FTO mediates cell-autonomous effects on adipogenesis and adipocyte lipid content by regulating gene expression via 6mA DNA modifications.

SNPs in the first intron of α-ketoglutarate-dependent dioxygenase () convey effects on adiposity by mechanisms that remain unclear, but appear to include modulation of expression of itself, as well as other genes in expression is lower in fibroblasts and iPSC-derived neurons of individuals segregating for obesity risk alleles. We employed in vitro adipogenesis models to investigate the molecular mechanisms by which Fto affects adipocyte development and function. expression was upregulated during adipogenesis, and was required for the maintenance of and / expression in murine and human adipocytes in vitro. knockdown decreased the number of 3T3-L1 cells that differentiated into adipocytes as well as the amount of lipid per mature adipocyte. This effect on adipocyte programming was conveyed, in part, by modulation of CCAAT enhancer binding protein (C/ebp)β-regulated transcription. We found that Fto also affected transcription by demethylating DNA N6-methyldeoxyadenosine in the promoter. Fto is permissive for adipogenesis and promotes maintenance of lipid content in mature adipocytes by enabling C/ebpβ-driven transcription and expression of These findings are consistent with the loss of fat mass in mice segregating for a dominant-negative allele.