How Genes Affect Human Obesity

Obesity is a medical condition characterized by an excessive accumulation of fat that can lead to negative effects on health [1]. Medically, it is measured as a body mass index (BMI) that is equal to or higher than 30. An ideal BMI is in the 18.5 to 24.9 range, while a BMI of 25 and up to 29.9 range, indicates an overweight condition.

Although BMI is widely used as a general indicator of whether a person has a healthy body weight, BMI is not always the best measure to use because there are other things that are considered when it comes to weight. For instance, muscle is denser than fat, and therefore, muscular people, such as athletes may have a healthy weight even if their BMI is classified as Obese.

Genetics and Obesity

Obesity has been associated with an unbalance in energy consumption. When food and drinks are consumed, the energy they provide is required to satisfy our needs when we are active and burning energy.

Therefore, excessive consumption of energy and without activity leads to the storage of energy in the form of fat. If this action is sustained for a long period of time, our BMI progresses from normal to overweight and finally to obesity.

However, a recent study in Science magazine demonstrated that excessive consumption of food and drinks consumption is not the only cause of obesity. The scientists sequenced the exosomes of 645,626 individuals from the UK, the US, and Mexico and estimated associations of rare coding variants with BMI [2].

Exosomes are budding vesicles from plasma membranes and endosomes of the cells that contain proteins, lipids, nucleic acids, and glycoconjugates [3].  The sequencing identified 16 genes including those encoding 5 brain-coupled G receptors, CALCR, MC4R, GIPR, GPR151, and GPR75.

Interestingly, the sequencing showed that protein-truncating variants in GPR75, were associated with lower BMI and lower odds of obesity in heterozygous carriers, protein-truncating variants in CALCR were associated with higher BMI and obesity risk. They also found that loss-of-function variants that are involved in the leptin-melanocortin pathway are associated with higher BMI [2].

Conclusion

The study suggests that higher BMI and obesity can be heritable and that human genetic studies can lead to biological and therapeutic insights.

References

[1] Bray, G.A., 2004. Medical consequences of obesity. The Journal of Clinical Endocrinology & Metabolism, 89(6), pp.2583-2589.

[2] Akbari, P., Gilani, A., Sosina, O., Kosmicki, J.A., Khrimian, L., Fang, Y.Y., Persaud, T., Garcia, V., Sun, D., Li, A. and Mbatchou, J., 2021. Sequencing of 640,000 exomes identifies GPR75 variants associated with protection from obesity. Science, 373(6550).

[3] Pegtel, D.M. and Gould, S.J., 2019. Exosomes. Annual review of biochemistry, 88, pp.487-514.