Fto-flox Mouse

Fto, short for fat mass and obesity associated protein, is the first reported RNA N6 -methyladenosine (m6A) demethylase in eukaryotic cells. m6A is a prevalent mRNA internal modification that impacts cellular processes such as alternative splicing, stability, and expression. Fto has been associated with various biological processes, including adipogenesis, nutrient sensing, regulation of mRNA translation, and general growth [1,2].

Genome-wide association studies (GWAS) have linked single-nucleotide polymorphisms (SNPs) within Fto to obesity, as well as multiple cancers like endometrial, breast, pancreatic, and melanoma [1]. In diabetes-induced vascular endothelial dysfunction, enhanced Fto reduces global m6A levels in hyperglycemia, and Fto knockdown in endothelial cells leads to less inflammation and compromised migration and tube formation abilities. EC-specific Fto-deficient (EC FtoΔ/Δ) diabetic mice show less retinal vascular leakage and acellular capillary formation, suggesting the Fto-TNIP1-NF-κB network could be a potential target for treating diabetic vascular complications [3]. In osteoporosis, variation in Fto disturbs m6A methylation in RNAs, regulating cell proliferation, differentiation, and apoptosis. Pharmacological inhibition of Fto affects bone mass, bone mineral density, and adipose tissue distribution, indicating Fto-targeting small molecules could be novel osteoporosis treatments [4]. In multiple myeloma, up-regulation of Fto leads to decreased m6A methylation in plasma cells, and Fto promotes tumor-promoting and pro-metastatic functions by post-transcriptionally activating HSF1 in an m6A-YTHDF2-dependent manner. Inhibition of Fto, especially combined with bortezomib, synergistically inhibits myeloma bone tumor formation and extramedullary spread [5].

In conclusion, Fto, as an m6A demethylase, plays crucial roles in multiple biological processes and diseases. Studies using gene knockout or conditional knockout mouse models, like the EC FtoΔ/Δ mice in diabetes-related vascular complications, have been instrumental in revealing Fto's functions. These findings in model-based research highlight Fto's significance in obesity, diabetes-related vascular diseases, osteoporosis, and multiple myeloma, providing potential therapeutic targets for these conditions.