Critical roles of FTO-mediated mRNA m6A demethylation in regulating adipogenesis and lipid metabolism: Implications in lipid metabolic disorders

The goal this review is to clarify the effects of the fat mass and obesity-associated protein (FTO) in lipid metabolism regulation and related underlying mechanisms through the FTO-mediated demethylation of m(6)A modification. FTO catalyzes the demethylation of m(6)A to alter the processing, maturation and translation of the mRNAs of lipid-related genes. FTO overexpression in the liver promotes lipogenesis and lipid droplet (LD) enlargement and suppresses CPT-1–mediated fatty acid oxidation via the SREBP1c pathway, promoting excessive lipid storage and nonalcoholic fatty liver diseases (NAFLD). FTO enhances preadipocyte differentiation through the C/EBPβ pathway, and facilitates adipogenesis and fat deposition by altering the alternative splicing of RUNX1T1, the expression of PPARγ and ANGPTL4, and the phosphorylation of PLIN1, whereas it inhibits lipolysis by inhibiting IRX3 expression and the leptin pathway, causing the occurrence and development of obesity. Suppression of the PPARβ/δ and AMPK pathways by FTO-mediated m(6)A demethylation damages lipid utilization in skeletal muscles, leading to the occurrence of diabetic hyperlipidemia. m(6)A demethylation by FTO inhibits macrophage lipid influx by downregulating PPARγ protein expression and accelerates cholesterol efflux by phosphorylating AMPK, thereby impeding foam cell formation and atherosclerosis development. In summary, FTO-mediated m(6)A demethylation modulates the expression of lipid-related genes to regulate lipid metabolism and lipid disorder diseases.