Sequence variants in the first intron of FTO are strongly associated with human obesity, with carriers of the risk alleles reported to have increased appetite and preference for high fat food. Perturbation of FTO expression in multiple mouse models affects body composition and weight. In particular, Fto deficient mice are resistant to high-fat diet (HFD) induced obesity, a condition well recognised to engender a state of leptin resistance. We have undertaken a range of in vivo studies to further explore the interaction between Fto and dietary challenge and determine mechanisms through which Fto may influence the development of leptin resistant states. In contrast to WT mice, Fto deficient mice on a HFD or exposed to an acute central application of palmitate, remain sensitive to the anorexigenic effects of leptin administration. To determine why FTO loss may lead to retained leptin sensitivity we analysed NFkB signalling, a pathway known to be activated by exposure to HFD and found that genes encoding components of the NFкB signalling pathway were down-regulated in Fto null mice following a HFD. Crucially, when we activated the NFкB pathway with a single low central dose of TNFα into Fto deficient mice pre-treated with palmitate, the mice became resistant to the effects of leptin, similar to that seen in WT mice. In determining a possible mechanistic link between FTO and NFкB signalling, we identified Thyroid Receptor Interacting Protein 4 (TRIP4), a transcriptional coactivator of NFkB, as a putative candidate. Using a luciferase reporter system within Fto null mouse embryonic fibroblasts, we demonstrate that FTO is necessary for TRIP4 dependent transactivation of NFкB.  In conclusion, we have demonstrated that FTO influences the ability of a HFD to induce central leptin resistance through alteration of hypothalamic NFкB signalling.