Damian Sendler: Having too much body fat has a negative impact on one’s health, and obesity is a disease with many contributing factors. There are no signs that the obesity epidemic will slow down any time soon, making it an unprecedented epidemic. Unhealthy noncommunicable diseases such as diabetes, heart disease, and musculoskeletal disorders are all exacerbated by an overweight or obese person’s high body mass index (BMI). Obesity is primarily caused by a long-term imbalance in energy intake and expenditure. The goal of this study is to uncover the underlying biological mechanisms that lead to obesity and to develop treatment plans that can be implemented immediately to help people lose weight in a healthy way.
Damian Jacob Sendler: A significant rise in obesity rates has occurred worldwide over the past 50 years. Obesity is defined as having a BMI (kg/m2) greater than or equal to 30; overweight is defined as having a BMI of 25.0-29.9, dividing a person’s weight by their height. There are more deaths associated with being overweight or obese than with being underweight, and being overweight or obese is more common around the world than being underweight. Even countries with low obesity rates (e.g., Sri Lanka) are affected by this global phenomenon, which is present in every region except parts of sub-Saharan Asia and Africa (1). (2).
Dr. Sendler: Being overweight increases the risk of a wide range of diseases and conditions that are linked to an increased mortality. Type 2 diabetes, cardiovascular disease, metabolic syndrome, chronic kidney disease, hyperlipidemia, hypertension, nonalcoholic fatty liver disease (NAFLD), certain types of cancer, obstructive sleep apnea, osteoarthritis, and depression are all examples of these conditions (3). It is estimated that the obese have a 30% higher medical cost than those with a normal BMI, which is why treating these conditions can put additional strain on healthcare systems (4). Obesity-related health care costs continue to rise at an alarming rate, posing a significant financial burden for patients (5).
Obesity can be caused by a variety of factors. Rather, the traditional view is that excess energy stored in the body is the primary cause of fatigue. There is a buildup of fat cells in the body due to excess energy being stored. When fat cells grow abnormally, the nutrient signals that cause obesity are altered (6). Recent studies have shown that the quality and source of nutrients in a diet are more important than the amount of nutrients in the diet for weight control and disease prevention, respectively (7). Obesity can be traced back to a variety of factors, including genetic and epigenetic, environmental and microenvironmental, as well as nurture and nature. Increasingly, we’re learning about how obesity increases a person’s appetite and satiation in the hypothalamus via gut hormones, fat tissue, or gut microbiota, as well as the role of gut dysbiosis in obesity development and the secondary health problems caused by impaired glucose and lipid metabolism (8). In addition, it is well-established that a person’s predisposition to weight gain is strongly influenced by genetic factors (9). Studies on epigenetics in the last few years have provided important resources for figuring out why obesity is on the rise everywhere (10). As a result of a number of studies, the role of epigenetic factors in metabolism regulation, obesity risk, and obesity-related complications has been examined (11).
Overwhelming new scientific evidence is causing changes in the field of obesity research at a rapid pace. To better understand obesity, we’ll look at its epidemiology, which includes a look at the underlying pathophysiology and pathogenesis as well as the genetics, epigenetics, and environmental factors that contribute to obesity. We’ll wrap things up with a list of some management and prevention options.
According to World Health Organization (WHO) guidelines, BMI is used to define and diagnose obesity (4). WHO considers an adult to be “overweight” if their body mass index (BMI) is between 25 and 29.9, and an obese individual has a BMI greater than 30. There are three severity levels of obesity: class I (BMI 30.0-34.9), class II (BMI 35.0-39.9) and class III (BMI 40.0). (12). However, the percentage of body fat for a given BMI value varies widely among individuals, and this can be attributed to factors such as gender, ethnicity, and age (13). Obesity that has accumulated around the midsection is known as “abdominal obesity,” and it is linked to a plethora of health issues (14). From the World Health Organization (WHO), the International Diabetes Federation (IDF), and the American Heart Association (AHA), the definition and measurement guidelines for abdominal obesity varied (15). However, there is no universally applicable international standard.
The prevalence of excessive weight gain has doubled worldwide since 1980, and about a third of the global population has been determined to be obese or overweight (16). Obesity rates have increased dramatically in both men and women, and across all ages, with women and the elderly particularly vulnerable (4). While this trend is prevalent around the world, the absolute prevalence rates vary greatly between regions, countries, and ethnic groups. Socioeconomic status affects the prevalence of obesity, with higher-income and some middle-income countries seeing slower increases in BMI. However, despite the fact that obesity was once thought to be a problem unique to high-income countries, the incidence rates of obese or overweight children in these countries have decreased or plateaued since the early 2000s (17).
Overweight and obesity are on the rise, especially in cities, in low- and middle-income countries. The prevalence of age-adjusted obesity in China rose from 2.15 percent to 13.99 percent in both sexes, going from 2.78 percent to 13.22 percent in females and from 1.46 percent to 14.99 percent in males, according to a study of 12,543 participants (18, 19). Since the year 2000, the percentage of African children under the age of five who are overweight has risen by 24%. Nearly half of Asian children under the age of five were either obese or overweight as of 2019. (20). According to WHO data collected in Sub-Saharan Africa, adult obesity and overweight are inversely related to child stunting, underweight, and wasting (21).
There are many factors involved in the development of obesity, including genetics, socioeconomic status, and a host of others that influence calorie intake, food intake, and physical activity.
Obesity’s root causes are still up in the air. The underlying physiological property that fat accumulation is driven by an energy imbalance between consumed and expended calories is the basis for current health recommendations to manage obesity. Increased availability of high-rewarding and energy-dense food has been a major factor in fueling the obesity epidemic. There is a direct correlation between food supply and the ability of a patient to achieve a state of equilibrium (22). Following up on 3,000 young people over a period of 13 years, researchers discovered that those who consumed the most fast food tended to weigh more and have larger waist circumferences than those who consumed the least. A higher incidence of weight-related health problems, such as elevated triglycerides, was also discovered, as were twofold higher odds of developing Metabolic Syndrome (MetS) (23). These problems are exacerbated in people who have a predisposition to fat accumulation due to interactions between homeostatic circuits and brain reward, which may be hereditary. Other hypothalamic neuron impairing mechanisms may also lead to obesity, which may explain the biological defense of an elevated body fat mass (24).
Obesogenic marketing, which promotes sugary and fatty foods, has a negative effect on human behavior. It’s possible that these kinds of commercials will lead people to seek out more high-energy foods and beverages (25). Food advertisements were more prevalent in African American programs than in general market programs, according to the results of the study There were more meat, candy, soda, and fast food ads than there were for whole grains, pasta, cereals, vegetables, and fruits combined in all. Products advertised as “irresistible tasting” and “cheap” were created with these characteristics in mind. Foods high in fat and sugar, such as candy and soda, can activate the brain’s reward centers, the same part of the brain that is activated by cocaine and heroin and other addictive drugs (25). The brain reward theory provides a plausible explanation for an individual’s increased body fat mass, but it appears to only apply to a small number of people.
Treatment of obesity requires a thorough assessment of patient health factors that influence energy intake, metabolism, and expenditure by clinicians. Obesity management through behavioral changes aimed at addressing these three factors is often unsuccessful. Energy management and the interplay between intake, metabolism, and expenditure are still a mystery to many (26).
Obesity is a result of a combination of genetic, environmental, and psychological factors. Obesity risk can be influenced by both genetics (a predisposition to fat storage) (27) and environmental factors (a poor diet or lack of physical activity) (28). One obese parent raises a child’s risk of becoming obese by three times, while if both parents are obese, the child’s risk rises to ten times. 260 children (139 females and 121 males) ranging in age from two months to seventeen years were examined in a cross-sectional observational study to determine the importance of family history of cardiometabolic disease and obesity as indicators of childhood obesity severity (29).
Damian Jacob Markiewicz Sendler: Many factors have been found to increase the risk of childhood obesity, including parents’ obesity, frequent snacking, sleep deprivation (less than eight hours per night), and daily consumption of sugary beverages and sugary foods by 3148 Ariana schoolboys (aged six to ten) (30). There was a strong correlation between a mother’s healthy lifestyle during her children’s childhood and adolescence and a lower risk of obesity in their children, according to two studies conducted in the US (31). These findings demonstrate the advantages of family or parental intervention in reducing the risk of childhood obesity (31).
However, obesity in children is not solely the fault of parents. The United States, for example, had a public school curriculum that included regular physical education (32). Programs were reduced in 2011 so that just 25 percent of students could meet the national standards for at least 225 minutes weekly at the high school and primary levels, respectively (33). Increased use of video games and mobile devices, as well as less time spent actively or outdoors, may have contributed to the decline in children’s physical activity. Technological advancement is hard to argue against, but these studies suggest that it may be harming children’s health (34).
Recently, we’ve learned a lot more about the gut microbiome and how it’s linked to various health problems. The altered gut microenvironment caused by obesity, for example, supports a greater diversity of viral species than is found in leaner hosts (35). Because of this, pathogenic variants with the potential to cause more severe disease are more likely to arise (36). It’s becoming more and more clear that the microbiome of a person’s gut affects their weight and metabolism. Germ-free male mice (without gut microflora) had 42 percent less total body fat than mice with normal gut microbiota, even when they consumed 29 percent more food per day. But after colonization with cecal microbes, these mice’s total body fat increased by 57%, lean mass decreased by 7%, and daily food intake decreased by 27%. (35). After microflora colonization, capillary density in the distal small intestinal villi increased by 25 percent, suggesting that these changes were caused by decreased metabolic rates and increased adipose tissue deposition. Female mice produced similar results, as well (37).
The gastrointestinal tract is home to the vast majority of the body’s 3.8 1013 microorganisms. Bacteria make up the majority of the microbial population, with Archaea and Eukarya making up the rest (38). Multiple microbes can perform similar functions in a healthy digestive system because of the diversity of the microbiome. Normally, the gut microbiota play a significant role in the host’s metabolism of carbohydrate and lipid, the synthesis of vitamins and amino acids, the proliferation of epithelial cells, protection against pathogens, and the modulation of hormone levels. Digestible molecules such as oligosaccharides in human milk and polysaccharides in plants can also be broken down by gut bacteria (39). Dysbiosis, or an unbalanced population of microorganisms, has been linked to a wide range of diseases, including neurological disorders, inflammatory bowel disease, malnutrition, cancer, diabetes, and obesity, to name just a few (40). Recent studies have shown that caloric restriction can improve the gut microbiome and antibiotic use can harm the gut microbiome in ways that lead to diabetes and obesity. Several human studies confirm the hypothesis that obesity is linked to changes in the microbiome, but the exact mechanisms (such as the ratios and quantities of microflora diversity) are still a mystery (41).
Microbes in the digestive tract play an important role in the human immune system. Inflammation of the intestinal lining can result from changes in the microflora of the gut (42). TLRs (toll-like receptors) have been shown to be a mediator of this response, which identifies and attacks the host microbes. TLR4 recognizes the bacterial LPS (lipopolysaccharides) in Gram-negative bacteria’s cell walls, while TLR5 recognizes the bacterial flagellins in Gram-positive bacteria. TLR5-knockout mice had a 20% increase in body mass and a 100% increase in epididymal fat pad size when compared to wild-type controls (43). As a result of the microbiome-induced fermentation of dietary fiber and starch in the lower digestive tract, SCFAs (Short-chain fatty acids) can be produced, which can regulate the production of gut hormones like peptide YY (PYY) in the intestinal epithelium and the glucagon-like peptides GLP-1 and GLP-2, as well as the secretion of gastric inhibitory peptides by K cells (44). Enzymes involved in or signaling through glucose signaling pathways are downregulated in obese patients. Is it more important to look at the specific microbial populations, rather than the overall phylogenetic ratio, to determine how these populations affect enzyme production, which then affects the insulin/glucose regulation? (41).
Damian Sendler
Around 40-70 percent of human obesity variation is a result of genetic factors, according to family and twin studies (45). Genetic factors are more important in the development of obesity than have environmental changes in the last two decades (46). Genes linked to type 2 diabetes have been found in over 400 GWAS studies (Genome-wide association scans) (47, 48). However, these genes only predict 5 percent of obesity risk (49). As a result of the lack of thorough identification of gene-environment and epigenetic interactions in the current population genetics methods, the predictive power of these methods may be low (50). Researchers have discovered a large number of genes associated with obesity that are involved in pathways that regulate energy homeostasis.
Damien Sendler: Obesity-related genetic disorders can be broadly divided into the following categories: 1) a single gene mutation in the leptin-melanocortin pathway results in a monogenic cause. Monogenic obesity is caused by mutations in genes like AgRP (Agouti-related peptide), PYY (orexogenic), or MC4R (the melanocortin-4 receptor), which disrupt the appetite and weight control system. Hormonal signal receptors in the arcuate nucleus of the hypothalamus sense ghrelin, leptin, and insulin (51). Neurodevelopmental abnormalities and other organ/system malformations cause severe obesity in patients with syndromic obesity. Gene or chromosomal region changes may be to blame, or it could be a combination of both (52). Obesity that is polygenic is the result of multiple genes working together. As a result, some people with obesity are genetically predisposed to gaining weight because of the many genes they carry (53). Increased caloric intake, increased hunger, decreased control over overeating, decreased feeling of fullness, an increased tendency to store fat in the body, and an increased tendency to be sedentary are all possible outcomes of having these types of genes (54).
Obesity in young children can be caused by rare single-gene defects that cause excessive hunger. Prior to the age of two, those who are severely obese and have MC4R Deficiency, Leptin Deficiency and POMC Deficiency should seek the advice of obesity medicine specialists (55). Diet-induced obesity and metabolic dysregulation can both be caused by a lack of leptin. Women with polymorphism are more likely to engage in binge eating than those without the condition (56). A polymorphism in the MC4R gene affects the amount of ghrelin secreted (57). Obesity and obesity-related traits have been linked to the 2p22 region of the chromosome, which contains the POMC gene (58). According to these findings, environmental and genetic factors may play a role in the development of childhood obesity (59).
Many genetic, neuroendocrine, and chromosomal factors can lead to obesity. In PWS (Prader-Willi Syndrome), the deficiency of imprinted genes results in hypothalamic dysfunction (60). PCOS (Polycystic Ovary Syndrome) and other endocrine disorders can also cause an increase in body fat (61). In some cases, chromosomal abnormalities can cause obesity, including deletion of 16p11.2, 2q37 (brachydactyly mental retardation syndrome; BDMR), 1p36 (monosomy 1p36 syndrome), 9q34 (Kleefstra syndrome), 6q16 (PWS-like syndrome) and 17p11.2 (Smith Magenis syndrome; SMS) (62). Traditional weight management methods may not work in these situations because of the current health recommendations that energy imbalance between calories consumed and expended is the primary cause of obesity.
However, we have identified some of the genes that contribute to monogenic forms of obesity, but the human genome changes too slowly for the genome to play a major role in the current obesity epidemic. There may be a reasonable explanation for the rise in obesity prevalence over the past few decades without requiring a radical change in the genome, however, thanks to epigenetics (63). Multicellular organisms have a uniform genetic code, but the way that code is expressed varies from cell to cell. Researchers found that epigenetics studies show that the heritable regulatory alterations in the genetic expression do not require alterations in the nucleotide sequence (64). An epigenetic modification, in this context, refers to differences in gene expression based on how DNA is packaged in different tissues. The epigenetic programming of parental gametes, as well as later-life programming, can be influenced by the microbiota in the gut and the environment (10).
DNA methylation, histone modifications, and miRNA-mediated regulation are all known epigenetic mechanisms. Meiotic or mitotic transmission is possible for these traits. Perinatal and embryo-fetal development is implicated in human tissue and organ programming, according to available research (65). For gene expression, epigenetic mechanisms appear to be most important, with DNA methylation being the most prominent. Many diseases, including cancer, can be identified by changes in DNA methylation (66). The hormone LEP (Leptin) plays an important role in the regulation of adipose tissue. The DNA methylation of the LEP profile at birth can be affected by the metabolic status of the mother, affecting obesity metabolic remodeling (67). The epigenetic status of Adiponectin (ADIPOQ) has also been linked to obesity, and both LEP and ADIPOQ DNA methylation have been linked to LDL-cholesterol levels (68). It’s also been found that fathers who are obese have lower levels of IGF2 (insulin-like growth factor 2) methylation, which is necessary for cell division and growth (69). TNF, HIF3A, NPY, IRS1, TFAM, IL6, LY86, and GLUT4 are just a few of the genes that have been studied in relation to metabolism and obesity in the context of metabolism and obesity (10, 63).
Histones are proteins that play a role in DNA packaging and in the epigenetic regulation of adipogenesis and the emergence of weight gain (70). PPAR, C/EBP, Pref-1, adipocyte protein 2 (aP2), and CCAAT-enhancer-binding protein (C/EBP ) are among five key adipogenesis regulator genes whose expression is influenced by histone modifications (71). Proteins involved in histone modification and obesity metabolism share enzymes. A large number of environmental factors participate in the epigenetic regulation of gene expression, which HDACs (histone deacetylases) play a role in (72).
Damian Jacob Sendler
A class of short noncoding RNAs, microRNAs (miRNAs), are noncoding RNAs that are 18 to 25 nucleotides in length and have the ability to silence or alter the expression of specific genes. Adipose tissue differentiation and proliferation is regulated by microRNAs, which are linked to low-grade inflammation and insulin resistance in obese individuals (73). Children with high BMI had elevated levels of miRNAs such as miR-486-3p, miR-142-3p, miR-486-5p, miR-423-5p, and miR-130b, and 10 of these miRNAs changed significantly as weight increased (74). People who had a high risk score for 8 of these miRNAs had a three-fold greater risk of weight gain than those who had a low risk score (75). Following weight loss and a decrease in insulin resistance following gastric bypass, changes in adipocyte-derived exosomal miRNAs are also observed (76). Metabolic changes linked to obesity may serve as biomarkers or therapeutic targets for miRNAs, according to recent research. Obesity treatment options that take genetic and epigenetic factors into account have many advantages.
Despite the lack of specific pharmacological interventions, ‘lifestyle modification’ remains the most important component of obesity management (4). Obese people should aim to lose at least 10% of their body weight through a combination of diet, exercise, and behavioral therapy (77). Consumption of portion-controlled diets can result in significant short-term weight loss (78). Physical activity and regular contact between the patient and the practitioner are necessary for long-term weight loss. Changing one’s diet and lifestyle can result in dramatic weight loss, which can reduce one’s risk of cardiovascular disease (79).
People’s food choices are heavily influenced by their surroundings, so it is critical that governments work to reduce the availability of unhealthy foods and increase the availability of nutritious ones. Policies should be changed so that more foods with less sugar, fat, and salt are developed and less obesogenic foods are available to children (80). In order to encourage weight-friendly food production and marketing, policymakers and practitioners must be made aware of the potential effects of food advertising on human health and behavior. Students should be taught how to evaluate food commercials by nutrition educators (81). Health promotion, nutrition education, incentives for healthy living, a tax on sugar-sweetened beverages, and social marketing are just a few examples of the types of interventions that are likely to have a significant impact on curbing the obesity epidemic (as are policy changes, regulations, and laws) (82).
Bariatric surgery or weight loss surgery is another option for people with a BMI of 40 or 35 with comorbidities who are unable to lose weight through lifestyle changes or pharmacotherapy (83). To varying degrees, standard bariatric procedures, such as BPD, SG (sleeve), RYGB (Roux-en-Y gastric bypass), and AGB (adjustable gastric banding), can improve the metabolic profiles of people in a variety of different ways (90). Bariatric surgery has been shown to have advantages beyond weight loss, according to research. Weight loss surgery reduces the long-term remission of type 2 diabetes (91–93) by altering biomarkers, the gut microbiota, and other biomarkers. RYGB, for example, has been shown to increase overall gut microbial diversity in human subjects (94). As the research went on, it became clear that RYGB had an impact on the expression levels of several genes found in white adipose tissue, as well as on the signaling pathways involved in transforming growth factor- (TGF-) (95). After bariatric surgery, the serum leptin levels usually fall, which is linked to a lower BMI. Presurgical baseline leptin levels appear to have a significant impact on weight loss after surgery, with women who had higher levels prior to the procedure finding it easier to maintain their weight loss, while those with lower levels were more likely to regain the weight. Although the degree of surgical success cannot be predicted by a patient’s serum leptin level, there is a correlation between changes in body mass, BMI, and total weight loss and the baseline leptin level (96).
Obesity treatment has recently received a lot of attention from researchers using FMT (97). Weight loss and maintenance may be affected by the FMT of microbes from healthy individuals into obese patients. Researchers from Ridaura et al. carried out a groundbreaking study in which they transferred fecal slurries from human twins who were obese into germ-free mice (98). Mice with the microbiota of obese people developed obesity, but mice with the microbiota of healthy people did not. Post-procedure stool samples showed that the human microbiomes were successfully infused, which indicated that functions related to obese or lean microbial communities were transferred (98). Efforts in humans are also showing promise: In obese, diabetic adult males, researchers Vrieze et al. found that taxa from lean donors improved microbial diversity and insulin sensitivity (99). Bacteroidetes and butyrate-producing bacteria were found to be on the rise, pointing to a shift in the microbial community’s phenotype. FMT is a potential replacement for obesogenic microbial communities, but it is still in the early stages of development (100).
More people worldwide are obese today than they were 40 years ago, and that number is expected to rise even faster. Obesity has overtaken smoking as the leading risk factor for early death in the United States. Public health policies aimed at reducing and treating obesity need to be implemented (17). So far, progress has been slow in implementing strategies outlined in WHO’s 2013-2020 “Global Action Plan for the Prevention and Control of Noncommunicable Diseases” (101). There is still work to be done in translating the main causes of obesity and moderating factors into effective actions.
Health and disease are strongly influenced by epigenetic modifications and interactions between our genes and the environment. There is increasing evidence that epigenetics play a role in the prevalence of obesity (9). The epigenetic remodeling of the early postnatal development and parental gametes can contribute to a person’s propensity to become obese. The risk of a child becoming obese could be significantly influenced by epigenetic marks, which could be passed down through generations (11). This’memory’ of epigenetic changes could explain why obesity and other diseases do not appear to have a genetic component. It is essential to understand the mechanisms of epigenetic inheritance in order to treat and prevent obesity effectively. In order to accurately predict the course of disease and select the most appropriate treatment, it is necessary to look into epigenetic changes. Many promising “epigenetic drugs for obesity therapies” are already on the market or in various stages of development because of their reversible nature (102). For example, there are therapies that inhibit DNA and protein arginine methyltransferase, histone acetyltransferase and histone deacetylase as well as compounds that activate sirtuin and inhibitors of histone demethylase (HDMis) (103).
The study of the microbiome holds great promise in the fight against epidemics like obesity and diabetes. As technology and bioinformatics in microbiology advance, it may be possible to create a capsule that alters the microbiome to promote a healthy, lean, and insulin-sensitive profile; however, this is still a work in progress (8, 104). Our understanding of microbes will also allow us to develop more targeted therapies, such as those that target inflammation and weight gain and insulin resistance, as well as preventing the development of obesity.
A better understanding of obesity’s various dimensions—including the propensity to regain lost weight, interindividual differences in pathogenesis, and response to therapy—is essential for developing effective and cost-effective interventions. As a result of the findings, the incidence of diabetes will be reduced. Finding methods of behavior modification that are both effective and accessible to people of all backgrounds will take more time and effort. For a long time, researchers worked on developing better, less-toxic medications to help obese people lose weight and keep it off. Furthermore, we need to devote more time and resources to preventing obesity in both children and adults, both of whom are at risk. As treatment alone is not very effective and cannot effectively reverse the obesity epidemic in the long term, prevention is essential.
