FTO Obesity Variant Mechanism (Homo sapiens)

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1, 2Lipid storage inwhite adipocytesPPARGC1AFTOIRX5IRX3PRDM16UCP1ARID5BTBX1Fatty Acid OxidationC risk alleleFTOBrowning mitochondrialthermogenesis andbeige adipocytesT risk allele


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/

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Ontology Terms



  1. 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; ''FTO Obesity Variant Circuitry and Adipocyte Browning in Humans.''; N Engl J Med, 2015 PubMed Europe PMC Scholia
  2. Rosen CJ, Ingelfinger JR; ''Unraveling the Function of FTO Variants.''; N Engl J Med, 2015 PubMed Europe PMC Scholia


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97679view13:16, 1 June 2018AMTanOntology Term : 'obesity' added !
89858view12:25, 6 October 2016MkutmonModified description
87514view01:52, 25 July 2016AlexanderPicoOntology Term : 'disease pathway' added !
87513view01:52, 25 July 2016AlexanderPicoOntology Term : 'obesity disease pathway' added !
81707view04:52, 24 August 2015EgonwEncoded the SNP information as states, so that both the gene and the SNP has xrefs.
81678view23:33, 22 August 2015AlexanderPicoAdding newlines characters to description
81677view23:32, 22 August 2015AlexanderPicoModified description
81676view23:28, 22 August 2015AlexanderPicoAdded second ref
81675view23:23, 22 August 2015AlexanderPicoModified description
81674view23:10, 22 August 2015AlexanderPicoAdjusted centering
81673view23:10, 22 August 2015AlexanderPicoCompleted datanodes, layout and lit ref
81672view22:58, 22 August 2015AlexanderPicoPeriodical save, work in progress
81664view17:53, 22 August 2015AlexanderPicoNew pathway

External references


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NameTypeDatabase referenceComment
ARID5BGeneProductENSG00000150347 (Ensembl)
FTOGeneProduct79068 (Entrez Gene)
Fatty Acid OxidationPathwayWP368 (WikiPathways)
IRX3GeneProductENSG00000177508 (Ensembl)
IRX5GeneProductENSG00000176842 (Ensembl)
PPARGC1AGeneProductENSG00000109819 (Ensembl)
PRDM16GeneProductENSG00000142611 (Ensembl)
TBX1GeneProductENSG00000184058 (Ensembl)
UCP1GeneProductENSG00000109424 (Ensembl)

Annotated Interactions

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