- Liz Ong, Martin Kueh

Obesity is a major public health concern of pandemic proportions, responsible for a large proportion of the burden of chronic non-communicable diseases, such as diabetes, cardiovascular disease (CVD), and some cancers (1). Very simplistically, obesity occurs due to an energy imbalance problem – the long-held model of calories in versus calories out. However, the reality is not so simple – the calories that the body receives and uses are modulated by a multitude of factors, such as the regulation of basal metabolic rate, appetite and satiety, eating habits, fat deposition and distribution, etc., by the brain and the hormonal system. Obesity, once considered a disease of lifestyle and a personal failure is now shown to be much more complex by scientific evidence from various disciplines. In this segment, we delve into the genetic underpinnings of obesity.

The Role of Genes in Obesity

Any abnormalities in the genes that regulate the above systems can easily tip that energy balance to promote obesity, including the more dangerous form of obesity that drives the chronic diseases associated with it. Indeed, one explanation for the obesity epidemic – the “thrifty gene” hypothesis – suggests that the energy-rich diets and sedentary lifestyles of today do not match the much lower caloric requirements of people who had the “energy-thrifty” genetic profile that was favoured in previous generations because of its survival advantage in the face of unpredictable food sources (2).

When a disease presents with severe signs and symptoms, often also at an early age, they could often be attributed to a monogenic cause, i.e. single-gene abnormalities – thankfully, they are also much rarer at around <5% of all cases (1). This also holds true for monogenic cases of obesity, such as a congenital deficiency of leptin or its receptor, which results in a severe form of obesity that occurs very early in life. Leptin is an important hormonal regulator of energy balance, an appetite suppressant, and an indirect regulator of glucose and lipid metabolism, fat deposition, and inflammation, among other things (3). Many of the monogenic abnormalities that result in severe childhood obesity in humans affect the leptin-melanocortin-MC4R (melanocortin-4 receptor) pathway, which is central to the regulation of appetite and satiety, among other functions.

Some cases of obesity are also part of syndromes due to specific genetic or chromosomal abnormalities, e.g. Prader-Willi syndrome, characterised by insatiable hunger leading to obesity and type 2 diabetes, along with other neurological, developmental, and musculoskeletal problems. 

However, the vast majority of obesity is caused by complex polygenic influences, i.e. they result from the cumulative effects of many different genetic variants, each of these variants contributing a small but additive effect. With the advent of genome-wide association studies (GWAS), many genetic variants that are associated with obesity have been identified, such as those related to the aforementioned leptin-melanocortin pathway (e.g. MC4R, PCSK1) and receptors present in the adipose tissue (e.g. PPARG, ADRB3). In 2007, the first obesity-susceptibility gene was identified – the fat mass and obesity-associated (FTO) gene locus, mutations of which were associated with a 20-30% increase in the risk of obesity (4) – and since then numerous more have been identified (1).

Gene-Environment Interactions (G x E)

However, your genetics are not your destiny. Global obesity rates have almost tripled since 1975 (5), rising far too rapidly to simply be attributable to evolutionary and genetic changes alone (2), thus pointing to the importance of environmental factors in driving this epidemic – termed the ‘obesogenic’ environment, i.e. the obesity-promoting environment (1). 

Obesity is most often a complex condition resulting from an interplay between both genetic (non-modifiable) and environmental (modifiable) risk factors – bringing us to the topic of gene-environment interactions (G x E). For example, physical activity (PA) has been found to reduce the effects of carrying the mutant FTO gene on the individual’s BMI by about 30% (FTO x PA interaction). However, connections are often not as simple as a unidirectional relationship – for example, dietary habits are another major factor that can influence the effects of the mutant FTO gene on BMI and waist circumference (e.g. a high protein intake is protective) (6), but carrying the mutant FTO gene also influences the quantities and composition of the dietary intake of people who carry that mutation (7). 

Apart from PA and dietary habits, other environmental and lifestyle risk factors that have been implicated in obesity include stress, poor sleep quality, inadequate hydration, and lower socioeconomic status (8, 9, 10). However, these factors are often interconnected and affect each other bidirectionally, contributing to vicious cycles that trap people in obesity.

So What You Can Do?

1: Be kind to others and yourself

The stigma and discrimination that surrounds obesity permeate both the general public and even the healthcare profession – those considered overweight often face challenges in social settings, career opportunities, and even healthcare provision (where excess fat may pose challenges to certain diagnostic and treatment methods, and where underlying diseases are often misattributed to a condition that losing weight would help with). Knowing that obesity is in part determined by genetics will allow us to be more compassionate towards others and ourselves – and to tackle this problem from a much better position.

2: Eat, drink, sleep – and do it well

Knowing that genetics is not destiny, there are many little things that you can do that will make it easier to stay away from tendencies to snack, binge, and make unhealthy food choices including drinking plenty of water and getting plenty of sleep, both of which are crucial in normal appetite regulation, as well as a diet high in fibre and low in sugar diets, which can help to curb cravings and promote early satiety. 

Setting reminders, using a pretty bottle and marking it up with goals to meet, accountability partners are all ways to encourage you to ingest more fluids – as can the incorporation of high-water foods and liquids into your diet, such as fruits, vegetables, teas, and soups. Maintaining a regular sleep schedule and ensuring good sleep hygiene (e.g. avoiding electronic gadgets before sleep) can promote good sleep habits that can go a long way in counteracting the physical, cognitive, and behavioural elements that are often dysregulated in many different diseases and conditions, including the increased risk of obesity.

3: Find ways to make movement part of your daily routine 

Finally, choose to live a more active lifestyle not for the goal of losing weight but to be fitter, faster, and healthier! Physical activity not only can help to suppress appetite if done to an adequate extent, but it can also help to reduce levels of stress, which is another factor that can promote unhealthy weight gain directly by physiological changes as well as indirectly via behavioural changes. 

Choosing to take the stairs, walk the extra mile with a friend, switch up your study or working positions every few hours, cycle instead of taking public transport or driving – little ways of incorporating movement can be a great start. Picking up a new sport, be it rock climbing, swimming, pole dancing, or marathoning, can also bring joys that only engaging with the community and pleasures that sports can bring.

Conclusion

Current evidence supports the link of genetics to obesity, converging on the fundamental role of the brain in governing body weight. However, what may be more important is the interaction of obesity susceptibility genes with obesogenic factors of environment and lifestyle that can be changed. Hence, individuals can still take control of their health by adopting positive lifestyle choices, altering their fate and lowering the risk of developing obesity-related health issues.

References

Loos RJF, Yeo GSH. The genetics of obesity: from discovery to biology. Nature Reviews Genetics. 2022;23(2):120-33.

1. Centers for Disease Control and Prevention (CDC). Obesity 2018 [updated 19 January 2018. Available from: https://www.cdc.gov/genomics/resources/diseases/obesity/index.htm.

2. Mendoza-Herrera K, Florio AA, Moore M, Marrero A, Tamez M, Bhupathiraju SN, et al. The Leptin System and Diet: A Mini Review of the Current Evidence. Front Endocrinol (Lausanne). 2021;12:749050.

3. Kilpeläinen TO, Qi L, Brage S, Sharp SJ, Sonestedt E, Demerath E, et al. Physical activity attenuates the influence of FTO variants on obesity risk: a meta-analysis of 218,166 adults and 19,268 children. PLoS Med. 2011;8(11):e1001116.

4. World Health Organisation (WHO). Obesity and overweight 2021 [updated 9 June 2021. Available from: https://www.who.int/news-room/fact-sheets/detail/obesity-and-overweight.

5. Merritt DC, Jamnik J, El-Sohemy A. FTO genotype, dietary protein intake, and body weight in a multiethnic population of young adults: a cross-sectional study. Genes Nutr. 2018;13:4.

6. Mehrdad M, Doaei S, Gholamalizadeh M, Eftekhari MH. The association between FTO genotype with macronutrients and calorie intake in overweight adults. Lipids Health Dis. 2020;19(1):197.

7. Chen A, Rosenbaum S, Wells R, Gould K, Ward PB, Steel Z. Obesity, physical activity and sleep quality in patients admitted to a posttraumatic stress inpatient ward. Australas Psychiatry. 2020;28(3):270-3.

8. Chang T, Ravi N, Plegue MA, Sonneville KR, Davis MM. Inadequate Hydration, BMI, and Obesity Among US Adults: NHANES 2009-2012. Ann Fam Med. 2016;14(4):320-4.

9. Anekwe CV, Jarrell AR, Townsend MJ, Gaudier GI, Hiserodt JM, Stanford FC. Socioeconomics of Obesity. Curr Obes Rep. 2020;9(3):272-9.