FTO as an epigenetic regulator in metabolic and inflammatory diseases

Abstract

Obesity has emerged as a global health crisis in the 21st century, driven by rising obesity rates and associated metabolic disorders. The genome-wide association studies led to the identification of a gene associated with obesity and thus named the fat mass and obesity-associated (FTO) gene. In humans, the FTO gene is expressed in various tissues, including the brain, liver, and adipose tissue. It is known to play a major role in regulating energy balance, appetite, and body fat mass. FTO encodes an N6-methyladenosine RNA demethylase that regulates key biological processes, including adipogenesis, energy homeostasis, and glucose metabolism, through a dynamic RNA modification process involving splicing, export, decay, and/or translation. Polymorphisms in the FTO gene, particularly within intron 1, are strongly associated with increased risk of body mass index and obesity. In addition, FTO has been implicated in the pathogenesis of type 2 diabetes mellitus, cardiovascular disease, chronic kidney disease, and various cancers, where it could function both as an oncogene and a tumor suppressor gene. Pre-clinical studies have established the functional relevance of FTO, where its overexpression promotes obesity, whereas its deletion allows maintenance of a normal body phenotype. This review covers the recent advances in the development of specific FTO inhibitors and highlights their potential as therapeutic agents for obesity and metabolic disorders, although their development is still in its early stages. Despite the significant progress made in understanding the role of FTO in metabolic diseases, further research is needed to elucidate the precise mechanisms linking FTO variants to specific pathological outcomes and to optimize targeted therapies.

Keywords

FTO / N6-methyladenosine / Metabolic dysfunction-associated steatotic liver disease / Obesity / RNA demethylase / Inhibitors / Single nucleotide polymorphisms / RNA demethylation

Acknowledgments

None.

Funding

This work was supported in part by the J.C. Bose National Fellowship (Grant no. SR/S2/JCB-80/2012) from the Department of Science and Technology, Government of India, New Delhi (to V.K.). S.G. received a senior research fellowship from the University Grants Commission, India.

Conflict of interest

The authors declare that they have no competing interests.

Author contributions

Conceptualization: All authors

Visualization: All authors

Writing - original draft: Sunita Giri

Writing - review & editing: Vijay Kumar

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Availability of data

Not applicable.

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