In recent years, the relationship between obesity and autoimmune diseases has been a widely discussed topic in the scientific literature. Mendelian randomization studies suggest that obesity may be a causal factor for diseases such as psoriasis, rheumatoid arthritis, and type 1 diabetes. However, a more in-depth analysis reveals that this correlation may be more complex than it seems, bringing to light the role of the FTO gene and its influence on the regulation of gene expression through m6A methylation.
Mendelian Randomization and Its Limitations
Mendelian randomization is a methodology used to determine causal relationships between genetic factors and diseases, avoiding the biases common in observational studies. In the case of obesity, these studies use genetic variants known to increase body mass index (BMI) to assess their influence on various health conditions.
However, one of the main challenges of this method is the superficiality in the analysis of the FTO gene, one of the genetic variants most associated with weight gain. What is often overlooked is that FTO is not only involved in regulating fat storage, but also plays a crucial role in the expression of thousands of genes, affecting multiple systems in the body.
The Role of the FTO Gene and the Regulation of Gene Expression
The FTO gene (Fat mass and obesity-associated gene) was one of the first genes identified in genome-wide studies as being strongly correlated with increased BMI. Its main function is related to the modulation of m6A methylation of messenger RNA (mRNA), a process that regulates which genes will be expressed or silenced in the body.
M6A methylation adds methyl groups to mRNA, preventing it from being translated into proteins. The FTO gene acts as an “eraser” of this marker, removing the methylation and allowing mRNA translation to occur. When variants of the FTO gene increase their expression, there is greater activation of certain genes, including those linked to metabolism and the immune system.
The Link Between FTO, Autoimmune Diseases, and Other Health Problems
If FTO’s sole function were to regulate body weight, the link between obesity and autoimmune diseases would seem clear. However, recent studies show that m6A methylation and the FTO gene are involved in a wide range of biological processes, including:
Autoimmune Diseases: Increased FTO expression can increase the production of inflammatory proteins, facilitating the development of autoimmune diseases.
Neurodegenerative Diseases: FTO affects the expression of genes related to Alzheimer’s and Parkinson’s, suggesting an impact beyond energy metabolism.
Cancer: FTO’s regulation of m6A has been linked to tumor progression in several types of cancer.
Cardiovascular Disease: The influence of m6A methylation on the modulation of inflammatory genes may be related to an increased risk of heart disease.
Thus, attributing causality solely to obesity in many medical conditions ignores the fact that individuals with FTO variants may be at high risk for autoimmune diseases, cancer, or heart disease regardless of their body weight.
The Debate on Therapeutic Interventions
The impact of this relationship has direct implications for public health policy and medical treatments. By arguing that obesity is a direct causal factor for autoimmune diseases, it creates an argument for interventions such as weight-loss medications, including GLP-1 inhibitors, which have been gaining popularity. However, if the risk of these diseases is more closely linked to FTO than to BMI per se, then losing weight may not significantly alter the genetic predisposition to these conditions.
Furthermore, exposure to environmental factors such as endocrine disruptors (BPA, phthalates) can modulate m6A methylation, which raises the need for further research into how these substances interfere with genetic mechanisms.
Conclusion
The relationship between obesity and autoimmune diseases is undeniably complex. While Mendelian randomization studies offer a statistical view of the correlation between these factors, molecular biology suggests that the role of the FTO gene and m6A methylation may be more significant than the simple equation between body weight and disease risk. Therefore, rather than focusing exclusively on weight loss strategies as a universal solution for autoimmune diseases, cancer, and cardiovascular problems, it may be more effective to direct research toward understanding how the regulation of gene expression influences these processes. The future of personalized medicine will depend on the ability to understand these nuances and develop therapies that act at the root of the problem, rather than just its symptoms.
