title: FTO is necessary for the induction of leptin resistance by high-fat feeding.
abstract: OBJECTIVE
  Loss of function FTO mutations significantly impact body composition in humans and mice, with Fto-deficient mice reported to resist the development of obesity in response to a high-fat diet (HFD). We aimed to further explore the interactions between FTO and HFD and determine if FTO can influence the adverse metabolic consequence of HFD.
  
  
  METHODS
  We studied mice deficient in FTO in two well validated models of leptin resistance (HFD feeding and central palmitate injection) to determine how Fto genotype may influence the action of leptin. Using transcriptomic analysis of hypothalamic tissue to identify relevant pathways affected by the loss of Fto, we combined data from co-immunoprecipitation, yeast 2-hybrid and luciferase reporter assays to identify mechanisms through which FTO can influence the development of leptin resistant states.
  
  
  RESULTS
  Mice deficient in Fto significantly increased their fat mass in response to HFD. Fto (+/-) and Fto (-/-) mice remained sensitive to the anorexigenic effects of leptin, both after exposure to a HFD or after acute central application of palmitate. Genes encoding components of the NFкB signalling pathway were down-regulated in the hypothalami of Fto-deficient mice following a HFD. When this pathway was reactivated in Fto-deficient mice with a single low central dose of TNFα, the mice became less sensitive to the effect of leptin. We identified a transcriptional coactivator of NFкB, TRIP4, as a binding partner of FTO and a molecule that is required for TRIP4 dependent transactivation of NFкB.
  
  
  CONCLUSIONS
  Our study demonstrates that, independent of body weight, Fto influences the metabolic outcomes of a HFD through alteration of hypothalamic NFкB signalling. This supports the notion that pharmacological modulation of FTO activity might have the potential for therapeutic benefit in improving leptin sensitivity, in a manner that is influenced by the nutritional environment.
authors.affiliation: University of Cambridge Metabolic Research Laboratories and MRC Metabolic Diseases Unit, Wellcome-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK.
authors.forename: Y C Loraine
authors.initials: YC
authors.lastname: Tung
authors.affiliation: University of Cambridge Metabolic Research Laboratories and MRC Metabolic Diseases Unit, Wellcome-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK.
authors.forename: Pawan
authors.initials: P
authors.lastname: Gulati
authors.affiliation: Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK.
authors.forename: Che-Hsiung
authors.initials: CH
authors.lastname: Liu
authors.affiliation: University of Cambridge Metabolic Research Laboratories and MRC Metabolic Diseases Unit, Wellcome-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK.
authors.forename: Debra
authors.initials: D
authors.lastname: Rimmington
authors.affiliation: University of Cambridge Metabolic Research Laboratories and MRC Metabolic Diseases Unit, Wellcome-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK.
authors.forename: Rowena
authors.initials: R
authors.lastname: Dennis
authors.affiliation: University of Cambridge Metabolic Research Laboratories and MRC Metabolic Diseases Unit, Wellcome-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK.
authors.forename: Marcella
authors.initials: M
authors.lastname: Ma
authors.affiliation: University of Cambridge Metabolic Research Laboratories and MRC Metabolic Diseases Unit, Wellcome-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Saudek
authors.affiliation: University of Cambridge Metabolic Research Laboratories and MRC Metabolic Diseases Unit, Wellcome-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK.
authors.forename: Stephen
authors.initials: S
authors.lastname: O'Rahilly
authors.affiliation: University of Cambridge Metabolic Research Laboratories and MRC Metabolic Diseases Unit, Wellcome-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK.
authors.forename: Anthony P
authors.initials: AP
authors.lastname: Coll
authors.affiliation: University of Cambridge Metabolic Research Laboratories and MRC Metabolic Diseases Unit, Wellcome-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK.
authors.forename: Giles S H
authors.initials: GS
authors.lastname: Yeo
keywords: FTO, FaT mass and Obesity related; Fto; GWAS, Genome-wide association studies; HFD, high-fat diet; High-fat diet; Hypothalamus; ICV, intracerebroventricular injection; Irx3, Iroquois Homeobox 3; Leptin resistance; MEF, Mouse embryonic fibroblasts; NFкB; Ob-R, leptin receptor; PTPs, protein-tyrosine phosphatase; SNPs, single nucleotide polymorphisms; SOCS3; SOCS3, suppressor of cytokine signalling; TRIP4; Tlr4, Toll-like receptor 4; WAT, white adipose tissue; Y2H, Yeast two-hybrid
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