FTO obesity variant mechanism (WP3407)

Homo sapiens

Mechanism underlying the association of FTO locus variants and obesity. The wild type T allele at rs1421085 in the FTO locus comprises a protein-DNA binding motif for ARID5B that represses the transcription of IRX3 and IRX5, which in turn de-represses a set of thermogenic genes, leading to mitochondrial thermogenesis and a browning adipocyte program. The C risk allele, on the other hand, disrupts the binding motif for ARID5B and activates a mesenchymal superenhancer and its targets, IRX3 and IRX5, which represses thermogenesis and leads to a shift to lipid storage, white adipocytes and, thus, increased risk of obesity. In addition to the primary literature references associated with the pathway, also refer to this blog article providing additional perspective and drug discovery potential by Roger Plenge, "Article of the week: ARID5B-FTO-IRX3/IRX5 regulatory axis for drug discovery in obesity (NEJM)." August 21, 2015. http://www.plengegen.com/blog/arid5b-fto-irx3irx5-regulatory-axis-drug-discovery-obesity-nejm/


Alex Pico , Egon Willighagen , Martina Summer-Kutmon , Andika Tan , and Eric Weitz


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Homo sapiens




Pathway Ontology

disease pathway obesity pathway

Disease Ontology



Label Type Compact Identifier Comment
PRDM16 GeneProduct ensembl:ENSG00000142611
FTO GeneProduct ncbigene:79068
ARID5B GeneProduct ensembl:ENSG00000150347
IRX5 GeneProduct ensembl:ENSG00000176842
PPARGC1A GeneProduct ensembl:ENSG00000109819
IRX3 GeneProduct ensembl:ENSG00000177508
UCP1 GeneProduct ensembl:ENSG00000109424
TBX1 GeneProduct ensembl:ENSG00000184058
FTO GeneProduct ncbigene:79068


  1. FTO Obesity Variant Circuitry and Adipocyte Browning in Humans. Claussnitzer M, Dankel SN, Kim KH, Quon G, Meuleman W, Haugen C, et al. N Engl J Med. 2015 Sep 3;373(10):895–907. PubMed Europe PMC Scholia
  2. Unraveling the Function of FTO Variants. Rosen CJ, Ingelfinger JR. N Engl J Med. 2015 Sep 3;373(10):964–5. PubMed Europe PMC Scholia