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Unravelling the Genetics of Polygenic Obesity: What We Know and What We're Still Discovering

Polygenic obesity is the most common form of obesity and results from the interaction of multiple genes with environmental and lifestyle factors, such as diet, physical activity, and behavior. Unlike monogenic obesity, which is caused by mutations in a single gene, polygenic obesity involves variations in several genes, each contributing a small amount to the overall risk of becoming obese. These genetic variations can influence factors like appetite, metabolism, fat storage, and energy expenditure. Here are some examples of genes that have been implicated in polygenic obesity:

1. FTO (Fat Mass and Obesity-Associated Gene): The FTO gene was the first gene associated with body mass index (BMI) and obesity risk in various populations. Variants of the FTO gene are related to increased energy intake, preference for high-calorie foods, and reduced satiety.

2. MC4R (Melanocortin 4 Receptor): Although MC4R mutations can cause monogenic obesity, common variants in this gene are also involved in polygenic obesity. These variants can influence energy homeostasis and appetite regulation.

3. TMEM18 (Transmembrane Protein 18): Variants near or in the TMEM18 gene are associated with BMI and obesity. The exact mechanism by which TMEM18 influences obesity is not fully understood, but it is believed to play a role in brain regions that regulate body weight.

4. SEC16B (SEC16 Homolog B, Exocyst Complex Component): Genetic variants near the SEC16B gene are linked to BMI and obesity. The function of SEC16B in adiposity is not completely clear, but it may be involved in the regulation of energy balance.

5. SIM1 (Single-Minded Family BHLH Transcription Factor 1): Like in monogenic forms, SIM1 also plays a role in polygenic obesity, with certain variants affecting the risk. It is crucial in the development of the hypothalamus, which regulates hunger and satiety.

6. BDNF (Brain-Derived Neurotrophic Factor): Variants in the BDNF gene, which plays a critical role in neural development and appetite regulation, have been associated with obesity. BDNF modulates energy balance partly by influencing food intake.

7. GNPDA2 (Glucosamine-6-Phosphate Deaminase 2): GNPDA2 gene variants have been associated with body weight regulation. This gene may impact obesity through pathways involving glucose and lipid metabolism.

Polygenic obesity's complexity makes it challenging to address, as it involves a myriad of genetic interactions with numerous environmental factors. Lifestyle interventions, including diet, physical activity, and behavioral changes, are the cornerstone of management and prevention strategies for polygenic obesity. Understanding an individual's genetic predisposition toward obesity can also provide insight into their risk and guide personalized prevention and treatment plans.

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