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Cambridge University Science Magazine
The World Health Organization estimates that approximately 40% of people across the globe are now overweight or obese — a 20% increase since 1975. Obesity increases the likelihood of many other diseases including cardiovascular disease, stroke, Alzheimer’s disease, and cancer. As of 2019, obesity has overtaken smoking as the biggest cause of cancer, with Cancer Research UK stating that obesity is now more likely to be the cause of bowel, kidney, ovarian, and liver cancers than smoking tobacco. Obesity is therefore a growing global health problem but what causes it?

Obesity is driven by a combination of a lack of exercise, poor nutrition, and genetics. However, the contribution of genetics is often overlooked in comparison to the other factors. The Director of Research and Weight Stigma Initiatives at Yale University, Dr Rebecca Puhl, shows this leads to false connotations of obese individuals being lazy, weak willed, unintelligent, and having low self discipline. These stigmatisms then manifest themselves into discrimination that people justify by saying it will incentivise weight loss. Dr Puhl and others demonstrate that this is not the case. The stigmatism and prejudice are factually unfounded, reduce the mental wellbeing of sufferers, and interfere with effective treatment of the disease.

Many  have discovered that if we consume more food than we need, our bodies store this excess as fat. We can then use this excess energy during exercise, heat production, and resting metabolism. However, just as the amount of energy we use for exercise differs between individuals, the energy expended during resting metabolism also differs. These differences are caused by genetics.

Genes within our DNA hold the information needed for life. Genes are the template for  creating messenger RNAs (mRNAs) which is then translated into amino acid sequences, known as proteins. To translate mRNA into an amino acid sequence, ribosomes read three bases of mRNA at a time and add a specific amino acid, corresponding to the three-base sequence, to the growing protein chain. Some individuals inherit gene mutations from their parents called single nucleotide polymorphism (SNP). A SNP occurs when a single base in a gene’s DNA and mRNA sequence is replaced with another. This one base change causes ribosomes to read the mRNA sequence differently and insert a different amino acid into the protein chain. Sometimes this change in amino acid sequence prevents the protein from functioning correctly and can lead to diseases including obesity.

Therefore, someone can inherit a variety of SNPs that predispose them to obesity from their parents. This increases the probability of an individual becoming obese and is independant of will power, intelligence, or laziness. One such SNP predisposing individuals to obesity is found in the AP-2β gene. Due to AP-2β regulating proteins involved in insulin signalling, changes to its structure can lead to insulin resistance, type 2 diabetes, and cardiovascular disease. Due to the high volume of proteins involved in regulating metabolism, the number of mutations that can predispose or protect an individual from obesity is equally as large, with over 445 SNPs being associated with obesity. Individuals are not limited to simply having one of these SNPs either, they can possess none or all 445 at once. A strong positive correlation is seen between the number of SNPs and a person’s BMI, which clearly shows that genetics largely controls a person’s weight. This is reaffirmed by Dr Adam Locke from Washington University’s McDonnell Genome Institute, who says up to 70% of the variability between people’s BMIs can be accounted for by genetic factors.

If people know they are at risk of putting on more weight due to their genetics, surely, they should just eat less? Genetics also plays a large role in people’s food choices, portion sizes, propensity to exercise, and more. This again is due to SNPs changing the molecular signals in our brains, which then changes how our brains think about food. One extreme example is the outcome of a mutation in the leptin pathway. Leptin is secreted by fat cells and signals to the brain that there are adequate fat stores in the body and to suppress hunger. Without this suppression, individuals demonstrate extreme overeating, so much so that fridges and freezers must be padlocked shut to prevent mass overeating. 

The leptin example is a monogenic effect (one gene is responsible for the disease). However, most obesity cases are polygenic (a combination of gene SNPs with smaller individual effects which sum up to cause the disease). One such SNP is in the GAD gene leading to a lack of control over food intake and higher carbohydrate consumption in women. Another SNP in the Ghrelin gene, which substitutes a leucine amino acid for a methionine, disrupts gene function and increases the likelihood of obesity and binge eating. This is because part of the Ghrelin gene encodes the protein obestatin, which plays a role in suppressing hunger. 

A single base change in the TAS2R38 gene, which controls whether we can taste the bitterness in brussels sprouts, can also predispose humans to obesity. This is because if you do not like the taste of sprouts, you are statistically more likely to avoid low-calorie foods in general and replace them with a more energy-dense food, which ultimately leads to a higher BMI. Clearly, this is a small effect. However, the likelihood of being overweight can be extremely high in the presence of many other obesity-causing SNPs.

Even the amount of exercise we are likely to do is approximately 50% explained by genetics. For example, the melanocortin receptor gene involved in the signalling of leptin also predicts how much we exercise. Four studies discovered different regions in the human genome which either increase or decrease an individual’s likelihood of exercising. In summary, just like genes controlling metabolism, genetic variation can also influence how our brains perceive food, from the amount we eat, what we eat, and even what we burn off through exercise. Once again, this dispels the misconceptions of obese individuals lacking will power and determination.

If our genetics as well as age, sex, ethnicity, and socioeconomic background combined can determine our likelihood of becoming overweight, should individuals just accept their fate? Certainly not! These factors only increase the probability of obesity and do not mean we are destined to be overweight. We can learn a lot from man’s best friend here. 80% of Labrador guide dogs have the POMC gene which increases their food motivation. However, with the right training and education, these dogs do not pull their owners around parks chasing chocolate wrappers all day. They have learnt that despite this urge they will receive the food they need once they get their owner home. Us humans can do the same! By spreading education on obesity, people can acknowledge their genetic predispositions but also learn and adopt healthier attitudes towards food over time.

Our collective awareness, as individuals and as a society, can change how we view obesity. Rather than regarding sufferers as lazy, I think the genetic aspects outlined above shows people are continually battling their biology. By re-evaluating the causes of obesity, we can prevent the spread of false perceptions and prejudice, and instead enable effective treatment, education, and resolution

Dean Ashley is a fourth year PhD student in Biochemistry at Hughes Hall College. Artwork by Erin Slatery.