title: Functional coupling analysis suggests link between the obesity gene FTO and the BDNF-NTRK2 signaling pathway.
abstract: BACKGROUND
  The Fat mass and obesity gene (FTO) has been identified through genome wide association studies as an important genetic factor contributing to a higher body mass index (BMI). However, the molecular context in which this effect is mediated has yet to be determined. We investigated the potential molecular network for FTO by analyzing co-expression and protein-protein interaction databases, Coxpresdb and IntAct, as well as the functional coupling predicting multi-source database, FunCoup. Hypothalamic expression of FTO-linked genes defined with this bioinformatics approach was subsequently studied using quantitative real time-PCR in mouse feeding models known to affect FTO expression.
  
  
  RESULTS
  We identified several candidate genes for functional coupling to FTO through database studies and selected nine for further study in animal models. We observed hypothalamic expression of Profilin 2 (Pfn2), cAMP-dependent protein kinase catalytic subunit beta (Prkacb), Brain derived neurotrophic factor (Bdnf), neurotrophic tyrosine kinase, receptor, type 2 (Ntrk2), Signal transducer and activator of transcription 3 (Stat3), and Btbd12 to be co-regulated in concert with Fto. Pfn2 and Prkacb have previously not been linked to feeding regulation.
  
  
  CONCLUSIONS
  Gene expression studies validate several candidates generated through database studies of possible FTO-interactors. We speculate about a wider functional role for FTO in the context of current and recent findings, such as in extracellular ligand-induced neuronal plasticity via NTRK2/BDNF, possibly via interaction with the transcription factor CCAAT/enhancer binding protein β (C/EBPβ).
authors.affiliation: Department of Neuroscience, Functional Pharmacology, Uppsala University, BMC, Uppsala SE 75124, Sweden.
authors.forename: Mathias
authors.initials: M
authors.lastname: Rask-Andersen
authors.forename: Markus Sällman
authors.initials: MS
authors.lastname: Almén
authors.forename: Hans R
authors.initials: HR
authors.lastname: Olausen
authors.forename: Pawel K
authors.initials: PK
authors.lastname: Olszewski
authors.forename: Jenny
authors.initials: J
authors.lastname: Eriksson
authors.forename: Rohit A
authors.initials: RA
authors.lastname: Chavan
authors.forename: Allen S
authors.initials: AS
authors.lastname: Levine
authors.forename: Robert
authors.initials: R
authors.lastname: Fredriksson
authors.forename: Helgi B
authors.initials: HB
authors.lastname: Schiöth
mesh_terms: D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics*; D019295:Computational Biology / Q000379:methods; D055106:Genome-Wide Association Study / Q000379:methods; D007031:Hypothalamus / Q000378:metabolism*; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D006899:Mixed Function Oxygenases / Q000235:genetics*; D009765:Obesity / Q000235:genetics* / Q000378:metabolism; D007652:Oxo-Acid-Lyases / Q000235:genetics*; D011505:Protein-Tyrosine Kinases / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics*; D020813:Receptor, trkB
chemical_list: D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO; D019208:Brain-Derived Neurotrophic Factor; D008562:Membrane Glycoproteins; D006899:Mixed Function Oxygenases; D007652:Oxo-Acid-Lyases; D011505:Protein-Tyrosine Kinases; C524916:FTO protein, mouse; C064371:Ntrk2 protein, mouse; D020813:Receptor, trkB
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