Causes of obesity
Obesity is a multifactorial disease with a complex aetiology.12 A simple balance between food intake, metabolism and energy expenditure is the main mechanism responsible for weight maintenance and weight gain.13 However, this balance is very much influenced by environmental factors as well as an individual’s genetic makeup.13 A full review of the causes of obesity is beyond the scope of this paper. However, it is important to note that the complex nature of this disease means that it is not easily treated in clinics and is a significant global public health problem. Understanding the intricate links between environmental and genetic causes of obesity and clinical challenges in managing this disease, sheds light on its complex nature, emphasising the need for holistic strategies that address both lifestyle and systemic factors in combating obesity.
Genetic causes
Studies have shown that obesity has a heritability of 40%–70%, demonstrating that there is a large genetic component to this disease.14 Obesity can be monogenetic, polygenetic or syndromic. Monogenic obesity is caused by mutations in a single gene. Most often, these mutations occur in genes that are part of the leptin-melanocortin pathway.15 Examples of genes involved in monogenetic obesity include leptin and leptin receptor (LEP and LEPR), pro-opio melanocortin (POMC) and melanocortin (MCR4) receptor.15 Polygenetic obesity is caused by mutations in multiple genes whose effects are amplified by ‘obesity-promoting’ or obesogenic environments.16 Syndromic obesity is associated with other phenotypes such as neurodevelopmental abnormalities and organ malformation.17 An example of syndromic obesity is observed in the rare cases of Bardet Biedl syndrome (BBS) and Prader-Willi syndrome (PWS).15 BBS is an autosomal recessive genetic ciliopathic syndrome affecting many body organs and causing intellectual disability, obesity, hypogonadism, genitourinary and urinary abnormalities, and polydactyly.18 PWS is the most common cause of syndromic obesity and is characterised by specific facial features, neonatal hypotonia, failure to thrive, hypogonadism, early childhood onset obesity, hyperplasia, developmental delay/mild intellectual ability and short stature.19
Obesogenic environments
The increase in obesity may be linked to the presence of an obesogenic environment, particularly in the context of a genetic predisposition to obesity. Researchers have suggested that obesogenic environments are an important cause of obesity in North America.20 The built environment, which encompasses a person’s surroundings and infrastructure, can affect an individual’s risk of developing obesity through behaviour modification and direct exposure.21 Environmental factors such as urbanisation, greenspace, walkability and exposure to air pollution can influence changes in a person’s weight.22 A 2021 umbrella review evaluating the associations between the built environment and obesity revealed that more exposure to fast-food, and increased urban sprawl were associated with increases in obesity.22 The flipping point from non-obesogenic to obesogenic environments in North America occurred in the early 1970s.13 At this time, carbohydrate and fat-rich foods became predominant and technological innovation reduced human energy expenditure.23 Coupled together, these changes resulted at the beginning of the obesity pandemic. Before 1960, decreased energy expenditure was matched by a decrease in energy intake, resulting in a stable level of obesity in the North American population13 (figure 3). From 1970 onwards, this balance was disrupted as energy intake began to increase and energy expenditure began to decrease.13
Figure 3Amount of individual energy expenditure (blue) and individual energy intake (red) from 1910 to 2000. Stable weight phase is indicated in green, energy flipping point in red and weight-gain phase in blue. Reproduced with permission from Blüher.13
Thrifty gene hypothesis
The thrifty gene hypothesis has also been explored as a possible cause for the current rise in overweight and obesity. According to this hypothesis, our ancestors underwent positive selection for genes with energy-conserving or fat-depositing functions since they increased an individual’s odds of survival during periods of famine.24 In modern obesogenic environments, these genes cause people to be overweight or obese. A comparison of the average body measurements for women in the 1960s versus the 2020s accurately displays this notion. In 1960, the average woman weighed 141 lbs or 64 kg and her height was 5′2″ or 160 cm.25 Consequently, her BMI was 25. In 2021, the average North American woman weighs 170.8 lbs or 77.5 kg and her height is 5′3″ or 161 cm, making her BMI 30.0.26 This classifies her as obese and puts her at an increased risk of cardiometabolic disease and mortality.
Several studies have been conducted to determine whether the thrifty gene hypothesis can be supported. To date, no specific genes or molecular mechanisms have been directly associated with this phenomenon.27 However, it is clear that the ‘thrifty phenotype’ is present in societies.28 Past evidence suggests that the body’s leptin resistance level and epigenetic modifications could be responsible for some ‘thrifty phenotypes’.29 Other potential players include genes responsible for encoding the insulin signalling and intermediary fat metabolism.30 Recently, the Peroxisome proliferator-activated receptor γ coactivator-1α gene has been identified as a potential contributor to high BMI in certain populations.31 Further investigation is required to validate this hypothesis.
Epigenetics
Epigenetics involves the study of heritable changes in gene expression.32 These changes are dynamic. Therefore, factors such as exposure to obesogenic environments can alter the epigenetic makeup of an individual’s DNA and can subsequently influence the phenotypic expression of obesity. Important epigenetic mechanisms in obesity include DNA methylation, histone modification and microRNA (miRNA) regulation.33
DNA methylation involves the transcriptional regulation of expression of certain genes by adding a methyl group to a cytosine base pair adjacent to a guanine base pair (also called CpG islands) in the DNA sequence.34 These cytosines are often located in promoter regions of genes and therefore affect their expression.35 DNA hypermethylation is associated with an inhibition of gene expression while hypomethylation causes activation of gene expression.36 Methylation changes in genes associated with appetite, growth, metabolism, insulin signalling and obesity-related phenotypes are potentially involved in the phenotypic expression of obesity.35 The LEP and POMC genes, both involved in weight regulation, have CpG islands in their genetic code.37 Elevated LEP methylation in maternal blood samples has been associated with pre-pregnancy obesity and subsequent infant blood LEB methylation.38 POMC methylation has been associated with metabolic syndrome and is an early indicator of such diseases.39 Other methylated genes of interest include the hypoxia-inducible factor 3a, adiponectin, peroxisome proliferator-activated receptor coactivator 1 α, insulin-like growth factor 2, insulin receptor substrate 1 and lymphocyte antigen 86.40
Histone modifications occur when proteins called histones bind to exposed DNA, thereby inhibiting further modification, such as DNA methylation or acetylation that could alter gene expression.41 This mechanism plays an important role in adipogenesis and obesity development through the modulation of key regulatory genes.42 These genes are preadipocyte factor-1 (Pref-1), CCAAT-enhancer-binding protein β (C/EBP β), C/EBPα, PPARγ and adipocyte protein 2 (aP2). During adipocyte differentiation, the Pref-1 gene is less active and the C/EBP β gene has increased active chromatin markers. On induction, C/EBPα significantly loses its repressive methylation and the PPARγ and the aP2 gene are significantly expressed during adipogenesis. Furthermore, differential expression of histone deacetylases is observed in the hypothalamus of fasting, fed and high-fat diet animals.43 Importantly, environmental changes have an impact on chromatin remodelling through histone modification. Alterations in diet have been shown to remodel chromatin, thus affecting the expression of liver transcription factors, nuclear factors and enhancer binder proteins.44 Other studies have shown that the POMC gene which regulates appetite undergoes histone acetylation in addition to DNA methylation.45 Therefore, it is possible that multiple epigenetic modification work in concert to regulate the phenotypic expression of obesity.
miRNA are short non-coding strands of RNA that regulate or silence gene expression.46 They bind to complementary mRNA sequences and cause degradation or inhibit protein translation. MiRNAs have been known to regulate metabolic processes.47 Their dysregulation has been associated with obesity.48 This regulatory mechanism modulates paracrine signalling between adipose tissue, skeletal muscles, the liver and other organs which can influence energy homeostasis and metabolism.49 Importantly, many miRNAs in the body can be found in adipose tissues and can regulate adipocyte proliferation, insulin resistance differentiation and inflammation.43 Previous studies have identified miR-328, miR-378, miR-30b/c, miR-455, miR-32 and miR-193b-365 as activators of brown adipogenesis while miR-34a, miR-133, miR-155 and miR-27b appear to inhibit this mechanism.50 During obesity, the miRNA population can be significantly altered in adipose tissue, further influencing the development of obesity and some forms of cancer.51 Further research is required to understand the full extent of miRNA’s impact on obesity phenotypes.
Exposure to obesogenic environments can alter epigenetics and influence obesity. Previous studies have linked exposure to phthalates, pesticides and bisphenol A to increased levels of obesity.45 These chemicals can act as endocrine disruptors and affect the regulation of obesity-related pathways in the body. Diet has also been linked to changes in epigenetics. Malnutrition of infants during the Dutch famine has been linked to obesity, hypertension and diabetes in later life.52 Endurance training and increased physical activity have also been shown to alter DNA methylation in 63 genes related to obesity.53 Exercise can reverse the epigenetic effects of a sedentary lifestyle that can contribute to obesity. Furthermore, reduced levels of sleep and alcohol consumption also have epigenetic effects on obesity. In all, epigenetics plays an important role in causing obesity.
Composition of gut microbiota
Gut microbiota, mainly located in the large colon, are involved in metabolism regulation, nutrient absorption, synthesis of vitamins, regulation of gene expression and food digestion.54 Several studies conducted in lean and obese mice have concluded that differences in the gut microbiome can contribute to the development of obesity and might be an essential player in energy regulation.55 Obese mice had 50% fewer Bacteroidetes and an increased amount of Firmicutes, two phyla that dominate the gut microbiome.56 Further animal and human studies have reached similar conclusions.57 Firmicutes can produce short-chain fatty acids (SCFAs) from non-digestible dietary starches.54 SCFAs can promote obesity by providing an increased caloric intake, increasing fat deposition in the body and acting on energy and metabolism pathways.58 Diet can also induce changes in gut microbiota.54 High-fat diets have been associated with increased gut permeability which causes gut inflammation and metabolic disturbances associated with obesity.59 High-fibre diets are beneficial in promoting weight loss, despite the diets not being calorie restrictive.60 Other factors such as physical activity level, stress, breastfeeding, mode of childbirth, sleep disturbances and antibiotic use are also associated with changes in the gut microbiome.54 To date, analysing the gut microbiome of patients with obesity does not confer any diagnostic knowledge nor does it provide indications as to which treatments will benefit the patient.61 More research is required to determine the exact profile of gut microbiota in obese individuals, should it exist and how this information can help optimise weight loss. Some studies have shown that in patients with obesity and metabolic disorders compared with patients with obesity without metabolic disorders have different gut microbiota profiles.62–64 However, confounders such as differing diets, environments and genetic factors are present in these studies. Further research assessing the impact of these factors on the gut microbiome must be conducted to increase the value of the gut microbiome in the treatment of obesity.
Consumption of subsidised crops leads to obesity
Studies have identified that the consumption of foods from subsidised crops is linked to an increased cardiometabolic risk.65 Agricultural subsidies primarily support the production of corn, soybeans, wheat, rice, sorghum, dairy and livestock feed.65 These crops are further processed and become calorie-dense foods such as high fructose corn syrup, cereals and alcohol.66 Populations that consume a high number of subsided foods are 49% more likely to be obese and 61% more likely to have a higher abdominal adiposity score than people who consume low amounts of subsided crops (figure 4). In addition, the prevalence of dysglycaemia also increased across these populations. This link is evidence that the consumption of subsidised crops is associated with a higher risk of cardiometabolic disorder.
Figure 4Adjusted prevalence of obesity (A), abdominal adiposity (B) and dysglycaemia (C) by subsidy score quartile in the National Health and Nutrition Examination Survey between 2001–2006 and 2009–2014. Subsidy score quartiles were defined as follows: Q1 is 0.00–0.41; Q2 is 0.42–0.53; Q3 is 0.54–0.63; and Q4 is 0.64–1.00. Obesity was defined as a body mass index of at least 30 kg/m2. Abdominal adiposity was defined as a ratio of waist circumference to height of at least 0.59. Dysglycaemia was defined as a self-reported diabetes diagnosis or haemoglobin A1c level of at least 5.7%. Reproduced with permission from Do et al.65
Calorie imbalance: intake versus expenditure
It is common for individuals to underestimate their daily caloric intake and overestimate the number of calories they burn during physical activity. The imbalance of calorie intake and energy expenditure most individuals experience is the main reason obesity is such a common and difficult disease to manage. A typical 50-year-old man who measures 5′8″, weighs 200 lbs and has a BMI of 30.4 requires 2090 calories per day to maintain their weight, assuming they have a sedentary lifestyle.67 To lose one pound per week, this individual would have to consume 75% of their daily requirements (1590 cal/day).68 To lose two pounds per week or approximately 1 kg, the individual would have to reduce their intake by almost 50% (1090 cal/day). This is a significant reduction from this individual’s original daily calorie intake. Therefore, individuals may be unaware how much of a reduction in calories are required to achieve a small weight change. An average 50-year-old woman measuring 5′3″, weighing 178 pounds with a BMI of 30 and a sedentary lifestyle requires less caloric intake to maintain her weight.67 She needs to consume 1676 cal/day to maintain her weight while a male requires 2090 cal/day.68 To lose one pound a week, this individual has to reduce her calorie intake by 30% to 1176 cal/day. She would have to reduce her intake by 60% to 676 cal/day to lose two pounds a week.
Not only do individuals overestimate their daily calorie requirement, but they also underestimate the number of calories their food contains and the amount of physical activity required to burn off these calories. For instance, a big Mac Trio, which includes a Big Mac hamburger, medium fries and a large soft drink, contains 1100 calories. This is 59% of the daily caloric requirements for an average 50-year-old man and 74% of the daily caloric intake for a 50-year-old woman.69 The amount of exercise required to expend 1000 calories is significant. Examples include running vigorously for 70 min, walking for 5 hours at a brisk pace or cycling at 14 mph for 70 min.70 The disparity between calorie intake and energy expenditure makes obesity a particularly challenging condition to address.
