Functional coupling analysis suggests link between the obesity gene FTO and the BDNF-NTRK2 signaling pathway

Abstract

BackgroundThe 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.ResultsWe 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.ConclusionsGene 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).

Fat Mass- and Obesity-Associated (FTO) Gene and Antipsychotic-Induced Weight Gain: An Association Study

“…The few studies that have been performed place FTO amid complex gene interactions involved in both lipolysis and eating behavior. For example, there is support that FTO participates in regulating neuronal plasticity through interactions with brain-derived neurotropic factor (BDNF) and type 2 neurotropic tyrosine kinase receptor [15]. Along with its role in neuronal development and survival, variants in the BDNF gene have been significantly associated with weight gain, and a number of studies have targeted BDNF for a role in energy expenditure and AIWG [16,17,18].…”

Association between FTO gene polymorphism and excess body weight in women from before to after pregnancy: A cohort study

“…Furthermore, homozygous AA individuals are more prone to an elevated post‐prandial appetite level, which is linked to an interaction between the FTO genotype and circulating levels of ghrelin, a key mediator of digestive behavior (Karra et al, ). Other studies also suggest an effect of FTO on the regulation of proteins in pathways involved in energy intake, such as leptin levels (Labayen et al, ) and leptin sensitivity (Wang et al, ), and other signaling proteins (Lin et al, ; Rask‐Andersen et al, ). The FTO ‐rs9939609 genotype is also associated with some metabolites, with evidence having been obtained of changes in phospholipid and amino acid metabolisms that may be linked to obesity and type 2 diabetes in A allele carriers (Kim et al, ).…”

Effects of breed, postnatal development, and nutrition on mRNA expression of the FTO gene in porcine muscle and its relationship with intramuscular fat deposition

“…However, the existing papers showed that feeding status had indeed affected FTO mRNA expression. Hypothalamic FTO mRNA levels have been reported to be higher (Fredriksson et al, 2008;Olszewski et al, 2009;Rask-Andersen et al, 2011), decreased (Poritsanos et al, 2011 or without difference (McTaggart et al, 2011) in fasted mice. Fasting was also found to change hepatic FTO mRNA expression, but had no effect on FTO mRNA expression in muscle and adipose tissues both in mice and broiler chickens (Poritsanos et al, 2010;McTaggart et al, 2011;Tiwari et al, 2012).…”