Is There an ‘Obesity’ Gene?

Check out this answer from Consensus:

While there is no single ‘obesity’ gene, multiple genetic factors contribute to the condition. Both polygenic and monogenic forms of obesity share common genetic and biological mechanisms, particularly involving the brain’s regulation of body weight. Advances in genetic research, including GWAS and NGS, have identified numerous obesity-associated loci, providing new insights into the condition’s pathophysiology and potential treatment strategies.

Obesity has become a global epidemic, contributing to a range of health issues including type 2 diabetes, cardiovascular disease, stroke, certain types of cancer, and premature death. The condition is highly heritable, arising from the interactions of multiple genes, environmental factors, and behaviors. This article explores the genetic underpinnings of obesity, examining whether there is a specific ‘obesity’ gene and how various genetic factors contribute to the condition.

Genetic Basis of Obesity

Polygenic and Monogenic Obesity

Obesity can be classified into polygenic (common) and monogenic (rare, severe, early-onset) forms. Both types share genetic and biological underpinnings, particularly involving the brain’s role in body weight regulation2. Monogenic obesity is caused by variants in single genes, while polygenic obesity involves multiple genes with smaller individual effects5.

Key Genetic Findings

Genome-wide association studies (GWAS) have identified numerous loci associated with obesity. For instance, the FTO gene has been repeatedly linked to body mass index (BMI) and other obesity-related traits across various populations4 7. Other significant genes include LEPR, PPARG, and CTNNBL1, which have shown associations with obesity phenotypes in diverse ancestries4.

Gene-Gene and Gene-Environment Interactions

The interaction between different genes and between genes and environmental factors plays a crucial role in obesity. For example, certain genetic variants can influence the effect of dietary intake and physical activity on obesity-related phenotypes1. Additionally, sex-specific and ethnic-specific effects have been observed, particularly with FTO variants4.

Advances in Genetic Research

Technological Progress

The advent of GWAS and next-generation sequencing (NGS) has significantly advanced our understanding of the genetic basis of obesity. These technologies have facilitated the discovery of numerous genetic variants associated with obesity and have highlighted the importance of the central nervous system in obesity susceptibility2 6.

Functional Genomics and Proteomics

Integrating genetic epidemiology with functional genomics and proteomics is essential for fully understanding the role of genetic variants in obesity. This approach can help translate genetic loci into meaningful biological insights and potential treatment avenues1 2.

 

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Is there an ‘obesity’ gene?

Richard Edwards has answered Unlikely

An expert from UNSW Sydney in Bioinformatics, Molecular Biology, Evolutionary Biology, Genomics, Genetics

Is obesity affected by genetics? Certainly. However, there is no “obesity gene” that will definitely make you fat, or not. Obesity is an extremely complex trait controlled by interactions between many genetic and environmental factors. One only needs to look at the changes in obesity levels we are seeing in modern populations versus our recent ancestors – our genes have not changed notably during this period.

The biggest genetic factor is most likely an “epigenetic” one – not to do with what genes you have, but rather how they are expressed and controlled. It is entirely plausible that changes to diet etc. have meant that modern humans are epigenetically programmed to be obese from before birth, but I think more data is needed to make this link solid. Either way, obesity is very unlikely to be a purely behaviour-linked trait, but even less likely to be down to the inheritance of an “obesity gene”.

That said… is the article correct that a particular variant in a particular gene will give people with the right genetic background an increased likelihood of becoming obese on a modern “Western” (i.e. high fat) diet? Extremely likely. So, like many things, I think the answer depends on what precisely is meant by the question.

 

Is there an ‘obesity’ gene?

Cornelie Nienaber-Rousseau has answered Unlikely

An expert from North-West University in Nutrition

The prevalence of obesity has rapidly increased worldwide in recent decades (Ng et al., 2013). While monogenic disorders, which are genetic conditions caused by mutations in a single gene, can lead to a wide range of health problems, they are relatively rare and cannot solely account for the obesity epidemic we currently face. This is because body weight is a multifaceted phenotype that is influenced by environmental and genetic factors, which interact with each other (Qi & Cho, 2008; Reddon et al., 2016). The global increase in obesity rates is primarily due to changes in diet and physical activity patterns, as well as other environmental factors such as urbanization, sedentary lifestyles, and increased access to high-calorie foods (Ng et al., 2014).

Monogenic obesity syndromes, such as leptin deficiency and Prader-Willi syndrome, are rare genetic disorders that result from mutations in a single gene and account for a small proportion of all obesity cases. For instance, the prevalence of monogenic obesity is estimated to be less than 5% in adults with severe obesity and less than 1% in adults with a body mass index (BMI) of 30 or higher (Farooqi and O’Rahilly, 2006). It would be inaccurate to suggest a single “obesity gene” for the general population because of the rarity of monogenic obesity syndromes (Farooqi, 2006; Mutch & Clément, 2006).

In the general population, several genes have been linked to obesity, and various genetic variations have been associated with the condition, affecting diverse aspects of energy balance, such as appetite regulation, satiety, and metabolism. Large-scale genome-wide association studies (GWAS) have identified several loci associated with body mass index (BMI), including the FTO gene, which encodes the protein FTO, and MC4R, which encodes the melanocortin 4 receptor, a protein involved in appetite regulation (Loos et al., 2008; Wang et al., 2010). The PCSK1 gene has also been identified as a significant contributor to obesity risk and related traits in the general population (Speliotes et al., 2010; Locke et al., 2015).

Despite the identification of several genes and genetic variations associated with obesity, body weight is a multifactorial phenotype influenced by both genetic and environmental factors. Genetic factors account for approximately 40% of the variance in BMI, while environmental factors such as physical activity, diet, and lifestyle account for the remaining 60% (Locke et al., 2015). Furthermore, associations between certain genetic variations and obesity risk often depend on other factors, such as ethnicity and gender. For instance, the FTO gene was linked to obesity risk in European populations but not in African or East Asian populations (Frayling et al., 2007).

Despite the identification of several genes and genetic variations associated with obesity, body weight is a multifactorial phenotype influenced by both genetic and environmental factors. Genetic factors account for approximately 40% of the variance in BMI, while environmental factors such as physical activity, diet, and lifestyle account for the remaining 60% (Locke et al., 2015). Furthermore, associations between certain genetic variations and obesity risk often depend on other factors, such as ethnicity and gender. For instance, the FTO gene was linked to obesity risk in European populations but not in African or East Asian populations (Frayling et al., 2007).

The Hardy-Weinberg principle is a fundamental principle in population genetics stating that allele and genotype frequencies remain constant without selection, migration, mutation, or random genetic drift. Populations with high obesity rates would diverge from this equilibrium if there were a single obesity gene, but several studies show no significant deviation (Wang et al., 2012; Zhu et al., 2014; Bhatti et al., 2017). The lack of deviation and the results of GWAS provide robust evidence that obesity is a complex trait influenced by multiple genetic and environmental factors, negating the notion of a single obesity gene.

Therefore, while genetic factors can influence an individual’s susceptibility to obesity, they do not determine an individual’s destiny. The complex interplay between genes and the environment underscores the need for a multifaceted approach to combating obesity. The lack of deviation from the Hardy-Weinberg equilibrium principle and the results of GWAS provide evidence that obesity is a complex trait influenced by multiple genetic and environmental factors, negating the notion of a single obesity gene.

References:

Benzinou, M., Creemers, J. W., Choquet, H., Lobbens, S., Dina, C., Durand, E., … & Elliott, P. (2008). Common nonsynonymous variants in PCSK1 confer risk of obesity. Nature genetics, 40(8), 943-945.

Farooqi, I. S. (2006). Genetic, molecular and physiological insights into human obesity. European Journal of Clinical Nutrition, 60(5), 574-577.

Farooqi, I. S., & O’Rahilly, S. (2006). Genetics of obesity in humans. Endocrine Reviews, 27(7), 710-718.

Frayling, T. M., Timpson, N. J., Weedon, M. N., Zeggini, E., Freathy, R. M., Lindgren, C. M., … & Hattersley, A. T. (2007). A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science, 316(5826), 889-894.

Hill, J. O., Wyatt, H. R., Peters, J. C., et al. (2012). The importance of energy balance. European Journal of Clinical Nutrition, 66, 1170–1178.

Locke, A. E., Kahali, B., Berndt, S. I., Justice, A. E., Pers, T. H., Day, F. R., … & Speliotes, E. K. (2015). Genetic studies of body mass index yield new insights for obesity biology. Nature, 518(7538), 197-206.

Loos, R. J. F., Bouchard, C., & FTO Gene, Collaborative (2008). FTO: the first gene contributing to common forms of human obesity. Obesity Reviews, 9(3), 246-250.

Mutch, D. M., & Clément, K. (2006). Unraveling the genetics of human obesity. PLoS Genetics, 2(12), e188.

Ng, M., Fleming, T., Robinson, M., Thomson, B., Graetz, N., Margono, C., … & Abraham, J. P. (2014). Global, regional, and national prevalence of overweight and obesity in children and adults during 1980–2013: a systematic analysis for the Global Burden of Disease Study 2013. The Lancet, 384(9945), 766-781.

Qi, L., & Cho, Y. A. (2008). Gene-environment interaction and obesity. Nutrition Reviews, 66(12), 684-694.

Reddon, H., Gerstein, H. C., & Engert, J. C. (2016). Genetics of common complex obesity: a focus on Mendelian disorders. Obesity Reviews, 17(5), 485-493.

Wang, K. S., Liu, X. F., Aragam, N., Jian, X., & Trajanoska, K. (2010). A genome-wide association study of obesity and waist-to-hip ratio in a Chinese population. PloS One, 5(7), e11962.

 

Is there an ‘obesity’ gene?

Sadaf  Farooqi has answered Near Certain

An expert from University of Cambridge in Obesity, Medicine, Cardiovascular Disease, Genetics

Yes, there are several obesity genes. See www.goos.org.uk for more information.

 

Is there an ‘obesity’ gene?

Ivor Ebenezer has answered Unlikely

An expert from University of Portsmouth in Neuroscience

A simple answer to the question is no. There is no single gene that is responsible for obesity. The regulation of body weight is dependent on complex interactions between our lifestyle, our genetic make and our gut microbiome. If we look back in history, to a time when our hunter-gatherer ancestors roamed the earth, we find that early man lived mainly on root vegetables (which are high in carbohydrate) and hunted animals for proteins and fats. There were periods of many days and sometimes weeks when they went hungry. Those who survived were able to store body fat during times of plenty to provide energy during times of hardship. Thus, the majority us have inherited genes from our ancestors that predispose us to accumulate body fat. It is also worth noting that if our ancestors expended most of their energy in their search for food and other physical pursuits, then they would burn up their fat stores. Thus, they had to protect their fat supplies by avoiding unnecessary work or exercise. It is likely that they had genes that programmed them to conserve energy. We would have also inherited these genes from our ancestors.

Today, in most countries in the world, we have easy access to a variety of different foods. We also have labour-saving devices, such as washing machines and motorcars, and we spend a lot of our leisure time engaged in non-physical activities, such as watching television, playing games on the computer, or sunbathing. In simple terms, obesity is due to an excess of energy (food) intake coupled with a decrease in energy expenditure. It is therefore not surprising that, at the latest estimates, approximately one in four of the population of the UK and one in three in the USA are considered obese. The prevalence of obesity is escalating at an alarming rate, increasing almost twofold in the last 20 years.

Data from animal and human studies have implicated variants in a number of genes, such as the fat mass and obesity-associated (FTO) gene, the ankyrin-B gene, and the leptin gene, in the development obesity. Such genes control the hormones, neurotransmitters, neuromodulators, and enzymes involved in the regulation of food intake and energy homeostasis. Environmental factors, such as maternal starvation or consumption of foods with high sugar content, can produce epigenetic changes in the foetus that can results in obesity in the offspring. More recently, it has been found that the gut microbiome plays an important role in the control of hunger and satiety by modulating the hormones and neurotransmitters involved. Thus, it is unlikely that a single gene is responsible for obesity. It is more likely that obesity is due to a complex interplay among various factors that include diet, genes, lifestyle and the gut microbiome.