Fto, also known as fat mass and obesity-associated protein, is the first reported RNA N6-methyladenosine (m6A) demethylase in eukaryotic cells. m6A is the most abundant mRNA internal modification, involved in regulating processes like alternative splicing, stability, and expression. Fto has been associated with multiple biological processes and diseases, with its role in adipogenesis and tumorigenesis being of particular interest [1].

Genome-wide association studies (GWAS) identified Fto single-nucleotide polymorphisms (SNPs) associated with obesity. In EC-specific Fto-deficient (EC FtoΔ/Δ) diabetic mice, there was less retinal vascular leakage and acellular capillary formation compared to EC Ftofl/fl diabetic mice, suggesting Fto's role in diabetes-induced vascular endothelial dysfunction [2]. In osteoporosis, pharmacological inhibition of Fto markedly altered bone mass, bone mineral density, and adipose tissue distribution [3]. In multiple myeloma, FTO promotes tumor-promoting and pro-metastatic effects, and its inhibition, especially combined with bortezomib, synergistically inhibited myeloma bone tumor formation and extramedullary spread in NOD-Prkdcem26Cd52il2rgem26Cd22/Nju (NCG) mice [4].

In conclusion, Fto, as an m6A demethylase, is involved in various biological processes. Through gene-knockout or conditional-knockout mouse models, its role in diseases such as obesity, diabetes-related vascular complications, osteoporosis, and multiple myeloma has been revealed. These findings contribute to understanding the molecular mechanisms of these diseases and may provide potential therapeutic targets.

References:

1. Azzam, Sarah Kassem, Alsafar, Habiba, Sajini, Abdulrahim A. 2022. FTO m6A Demethylase in Obesity and Cancer: Implications and Underlying Molecular Mechanisms. In International journal of molecular sciences, 23, . doi:10.3390/ijms23073800. https://pubmed.ncbi.nlm.nih.gov/35409166/

2. Zhou, Chuandi, She, Xinping, Gu, Chufeng, Chen, Haibing, Zheng, Zhi. 2023. FTO fuels diabetes-induced vascular endothelial dysfunction associated with inflammation by erasing m6A methylation of TNIP1. In The Journal of clinical investigation, 133, . doi:10.1172/JCI160517. https://pubmed.ncbi.nlm.nih.gov/37781923/

3. Huang, Mei, Guo, Jianmin, Liu, Lifei, Chen, Xi, Zou, Jun. 2023. m6A demethylase FTO and osteoporosis: potential therapeutic interventions. In Frontiers in cell and developmental biology, 11, 1275475. doi:10.3389/fcell.2023.1275475. https://pubmed.ncbi.nlm.nih.gov/38020896/

4. Xu, Aoshuang, Zhang, Jiasi, Zuo, Liping, Sun, Chunyan, Hu, Yu. 2021. FTO promotes multiple myeloma progression by posttranscriptional activation of HSF1 in an m6A-YTHDF2-dependent manner. In Molecular therapy : the journal of the American Society of Gene Therapy, 30, 1104-1118. doi:10.1016/j.ymthe.2021.12.012. https://pubmed.ncbi.nlm.nih.gov/34915192/