, economic, and environmental factors related to food availability also impact this balance. ¹⁹ Published studies have reported that those who consumed substantially more fast food weighed an average of 6 kg more and had larger waist circumferences than those who consumed the least amount of fast food in a 13‐year follow‐up study involving 3000 young adults. ²⁰ Additionally, it was discovered that they were twice as likely to develop MetS and had greater rates of health issues caused by being overweight, such as high triglyceride levels. ²¹ These problems are exacerbated in some individuals who are genetically predisposed to fat storage, which may be brought on by key linkages between brain reward and homeostatic circuitry. Due to the accumulation of lipid metabolites, inflammatory signals, and other processes that injure hypothalamic neurons, increased body fat mass may operate as a biological defense in obesity. ²²

It has been reported that fat marketing to promote drinks or food with high sugar can produce a negative impact on organism behavior. ²³ Such advertising may increase preference for high‐energy foods, especially carbohydrate drinks in daily life. Furthermore, according to published studies, the majority of the present food market is focused more on advertising for meat, sweets, soda, and fast food than it is on cereals, pasta, vegetables, and fruits. ²⁴ Advertising products are made to taste “irresistible,” have a lengthy shelf life, and be reasonably priced. The reward center of the brain, which is also a region of the brain excited by cocaine, heroin, and other addictive substances, is best stimulated by high‐fat, high‐sugar junk food. ²⁵ These goods have been purposefully made to be addictive. A plausible method to explain the occurrence of increased body fat content is provided by the brain reward; however, according to this idea, these seem to only influence who exhibits this trait.

For clinicians to effectively manage obesity with patients, a rigorous review of patient health factors influencing energy intake, metabolism, and expenditure is necessary. However, attempts to control obesity by behavioral changes intended to address these three causes are typically ineffective. ²⁶ This shows that we still have a lot to learn about how the body manages its energy and how intake, metabolism, and expenditure interact.

2.2. Family history and lifestyle

Family history, way of life, and psychological aspects all contribute to the likelihood of obesity. Family genetics (predisposition to acquire fat) and lifestyle (bad eating or exercise habits) might increase the probability of being obese. ²⁷ It has been reported that a child's risk of becoming obese as an adult is three times higher if one of their parents is obese, but the risk is ten times higher for a child whose parents are both obese. ²⁸ A cross‐sectional observational study of 260 children (139 girls and 121 boys, 2.4 to 17.2 years old) found that obesity and cardiometabolic disease history in the family are major risk factors for the severity of childhood obesity. ²⁹ The risk of childhood obesity is increased by a number of factors, including parental obesity, between‐meal snacking, especially after dinner, insufficient sleep (<8 h per night), and daily consumption of effervescent drinks, sugary meals, and juice, according to a prospective study of 3148 schoolchildren (six to ten years of age) in Ariana. ³⁰ Furthermore, a healthy lifestyle of mothers during the childhood and adolescence of their children was found to be highly related to a significantly lower incidence of obesity in two studies of mother–child pairings in the United States. ³¹ The above findings accentuate the benefits of family or parental intervention in lowering the likelihood of childhood obesity.

2.3. Microenvironment and gut microbiome

In recent years, both our understanding of the gut microbiota and its complex relationship to disease have significantly increased. For instance, obesity contributes to altered intestinal microenvironments that support a greater variety of virus species than those found in hosts that are slimmer. ³² In this context, pathogenic mutations that can cause severe disease are more likely to be produced. There is growing evidence that the host's weight and metabolism are impacted by the host's specific gut flora variations. ³³ For example, despite eating 29% more food per day, male germ‐free mice (without gut microflora) had 42% less total body fat than mice with normal gut microbiota. ³⁴ However, after cecal microbial colonization, the total body fat of these mice grew by 57%, their lean body mass dropped by 7%, and their daily food consumption dropped by 27%. A follow‐up study revealed that after microbial colonization, capillary density in the distal small intestine villi increased by 25%. This finding suggests that these changes were caused by lower metabolic rates and concurrently increased adipose tissue deposition. Similar outcomes were also observed in female mice. ³⁵

The stimulation, development, and protection of the host immune system and the provision of nutrients to the host are all crucially influenced by gut microorganisms. ³⁶ Changes in the composition of the gut microbiome can affect homoeostasis and cause dysbiosis, which is linked to a higher prevalence of chronic inflammation. TLRs (toll‐like receptors) orchestrate this response by identifying and eliminating host bacteria. ³⁷ For example, TLR4 recognizes bacterial flagellin, whereas TLR5 recognizes bacterial LPS (lipopolysaccharides) in the cell walls of gram‐negative bacteria. ³⁸ TLR5‐knockout mice had a 20% increase in body mass relative to wild‐type controls but a 100% increase in epididymal fat pad size. ³⁹ Short‐chain fatty acids (SCFAs) can control the synthesis of gut hormones such as peptide YY (PYY), which is produced by the intestinal epithelium, and GLP‐1 and GLP‐2 (glucagon‐like peptides) and the K‐cell‐mediated release of stomach inhibitory peptides. ⁴⁰ The microbiome can also stimulate starch and dietary fiber fermentation in the lower gastrointestinal tract. In people with obesity, the expression of enzymes involved in the signaling pathways for glucose is downregulated. The synthesis of enzymes and SCFAs may be altered as a result of changes in particular microbial communities, which may be more relevant than general phylogenetic ratios. ⁴¹ These changes may then influence insulin and glucose homeostasis, which may eventually lead to the development of obesity.

3. EPIGENETIC PHENOMENON

Epigenetic inheritance is a term used in biology for studying a set of reversible heritable changes in gene function or other cell characteristics that occur without a change in DNA sequence (genotype); this is also known as epigenetics. ⁴² Epigenetic modifications influenced by environmental factors, such as nutrition, illness, or lifestyle, can modify how genes are expressed by turning them on and off. ⁴³ As demonstrated in studies on obesity and the epigenetic diet, three processes (Figure 1), including (a) DNA methylation, (b) histone modifications, and (c) noncoding microRNAs (miRNAs), are primarily responsible for the epigenetic control of chromatin structure.

FIGURE 1.

Schematic diagram illustrating the mechanics of epigenetic regulation.

3.1. DNA methylation in obesity

Adding methyl groups (‐CH3) to the cytosine of DNA molecules is a conserved chemical alteration known as DNA methylation. ⁴⁴ In particular, these methyl groups frequently bind to cytosine residues in the DNA double helix. The process of DNA methylation is catalyzed by DNA methyltransferases (DNMTs) that transfer the methyl group offered by S‐adenosyl‐l‐methionine (SAM) to the 5′‐site of the cytosine ring in DNA. While hypermethylation silences or reduces the expression of genes, hypomethylation activates or increases the expression of genes. Depending on the regulatory requirements of the cell, it is possible to determine the global or gene‐specific patterns of DNA methylation. ⁴⁵ More importantly, when DNA methylation is not properly controlled, it can disrupt gene expression, affect biological pathways, and ultimately lead to the development of a variety of diseases.

In obese individuals, defective DNA methylation has been discovered in the promoter regions of genes related to food intake and energy homeostasis. ⁴⁶ Insulin signaling, the production of structural and functional proteins, and the peroxisome proliferator‐activated receptors [PPAR]g and PPARa involved in lipogenesis are all controlled by epigenetic processes. ⁴⁷ , ⁴⁸ A previous study confirmed that TNF‐ɑ and leptin gene promoter methylation levels are lower in obese women who effectively respond to calorie restriction. ⁴⁹ Early stages of development are essential for creating and preserving epigenetic markers. The nutritional habits of a mother during pregnancy have the potential to alter the fetal course of development and contribute to obesity later in life. ⁵⁰ An increasing body of evidence suggests that changes in DNA methylation lead to programmed obesity. A recent study found that eating a large amount of fat when pregnant caused hypermethylation in the POMC promoter region, which remained for a long period of time in the offspring and may eventually induce metabolic issues. ⁴⁷

Adipose tissue from obese patients undergoes hypoxia. ⁵¹ Dick et al. examined the connection between whole‐blood DNA methylation levels and BMI. ⁵² They discovered five CpG sites, and in the gene for the hypoxia‐inducible factor 3 subunit alpha (HIF‐3), three of the five CpG sites displayed enhanced methylation, which is associated with an increase in BMI. ⁵² In a further investigation, the researchers examined the connection between childhood obesity and DNA methylation in Chinese adolescents. At two locations in the HIF‐3 gene, 46 801 699 and 46 801 642, higher levels of methylation were observed in children with obesity. ⁵³ Additionally, the levels of the enzyme alanine aminotransferase (ALT), which is associated with the development of NAFLD, were positively correlated with the levels of methylation.

Overall, the development and progression of obesity are generally linked to DNA methylation. It is connected to hypoxia in addition to being associated with BMI and serves as a marker to reflect changes in weight.

3.2. Altered histone posttranslational modifications are critical for obesity

Histones are proteins that package genomic DNA into nucleosomes, the fundamental building block of chromatin, and they can undergo posttranslational modifications with at least eight different types of reversible changes that are carried out by various enzymes. ⁵⁴ These modifications, which are carried out by enzymes called histone deacetylases (HDACs), histone acetyltransferases (HATs), and histone demethylases (HDMs), include acetylation, methylation, phosphorylation, and ubiquitination. ⁵⁵ Histone modifications can affect the tightness of DNA packing and consequently the accessibility of transcription factors and subsequent gene expression. Histone acetylation has been the subject of the majority of investigations on histone modification to date.

Histone lysine methylation and acetylation are involved in regulating adipocyte differentiation. In the hypothalamus, altered HDAC expression has been linked to obesity caused by high‐fat diets. ⁵⁶ In animal experiments, calorie restriction was found to alter histone changes, which modified how genes associated with obesity were expressed. ⁵⁷ The amount of food consumed affected the ratio of cellular NAD+ to NAD+ hydrogen (NADH), which in turn affected the activity of sirtuins (group III HDACs). ⁵⁸ Sirtuins are a class of NAD+‐dependent protein deacetylases. They are present in all phyla of life and are widely dispersed. Substantial evidence indicates that they control metabolism in a number of organs, including adipose tissue and the hypothalamus. ⁵⁹ Further evidence also revealed that SIRT1 plays a significant role in the regulation of energy metabolism. Both AgRP and POMC neurons express SIRT1, and the overexpression of SIRT1 in POMC neurons increases adipose tissue sympathetic activity, resulting in increased energy expenditure. ⁶⁰ Overexpression of SIRT1 in AgRP neurons suppresses the expression of hypothalamic AgRP, thus reducing appetite. Additionally, SIRT1 improves the sensitivity of hypothalamic neurons to leptin.

3.3. Role of miRNAs in obesity

MicroRNAs (miRNAs) are a group of small RNAs with a length of 18–25 nucleotides. They are endogenous and single‐stranded, and they have been uncovered as important transcriptional and posttranscriptional regulators of gene expression. ⁶¹ In detail, by interacting with the RNA‐induced silencing complex (RISC) and attaching to the 3′‐untranslated regions (3′‐UTRs) of target mRNAs, miRNAs can control the translation of target mRNAs by suppressing their translation and/or encouraging their destruction. ⁶² Epigenetic machinery and miRNA expression interact, and there is a feedback loop between them. The expression of some miRNAs can be controlled by numerous epigenetic processes, including DNA methylation and histone modifications. Additionally, miRNAs influence important epigenetic modification enzymes, including DNMTs and HDACs, which are engaged in epigenetic processes.

It has been reported that miRNAs play critical roles in adipogenesis, fat metabolism, and the generation of insulin by controlling the expression of numerous genes. ⁶³ Obesity is associated with miRNA dysregulation, and in preadipocytes and mature adipocytes, the regulation of miRNA was altered in obese individuals compared to that in thin individuals. ⁶⁴ In children with obesity, a substantial correlation between body mass index (BMI) and elevated levels of specific miRNAs (miR‐4865 P, miR‐4863P, miR‐1423P, miR‐130 b, and miR‐423 5P) and a significant alteration in the profiles of 10 miRNAs with a change in weight were observed. ⁶⁵ Additionally, alterations in miR‐7 and miR‐17‐92 resulted in sexual dimorphism and altered expression of FOXO1. These microRNAs regulate body weight, and other genes that have variable sex‐specific expression patterns in the arcuate nucleus (ARC) may contribute to the traits. ⁶⁶ More intriguingly, connections between miR‐143 and obesity were also observed recently. Sabine D et al. constructed mice deficient in miR‐143 and observed that there was protection against the emergence of insulin resistance caused by fat. Further research indicated that miR‐143 can downregulate the expression of oxysterol‐binding‐protein‐related protein (ORP) 8 to produce benefits for obesity‐associated diabetes. ⁶⁷ In addition, miR‐146b inhibits the activity of SIRT1. ⁶⁸ It appears that leptin increases the risk of obesity through miRNA interference.

Exosomal miRNAs from many cells and tissues have been demonstrated to have a role in the pathophysiology of obesity as a shared exosomal component. The expression of miR‐155 is increased 6.7‐fold in the adipose tissue macrophages (ATMs) of obese individuals. ⁶⁹ By targeting PPAR and GLUT4, exosomal miR‐155 produced from ATMs may be taken up by nearby adipocytes to manage the metabolism of adipocytes. Exosomes carrying miR‐690 are secreted by M2‐polarized bone marrow‐derived macrophages (BMDMs) and can increase sensitivity to insulin and tolerance to glucose in obese rats by targeting Nadk. ⁷⁰ Additionally, Pan et al. discovered that the expression of miR‐34a was increased in the adipose tissues of obese mice. ⁷¹ MiR‐34a, which is produced from adipocyte exosomes, is transported to macrophages, where it prevents M2 polarization by inhibiting the production of Krüppel‐like factor 4 (KLF4). This worsens the inflammatory response, insulin resistance, and energy metabolism disorders caused by obesity. ⁷¹ It is interesting to note that exosomes from adipose tissue might promote adipogenesis and exacerbate obesity. Exosomes generated from adipose tissue contain high levels of miR‐122. miR‐122 can inhibit the expression of SREBF1 and VDR by targeting VDR and interacting with the BS1 region of the SREBF1 promoter, which advances the pathophysiology of obesity. ⁷²

In general, exosomal miRNAs and other miRNAs play a vital role in the pathogenesis and treatment of obesity by controlling the expression of associated genes. Identification of such roles will shed new light on the prognosis, pathogenesis, and treatment of obesity.

4. OBESITY AND EPIGENETIC THERAPY WITH NATURAL PRODUCTS

Numerous bioactive dietary ingredients have drawn attention in the investigation of epigenetics for a variety of human disorders as a result of the finding that dietary bioactive compounds can correct epigenetic dysfunction. ¹² Some nutrients found in natural foods, such as dietary polyphenols, can modulate epigenetic processes. There are four main groups of dietary polyphenols: phenolic acids, flavonoids, lignans, and stilbenes. ⁷³ They have a concentration‐dependent ability to inhibit DNA methylation, which results in the reactivation and demethylation of genes silenced by methylation. They also contribute to histone modifications and miRNA‐based epigenetic regulation. Through these epigenetic changes, they may reduce adipogenesis and increase fat oxidation to avoid obesity (Table 1 and Figure 2).

TABLE 1.

Overview of natural products and how they affect the development of obesity.

No.	Substances	Structure	Source	Epigenetic mechanism	Possible influence on obesity	Ref.
1	EGCG		Green tea, cocoa	Inhibition of DNMT activity and down‐regulation of HMTs expression	Adipogenesis↓, fat oxidation↑, adiponectin↑, leptin level↑	[76, 77, 78]
2	Resveratrol		Grapes, peanuts, mulberries, cranberries	Inhibition of DNMT activity and down‐regulation the HDAC expression	Adipogenesis↓, fat oxidation↑, inflammation↓	[83, 84, 85, 88]
3	Ellagic acid		Pomegranates, grapes, nuts, strawberries, black currents, raspberries	Down‐regulation of HMTs and HDAC expression	Fat oxidation↑, inflammation↓	[93, 94, 95]
4	Urolithin C		Ellagitannins, ellagic acid	Inhibition of HAT activity	Adipogenesis↓, fat oxidation↑, inflammation↓	[99]
5	Genistein		Soybean	Inhibition of DNMT activity and induction of changes in miRNAs and histone expression	Adipogenesis↓	[105]
6	Apigenin		Celery, tea, mint, oregano	Down‐regulation of DNMT and HDAC expression	Fat oxidation↑, inflammation↓	[107]
7	Naringenin		Citrus, turmeric	Regulation of miRNA expression	Adipogenesis↓, fat oxidation↑, inflammation↓	[112]
8	Curcumin		Citrus, turmeric	Inhibition of HAT activity and down‐regulation of DNMT expression	Adiponectin↓, fat oxidation↑, inflammation↓	[114, 115, 116, 117]
9	Sulforaphane		Broccoli, cabbage, kale	Inhibition of DNMT and HDAC activity and induction of changes in miRNAs	Adipogenesis↓, POMC and leptin expression↑	[120, 121]

FIGURE 2.

Natural products with therapeutic potential in obesity by targeting the epigenetic mechanisms.

4.1. Tea polyphenols

Different types of tea are made by processing the leaves of the Camellia sinensis plant in a number of different ways. More polyphenols are present in green tea than in black tea. In green tea, epigallocatechin‐3‐gallate (EGCG) is the catechin that is both most prevalent and most active. ⁷⁴ Catechins have long been recognized for their antioxidant properties. According to previous studies, EGCG forges hydrogen bonds between the residues in the active site of the enzyme; thus, it directly inhibits DNMTs and suppresses DNA methylation indirectly by increasing homocysteine levels and S‐adenosyl‐L‐homocysteine (SAH) while lowering SAM. ⁷⁵ Furthermore, EGCG also affects histone modifications by preventing HMTs. ⁷⁶ Green tea catechins have been reported to have anti‐obesity properties. The potential therapeutic mechanisms may be related to decreases in the intestinal absorption of lipids and activation of β‐oxidation enzymes in adipose tissue and the liver and the downregulation of adipocyte proliferation and differentiation‐related enzymes. ⁷⁷ Xi et al. administered a high‐dose (856.8 mg/kg/d) EGCG injection for 3 months to obese mice and found that animals treated with EGCG had significantly lower body weights and higher levels of circulating leptin. ⁷⁸ Notably, comparable human research, however, has produced inconsistent results. It was shown that EGCG injections result in weight reduction coupled with a decrease in ghrelin and a rise in adiponectin. However, leptin levels were not altered significantly in the blood of centrally obese women. ⁷⁹ Moreover, it was reported that there was no significant change in circulating leptin levels after long‐term use of a high dosage of EGCG in postmenopausal overweight and obese women. ⁸⁰ However, the methylation state of the gene promoters for adiponectin, ghrelin, and leptin has not yet been evaluated in any of the animal experiments mentioned earlier or human trials. It is highly necessary to investigate the impact of EGCG therapy on the methylation patterns and levels of expression of certain genes associated with obesity in both animal and human studies.

4.2. Resveratrol

Resveratrol is a well‐known plant polyphenol that is abundantly present in the skin of grapes, peanuts, mulberries, and cranberries and possesses strong antioxidant, anti‐inflammatory, anticancer potential, and neuroprotective effects. ⁸¹ With in‐depth research on resveratrol, its biological functions are constantly being discovered. It was reported that resveratrol alters histone posttranslational changes and suppresses DNMT activity. ⁸² As a potent SIRT1 activator, resveratrol has been confirmed to have anti‐obesity potential due to its strong ability to block preadipocyte development, decrease lipogenesis and adipocyte proliferation, increase apoptosis, and increase the capacity for lipolysis and fatty acid beta‐oxidation in adipocytes. ⁸³ , ⁸⁴ , ⁸⁵ Resveratrol was discovered to suppress the expression of the adipocyte‐specific genes PPARg, C/EBPa, SREBP‐1 c, FAS, hormone‐sensitive lipase, and lipoprotein lipase (LPL) in 3 T3‐L1 adipocytes. ⁸⁶ Triacylglycerol, a component of both circulating chylomicrons and very low‐density lipoproteins, is hydrolyzed by LPL, thus generating free fatty acids (FFAs) for tissue use. The majority of FFAs that are available for adipocyte absorption are produced by LPL, which mediates the hydrolysis of lipoproteins in the blood. ⁴⁰ LPL is necessary for adipose tissue to complete the efficient absorption and storage of fatty acids. It has been confirmed that resveratrol can produce hypertriacylglycemia by downregulating LPL, but it also reduces the amount of circulating fatty acids that can be absorbed by adipose tissue for adipogenesis. ⁸⁷ Notably, in rats fed an obesogenic diet, the FAS gene was discovered to be hypomethylated and activated. More interestingly, pterostilbene reversed the changes in the FAS methylation pattern induced by the obesogenic diet, while resveratrol did not.

SIRT1 is activated by calorie restriction. To adjust gene transcription in response to variations in nutrition levels, SIRT1 works in conjunction with transcription factors that regulate lipids. It has been demonstrated that activated SIRT1 participates in the deacetylation of transcription factors that control the biological mechanisms underlying inflammation. ⁸⁸ SIRT1 activation increases lipolysis and decreases fat accumulation by boosting insulin sensitivity and suppressing inflammation. ⁸⁹ It is not difficult to speculate that instead of NMT inhibition, SIRT1 activation appears to be the cause of the anti‐obesity potential of resveratrol.

4.3. Ellagic acid and its gut metabolites urolithins

Ellagic acid is a naturally occurring phenolic component found in ellagitannins (ETs) in foods, including grapes, almonds, strawberries, black currants, raspberries, pomegranates, and herbal medicines. ⁹⁰ It possesses antioxidant, anti‐inflammatory, antimutagenic, and obesogenic properties. In LPS‐stimulated macrophages and adipocytes, TNF‐ɑ, nitric oxide, and chemokine C‐C motif ligand‐2 (CCL‐2) gene expression levels have been observed to be decreased by EA, indicating that EA may effectively lower in vitro adipose inflammation. ⁹¹ In addition, pomegranate fruit extract containing EA (30 mg/kg BW) or EA supplementation (0.1% in the diet), which are strongly related to hepatic steatosis, dyslipidemia, and chronic inflammation, were also found to diminish these conditions in a study. ⁹²

Even though EA does not seem to accumulate in adipose tissue, a recent study unequivocally showed that raspberry seed EA reduces pro‐inflammatory cytokine release in adipose tissue and reduces macrophage infiltration when a high‐fat, high‐sugar diet is consumed. ⁹³ More interestingly, a study conducted by Kang et al. inspected whether EA alters chromatin remodeling in human adipogenic stem cells (hASCs) to prevent adipogenesis. The results showed that EA is the polyphenolic substance in muscadine grape polyphenols (MGPs) and that 10 μmol/L EA significantly inhibits histone deacetylase (HDAC)9 downregulation. ⁹⁴ Furthermore, the fact that EA therapy was linked to lower levels of histone 3 arginine 17 methylation (H3R17me2) suggests that EA inhibits the activity of coactivator‐associated arginine methyltransferase 1 (CARM1) during adipogenesis. ⁹⁵

Urolithins (Uros) are dibenzo[b,d]pyran‐6‐one derivatives generated by the gut microbiota from the dietary polyphenols ETs and EA. ⁹⁶ The potential beneficial effects of urolithins on obesity have been well documented. Vergadi E et al. reported that rats were protected from obesity‐causing high‐fat diets by daily intraperitoneal injections of Uro A because it reduced oxidative stress, decreased lipogenesis, and offered antioxidant defences. ⁹⁷ Abdulrahman et al. found that body weight gain was decreased in male obese Wistar rats by modulating the composition of the gut microbiota after the administration of 2.5 mg/kg Uro B via intraperitoneal injection four times a week for 4 weeks. ⁹⁸ These results suggest that Uros are potential therapeutic agents for the management of obesity‐associated inflammation and metabolic dysfunction. However, it is relatively uncommon to find direct proof that EA metabolites modify epigenetic enzymes to control obesity‐related adipose growth. Kiss AK et al. demonstrated that Uro C inhibits monocyte histone acetyltransferase (HAT) activity, thereby reducing TNF‐ɑ‐induced inflammation. ⁹⁹ Therefore, more epigenetic research is needed to clarify the epigenetic mechanisms of EA and its metabolites in obesity.

4.4. Genistein

Genistein is a natural isoflavone that is contained in soybean and was shown to affect the DNA methylation state to regulate gene transcription. ¹⁰⁰ The genes that had been silenced by methylation can be reactivated by genistein through the inhibition of DNMT1, DNMT3a, and DNMT3b. ¹⁰¹ Additionally, genistein affects miRNAs and histone changes. ¹⁰² , ¹⁰³ It has been shown that dietary genistein improves lipid and glucose metabolism, lowers body weight, and regulates hypothalamic circadian entrainment, all of which are protective against metabolic diseases. ¹⁰⁴ Important transcription factors, such as PPARg and C/EBPa, regulate adipogenesis. Genistein has been demonstrated to impede the development of adipocytes even in low quantities in mature adipocytes by altering the expression of the mRNAs for C/EBPa, PPARg1, PPARg2, and GLUT4. ¹⁰⁵

4.5. Apigenin

Apigenin is a plant trihydroxyflavone possessing anti‐inflammatory and antioxidant properties that has been proposed as an anti‐obesity natural product. ¹⁰⁶ Through a literature search, apigenin was reported to dramatically lessen body weight increase, glucose intolerance, and insulin resistance in male C57BL/6 mice fed a high‐fat diet for 12 weeks. ¹⁰⁷ This advantageous outcome was attributed to increased fatty acid oxidation, enhanced thermogenesis, activated lipolysis, and decreased adipose tissue inflammation. Furthermore, apigenin was discovered to reverse the hypermethylated promoter of the Nrf2 transcription factor in a dose‐dependent manner; this strategy also aims to decrease the expression of some HDACs and DNMTs in mouse skin epidermal JB6 P⁺ cells. ¹⁰⁸ However, it is still unknown whether the expression of genes related to obesity is impacted by apigenin.

4.6. Citrus flavonoids

Citrus flavonoids, such as naringenin, hesperidin, nobiletin, and tangeretin, have demonstrated excellent anti‐inflammatory and antioxidant properties, making them prospective therapeutic agents for the treatment of obesity. ¹⁰⁹ Citrus flavonoids have been found to decrease the number of adipocytes, enhance energy expenditure, promote fatty acid oxidation, and prevent obesity in animal experimental studies. Naringenin increases the expression of fatty acid oxidation genes, such as CPT‐1 and UCP2, both of which are known to be regulated by PPAR. Thus, naringenin was administered to rats, and this led to a reduction in adiposity and triglyceride levels in parametrial adipose tissue. ¹¹⁰ However, there are very few studies investigating how citrus flavonoids affect the epigenetic control of the genes associated with obesity. ¹¹¹ According to research by de la Garza et al., extracts from grapefruit and helichrysum were found to reduce the expression of several pro‐inflammatory genes and increase DNA methylation at the gene promoter for TNF‐α in the liver and epididymal adipose tissue. In addition, it has been established that naringenin exerts its antioxidant effect via epigenetic regulation influenced by miR‐173P and miR‐255P. ¹¹²

4.7. Curcumin

The biphenolic active ingredient in turmeric known as curcumin (diferuloylmethane) has been utilized for centuries to treat inflammatory diseases. ¹¹³ Evidence from a mechanistic study conducted by Apei Jiang et al. showed that curcumin had the ability to lower DNMT3b mRNA levels. ¹¹⁴ Further study showed that curcumin can increase lipolysis by specifically inducing fatty acid β‐oxidation and downregulating FAS by regulating acetyl‐CoA carboxylase and hormone‐sensitive lipase. ¹¹⁵ In an obesity mouse model fed a high‐fat diet (22%), supplementation with curcumin was found to decrease body weight growth without affecting food intake and enhance fatty acid beta‐oxidation and energy metabolism in adipocytes. ¹¹⁶ In addition, Yun et al. reported that curcumin treatment significantly inhibited inflammation by reducing HAT activity, the level of p300 and acetylated CBP/p300 gene expression in a high glucose‐induced inflammation cell model in THP‐1 cells. ¹¹⁷ Taken together, the findings from these in vivo and in vitro studies suggested that curcumin reduced inflammation and promoted fat oxidation to combat obesity.

4.8. Isothiocyanates

Sulforaphane is a naturally occurring substance created from the isothiocyanate found in cruciferous vegetables, such as collards, mustard greens, and turnips, and exerts beneficial effects on obesity by exerting antioxidant and anti‐inflammatory functions. ¹¹⁸ In MDA‐MB‐231 and MCF‐7 breast cancer cells, sulforaphane was found to inhibit DNMTs and HDACs and modify miRNAs. ¹¹⁹ In high‐fat diet‐induced animal studies, benzyl isothiocyanate and phenethyl isothiocyanate were found to reduce HFD‐induced obesity and fatty liver by suppressing orexigenic NPY/AGRP expression, enhancing anorexigenic POMC expression, and downregulating adipocyte differentiation and the expression of lipogenic transcription factors and enzymes. ¹²⁰ It is unknown whether the changes in gene expression are caused by these epigenetic processes. Yagi et al. showed that oral treatment of mice with phenethyl isothiocyanate dramatically decreases food intake by enhancing hypothalamic leptin signaling. ¹²¹ Overall, these findings suggest that phenethyl isothiocyanate can help prevent and improve obesity.

5. NEW TECHNOLOGIES FOR STUDYING EPIGENETIC MECHANISMS AND CORRESPONDING DRUG DEVELOPMENT IN OBESITY THERAPY

5.1. Spatial transcriptomics and spatial epigenomics

Single‐cell RNA sequencing (scRNA‐seq), which was developed a decade ago, is now a standard technique for identifying transcriptional heterogeneity in individual cells. ¹²² The processes of gene regulation can be uncovered using single‐cell multiomics across several omics layers. However, spatial information is lacking, and this is essential for comprehending cellular activity in tissue. ¹²³ Recent advances in spatial epigenomics, transcriptomics, and proteomics have only been able to capture a single layer of omics data. Although computational approaches can combine data from several omics strategies, they struggle to quickly identify the mechanistic connections between the omics layers. ¹²⁴ Prior to the realization of the 10X Visium platform, for the spatially resolved measurement of a panel of proteins and the transcriptome, Ben‐Chetrit et al. constructed deterministic barcoding in tissue for omics sequencing. ¹²⁵ More interestingly, a recent study by Di Zhang et al. developed spatially resolved, genome‐wide comapping of the epigenome and transcriptome by concurrent profiling of chromatin accessibility and messenger RNA expression (spatial assay for transposase‐accessible chromatin and RNA using sequencing, or spatial assay of cleavage unc‐seq), histone modifications and mRNA expression (spatial ATAC‐RNA‐seq), or histone modifications and mRNA expression on the same tissue segment at the cellular level to combine the chemistry of spatial‐ATAC‐seq3 or spatial‐CUT&Tag2 with that for spatial transcriptomics (spatial CUT&Tag‐RNA‐seq; applied to H3K27me3, H3K27ac, or H3K4me3 histone modifications). ¹²⁶ In the future, we hope this will be the impetus for application in adult human fat tissue to analyze how epigenetic and transcriptional changes affect the dynamics of different cell types in a tissue to help us better understand the epigenetic mechanisms of obesity. ¹²⁷

5.2. Spatial metabolomics

At present, obesity and other metabolic illnesses continue to pose a risk to human health. The development of tissue biopsy based on biomarkers of obese tissue or blood cannot satisfy the objectives of translational medicine clinical research with the advent of spatial multiomics. ¹²⁸ Due to the COVID‐19 pandemic, we now know less than we used to about diseases such as diabetes and the physiological causes of fat storage and pathogenesis. The main focus of future research will be on how to develop a quick and efficient drug screening platform for tissue space biomarker identification and how to integrate it with clinicopathology. ¹²⁹ In recent years, spatial metabolomics has become increasingly appreciated. Spatial metabolomics is a technology that integrates mass spectrometry imaging and metabolomics technology to precisely assess the kind, quantity, and geographic distribution of medicines, other small molecules, and endogenous metabolites in tissues. ¹³⁰ It broadens the scope of metabolome data and is essential for life science functional research. This technology has significant benefits over other imaging techniques with high specificity and throughput as well as the retention of spatial information (such as fluorescence imaging, radiolabeled imaging, etc.) and the lack of need for chemicals, radio labeling, or laborious sample pretreatment. ¹³¹ With its ability to fully explain the spatiotemporal patterns of metabolism and the actions of endogenous substances or drugs in adipose tissue, spatial metabolomics technology offers a unique perspective on the regulation of obesity.

5.3. hPSC‐derived models of adipose organoids

Recently, cell research models for metabolic illnesses have been created using human‐induced pluripotent stem cell (hPSC) technology, which was created by the Yamanaka group. ¹³² Although significant efforts have been made over the past 10 years to better understand how the environment affects adipose tissue, the physiological differences between human and rodent models of adipose tissue make systematic understanding of the important function of epigenetics in the development of obesity challenging. ¹³³ Since the advent of stem cell technology, translational medicine has undergone a significant transformation. In vitro models of metabolic disorders have been established and put to use. Human adipocyte cells may be directly extracted and their genomes edited using the CRISPR/Cas system, and this technology is already ushering in a new era of personalized treatment. ¹³⁴ Additionally, it is possible to recognize and study the physiological and histological problems in people with obesity without using human adipose tissue, which is obtained through autopsy and surgical operations. ¹³⁵ In the future, we believe that this will serve as the catalyst to broaden the combined application of in vitro patient‐derived iPSC models and in vivo rodent models to aid in our understanding of the various facets of obesity and other metabolic diseases. ¹³⁶

New insights are continuously offered to us by technological breakthroughs. Numerous scientific advancements are currently taking place in fields including single‐cell proteomics, transcriptomics, metabolomics, and stem cell technology. Application of these novel methods is certain to uncover previously undiscovered epigenetic characteristics and launch a crucial new line of inquiry into obesity (Figure 3).

FIGURE 3.

New technologies to study epigenetic mechanism of obesity. Spatial transcriptomics, spatial epigenomics, spatial metabolomics, and hPSC‐derived of adipose organoids can be applied to study the molecular mechanism of obesity.

6. CONCLUSION AND FUTURE OUTLOOK

The primary molecular strategies for managing obesity include driving fat oxidation, reducing gastrointestinal tract lipid absorption, and inhibiting adipogenesis. The great majority of metabolic process‐related genes are controlled by epigenetic mechanisms. Accumulating evidence has shown that there is a close link between obesity and epigenetic dysregulation in the genes responsible for adipogenesis and fat oxidation. Tea polyphenols, resveratrol, ellagic acid, urolithins, citrus flavonoids, isothiocyanates, curcumin, and apigenin are well known for their antioxidant properties as well as being epigenetic regulators that can remedy related diseases by resolving epigenetic dysregulations. The citrus flavonoid naringenin has been found to exert its antioxidant action via miRNA‐controlled epigenetic regulation. ¹³⁷ According to what is now known, these natural substances very certainly have significant effects on how adipogenesis and fat oxidation are regulated by changing the expression of linked genes.

To the best of our knowledge, there is no information in the literature about how these natural substances affect the epigenetic regulation of lipid absorption from the stomach. Even though some of these compounds, such as tea polyphenols, have been recognized to reduce the absorption of fat from the gastrointestinal tract, this is assumed to be because they block pancreatic lipase. Diets with these phytochemicals are being studied as a way to treat obesity and prevent weight gain. ¹³⁸ Human studies are still needed to be conducted to fully understand the effect of these natural compounds on the expression of genes linked to obesity from an epigenetic perspective despite the promising results from animal studies.

Another issue should be considered is that despite the capacity of chaperones and other homeostatic components to restore folding equilibrium, cells appear poorly adapted for chronic oxidative stress that increases in cancer and in metabolic and neurodegenerative diseases. ¹³⁹ Modulation of endogenous cellular defense mechanisms maybe an innovative approach to therapeutic intervention in diseases causing chronic tissue damage, such as in neurodegeneration. ¹⁴⁰ Epidemiological evidence showed that patients suffering from obesity and T2DM are significantly at higher risk for chronic low‐grade inflammation, oxidative stress, nonalcoholic fatty liver (NAFLD), and intestinal flora imbalance. ¹⁴¹ Increasing evidence of pathological characteristics illustrates that some common signaling pathways participate in the occurrence, progression, treatment, and prevention of obesity and T2DM. ¹⁴² These signaling pathways contain the pivotal players in glucose and lipid metabolism, for example, AMPK, PI3K/AKT, FGF21, Hedgehog, Notch, and WNT; the inflammation response, for instance, Nrf2, MAPK, NF‐kB, and JAK/STAT. ¹⁴³ Bioactive compounds from plants have emerged as key food components related to healthy status and disease prevention. They can act as signaling molecules to initiate or mediate signaling transduction that regulates cell function and homeostasis to repair and re‐functionalize the damaged tissues and organs. ¹⁴⁴ Therefore, it is crucial to continuously investigate bioactive compounds as sources of new pharmaceuticals for obesity and T2DM. In numerous experimental models, natural antioxidants induce hormetic dose responses displaying endpoints of biomedical and clinical relevance. ¹⁴⁵ Interestingly, the mechanistic profile of natural antioxidants is similar to that of numerous other hormetic agents, indicating that activation of the Nrf2/ARE pathway is probably a central, integrative, and underlying mechanism of hormesis itself. ¹⁴⁶ The Nrf2/ARE pathway provides an explanation for how large numbers of agents that both display hormetic dose responses and activate Nrf2 can function to limit age‐related damage. ¹⁴⁷ This notion is consistent with experimental disease models, in which hormetic activation of Nrf2 effectively reduce the occurrence and severity of a wide range of human‐related pathologies, including major neurodegenerative disorders. Thus, interplay and coordination of redox interactions with endogenous and exogenous antioxidant defense systems is an emerging area of research interest in anti‐inflammatory anti‐degenerative therapeutics.

Furthermore, the biomolecular aspect of energy homeostasis induced by epigenetics changes are not well explained. As is well known, obesity prevalence has rapidly increased in the last 40–50 years, and the time span is insufficient to develop a considerable number of novel DNA variations that cause obesity. ³ , ⁶ It is conceivable that epigenetic regulation, which is dynamic and allows the cell to alter gene expression in response to multiple signaling pathways and environmental stimuli, is a strong contender for explaining the so‐called “developmental programming” of body weight management. ¹⁴⁸ The balance between energy intake/absorption and energy expenditure/loss maintains whole‐body energy homeostasis. ¹⁴⁹ When energy intake/absorption exceeds energy expenditure/loss, like in sedentary lifestyle combined with energy‐dense nutrition, the surplus energy is stored in adipose tissue, leading to obesity. ¹⁵⁰ To regulate energy metabolism, many genes are activated or deactivated, and epigenetic factors are the key methods for modifying gene expression. ¹⁵¹ Accordingly, the roles of epigenetic modifications in modulating energy metabolism have gained great interest. However, the information on advancement in epigenetic regulation of energy metabolism in obesity was not mentioned in the current review. Therefore, more studies and summaries on the molecular mechanisms for energy metabolism are expected in the future.

Finally, rapid development in cutting‐edge techniques such as sequencing and omics techniques and the increasing body of epigenomic data offer unprecedented opportunities to study epigenetic mechanisms and corresponding drug development in obesity therapy. ¹⁵² , ¹⁵³ Spatial transcriptomics, spatial epigenomics, spatial metabolomics, and hPSC‐derived models of adipose organoids can be employed to study the molecular causes of obesity and the metabolic organs, which will help us understand the epigenetic mechanism of obesity.

AUTHOR CONTRIBUTIONS

Peng Chen, Yulai Wang, Fuchao Chen and Benhong Zhou reviewed past literature and wrote this manuscript.

CONFLICT OF INTEREST STATEMENT

The authors have no conflict of interest.

Chen P, Wang Y, Chen F, Zhou B. Epigenetics in obesity: Mechanisms and advances in therapies based on natural products. Pharmacol Res Perspect. 2024;12:e1171. doi: 10.1002/prp2.1171

DATA AVAILABILITY STATEMENT

The data sets used and/oranalyzed during the current study are available from the corresponding author upon reasonable request.