FTO-Mediated m6A Demethylation in Insulin Resistance and Type 2 Diabetes: Tissue-Specific Mechanisms - a Narrative Review

This narrative review aims to clarify the tissue-specific effects of the fat mass and obesity-associated (FTO) gene, which encodes a demethylase enzyme, on lipid and glucose metabolism and appetite regulation. Some FTO single-nucleotide polymorphisms (SNPs) regulate neighboring genes, while the FTO protein demethylates single-stranded nucleic acids. The FTO enzyme modulates RNA lifecycle processes, including splicing, export, decay, and translation. However, recent studies suggest that FTO expression and activity may influence metabolic signals across multiple tissues. Evidence from genetic-association studies, experimental cellular and animal models, and human metabolic studies suggests tissue-specific effects of FTO, although findings are not always consistent across evidence types. In the liver, FTO has been reported to promote lipogenesis through effects on SREBP-1c maturation and the expression of lipogenic genes. In adipocytes, FTO has been implicated in adipogenesis through effects on Mitotic Clonal Expansion (MCE), including regulation of RUNX1T1 splicing, during terminal differentiation through effects on C/EBP-β transcription. In addition to effects attributed to FTO protein, the FTO locus-mediated mechanisms can influence neighboring genes such as IRX3, which has been implicated in adipocyte thermogenic programs. FTO has also been implicated in the regulation of gluconeogenic gene expression in the liver. In skeletal muscle, FTO has been associated with altered AMPK signaling and lipid accumulation. In pancreatic β-cells, FTO has been reported to affect insulin secretion, although findings are inconsistent across experimental models. In the hypothalamus, FTO-related mechanisms have been linked to RPGRIP1L and leptin signaling, suggesting a potential role in appetite regulation. FTO inhibitors have also been investigated for their potential to modulate FTO-related effects. In summary, FTO dysregulation may be involved in insulin resistance and metabolic risk factors associated with T2D. However, the underlying mechanisms and causal relationships remain incompletely established, particularly given differences among genetic-association studies, experimental models, and human metabolic studies.