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/ fab af6 C risk allele (rs1421085) 26287746 PubMed FTO Obesity Variant Circuitry and Adipocyte Browning in Humans. N Engl J Med 2015 Claussnitzer M Dankel SN Kim KH Quon G Meuleman W Haugen C Glunk V Sousa IS Beaudry JL Puviindran V Abdennur NA Liu J Svensson PA Hsu YH Drucker DJ Mellgren G Hui CC Hauner H Kellis M 26287747 PubMed Unraveling the Function of FTO Variants. N Engl J Med 2015 Rosen CJ Ingelfinger JR obesity disease pathway PW:0000540 Pathway Ontology disease pathway PW:0000013 Pathway Ontology obesity DOID:9970 Disease