Inhibition of Hypothalamic FTO Activates STAT3 Signal through ERK1/2 Associated with Reductions in Food Intake and Body Weight

Abstract

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.

The Functional Role and Regulatory Mechanism of FTO m6A RNA Demethylase in Human Uterine Leiomyosarcoma

“…Notably, FTO as a therapeutic target has been reported in many types of cancers and experimental models. Accordingly, several FTO inhibitors have been developed, including GS1 and GS2 [31], 18077 and 18097 [13], 13a [55], C6 [39], Rhein [56], FB23-2 [16], and Dac51 [41]. The latter showed a potent inhibitory effect as an FTO inhibitor.…”

Identifying Potent Fat Mass and Obesity-Associated Protein Inhibitors Using Deep Learning-Based Hybrid Procedures

“…The FTO gene exhibits significant expression in adipose tissues and skeletal muscles within human anatomical structures [25]. Notably, the highest expression level is observed in the hypothalamus, specifically in the arcuate nucleus, which governs energy balance [26]. This finding suggests that FTO likely plays a crucial role in regulating appetite and energy metabolism [27].…”