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

Abstract

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 m⁶A modification. FTO catalyzes the demethylation of m⁶A 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 m⁶A demethylation damages lipid utilization in skeletal muscles, leading to the occurrence of diabetic hyperlipidemia. m⁶A 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 m⁶A demethylation modulates the expression of lipid-related genes to regulate lipid metabolism and lipid disorder diseases.

Keywords: Adipose tissue; FTO; Lipid disorder diseases; Lipid metabolism; Liver; Skeletal muscle.

Figure 1

The structure of human FTO. (A) Human FTO is approximately 400 kb in length, comprises 8 introns and 9 exons and encodes multiple protein products. The approximately 3.4-kb region upstream of the human FTO gene contains a transcriptional initiation site for the RPGRIP1L gene. The first intron of FTO harbors a binding site for the transcription factor CUX1 which promotes the expression of RPGRIP1L after binding to this site. The region downstream of the FTO gene is adjacent to IRX3 and IRX5 which belong to the Iroquois gene family. The first intron of the FTO gene possesses an enhancer sequence for the IRX3 gene, which binds to the promoter of IRX3 to promote its expression. (B) The conformation of FTO protein. The FTO protein contains an NTD and a CTD with a novel fold. The catalytic core of NTD consists of a DSBH with the highly conserved residues: His231, Asp233 and His307, which are coordinated with Fe(II), and Arg316 and Arg322, which form a salt bridge with NOG. One side of the DSBH motif is buttressed by two α-helices α3 and α4, whereas the other side is covered by a long loop linking β5 and β6. The CTD contains approximately 170 residues and primarily forms α-helixes, of which α7, α8 and α10 form a triple helical bundle.

Figure 2

The reversible processes of methylation and demethylation of m⁶A modification. METTL3, METTL 4 and WTAP act as methylases to transfer the methyl-group onto the sixth carbon atom of substrate mRNA from the reactive methyl compound SAM. The demethylase FTO and ALKBH5 erase the m⁶A modification from the methylated mRNA strand.

Figure 3

The roles and underlying mechanisms of FTO in hepatocellular lipid metabolism. FTO-dependent m⁶A demethylation promotes the mRNA processing, translation and nuclear translocation of SREBP1C. SREBP1C binds to the promoters of lipogenic genes, including FAS, SCD, ACC1 and DGAT, to enhance their expression and facilitate lipid synthesis in the liver. SREBP1c-upregulated ACC1 catalyzes the synthesis of malonyl COA which inactivates CPT1 activity and suppresses CPT1-mediated β-oxidation of long-chain fatty acids. The failure of fatty acid oxidation in mitochondria triggers oxidative stress and leads to high ROS generation in hepatocytes, which further aggravates mitochondrial dysfunction and hinders TG decomposition. SREBP1C also promotes the transcription and expression of CIDEC which often resides on the surface of LDs to accelerate the expansion of hepatocellular LDs.

Figure 4

The roles and underlying mechanisms of FTO in lipid metabolism in adipose tissue. FTO-dependent m6A demethylation downregulates the expression of miRNA130 and miRNA155, causing the upregulation of C/EBPβ and the induced differentiation of preadipocytes. FTO-upregulated C/EBPβ expression reduces UCP-1 expression and inhibits the yield of brown adipocytes. FTO-dependent m⁶A demethylation alters the alternative splicing of RUNX1T1 and increases the production of the spliceosome subtype, which stimulates adipogenesis in preadipocytes and increases body fat mass. FTO-downregulated miRNA130 expression enhances PPARγ expression and adipogenesis in preadipocytes. FTO disrupts the binding of CTSB with LDs and inhibits phosphorylation of plin1 by CTSB, resulting in the failure of TG hydrolysis in preadipocytes. FTO-dependent m⁶A demethylation reduces ANGPTL4 protein levels, accelerating LPL release and extracellular TG hydrolysis which provides the material for the synthesis of TGs and LDs in adipocytes. The long-range enhancer of the FTO gene downregulates hypothalamic IRX3 and inhibits lipolysis in peripheral adipocytes. In specific subsets of hypothalamic neurons, the binding site in FTO intron 1 interacts with the transcription factor CUX1 to increase RPGRIPLl expression, which reduces leptin signal transduction and leptin-induced lipolysis in adipocytes.