FTO is necessary for the induction of leptin resistance by high-fat feeding

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.

Fat Mass and Obesity Associated (FTO) Gene and Hepatic Glucose and Lipid Metabolism

“…High-fat diet-induced obesity is attenuated and exaggerated in Fto-deficient mice and transgenic mice overexpressing FTO, respectively [23][24][25]. Contrary to these findings, other studies demonstrated that increased fat mass or percent body fat in mice lacking FTO [24,26,27]. These findings suggest that FTO plays a role in the regulation of whole body metabolism in mice.…”

Central Leptin and Tumor Necrosis Factor-α (TNFα) in Diurnal Control of Blood Pressure and Hypertension

“…Finally, it is worth discussing that, although high-dose TNF␣ is often known as a cachectic cytokine in diseases like cancers and infections, low-dose TNF␣ in the hypothalamus at the level of obesity-associated inflammation has been implicated to reduce the sensitivity of leptin in the control of feeding (57,58). This effect of TNF␣ in decreasing leptin sensitivity in feeding is in contrast with its augmentation in the BP-raising effect of leptin.…”

Leptin applications in 2015

“…Several mechanisms and pathways related to the development of leptin resistance have been described in the past [76,77] and new ones are continuously discovered. The phosphodiesterase-3B (PDE3B)-cAMP- and Akt-pathways of leptin signaling in the hypothalamus, the fat mass and obesity-related (FTO) gene, transient receptor potential vanilloid type (TRPV)-1 channel, 15-deoxy-Δ(12,14) -prostaglandin J2 (15d-PGJ2), estradiol (E2) and peroxisome proliferator-activated receptor γ (PPARγ) are some of the recently identified molecules/pathways to be involved in leptin’s resistance development in animal studies [78*,79*,80*,81*,82*,83*]. Although this new knowledge creates new pathways for understanding leptin resistance, these still need to be confirmed in humans.…”