Abstract
ObjectiveLoss 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.MethodsWe 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.ResultsMice 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.ConclusionsOur 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.
Highlights
Genome-wide association studies (GWAS) have indicated that single nucleotide polymorphisms (SNPs) on chromosome 16 within the first intron of FTO (FaT mass and Obesity related) are robustly associated with human obesity [1]
Eight week old WT, Ftoþ/À and FtoÀ/À mice were given a 60% high-fat diet (HFD) for five weeks and their body composition subsequently compared to age-matched mice of the same genotypes that had been continuously provided with regular chow for the same time period
We report that mice deficient in Fto significantly increase their fat mass in response to HFD and that Ftoþ/À and FtoÀ/À mice remain sensitive to the anorexigenic effects of leptin, both after exposure to a HFD or after acute central application of palmitate
Summary
Genome-wide association studies (GWAS) have indicated that single nucleotide polymorphisms (SNPs) on chromosome 16 within the first intron of FTO (FaT mass and Obesity related) are robustly associated with human obesity [1]. These SNPs are associated with obesityrelated anthropometric traits such as fat mass, leptin levels and waistto-hip ratio, as well as an increase in food intake and a reduction in satiety. Ftoþ/À and FtoÀ/À mice have been reported to be protected from the development of obesity on a high-fat diet (HFD) [10] while high-fat feeding exacerbates the obesity of mice overexpressing Fto [13]
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