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Introduction: Fat mass and obesity associated (FTO) gene is strongly associated with obesity which brings to a major health threat. Altered expression of its encoded protein FTO in the hypothalamus has been identified to contribute to central control of appetite and body weight. However, its molecular mechanisms remain elusive. Methods: Mouse hypothalamic POMC cell line N43/5 was treated with FTO inhibitor rhein, FTO shRNA or extracellular signal-regulated kinase 1/2 (ERK1/2) inhibitor U0126 to inhibit FTO or ERK1/2. Rhein and U0126 were injected into lateral ventricle of the mice by intracerebroventricular cannulation. Western blotting and immunofluorescent assays were performed to monitor protein level. Results: This study identified that inhibition of FTO in N43/5 cells led to phosphorylation of signal transducer and activator of transcription 3 (STAT3) at S727 site and induced p-STAT3-S727 nuclear translocation. We further showed that FTO inhibition promoted phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2); and specific inhibition of ERK1/2 signaling by U0126 could abolish the effect of FTO inhibition on STAT3-S727 phosphorylation and nuclear translocation. Furthermore, we found that inhibition of hypothalamic FTO promoted STAT3-S727 phosphorylation in the hypothalamic arcuate nucleus, and the mice showed reductions in food intake and body weight. In addition, inhibition of hypothalamic ERK1/2 could abolish the effects of FTO inhibition on STAT3-S727 phosphorylation, reductions of food intake and body weight. Conclusion: our in-vitro and in-vivo data suggest that the inhibition of hypothalamic FTO could activate STAT3 through ERK1/2, which is potentially associated with reductions in food intake and body weight.

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