Research on energy homeostasis has focused on neuronal signaling; however, the role of glial cells has remained little explored. Glial endozepines exert anorexigenic actions by mechanisms which remain poorly understood. In this context, the present study was designed to decipher the mechanisms underlying the anorexigenic action of endozepines and to investigate their potential curative effect on high-fat diet-induced obesity. We carried out a combination of physiological, pharmacological, and molecular analyses together to dissect the underlying mechanisms of endozepine-induced hypophagia. To evaluate the potential anti-obesity effect of endozepines, different model of obesity were used, i.e., ob/ob and diet-induced obese mice. We show that the intracerebral administration of endozepines enhances satiety by targeting anorexigenic brain circuitry and induces STAT3 phosphorylation, a hallmark of leptin signaling. Strikingly, endozepines are entirely ineffective at reducing food intake in the presence of a circulating leptin antagonist and in leptin-deficient mice (ob/ob) but potentiate the reduced food intake and weight loss induced by exogenous leptin administration in these animals. Endozepines reversed high fat diet-induced obesity by reducing food intake and restored leptin-induced STAT3 phosphorylation in the hypothalamus. Interestingly, we observed that glucose and insulin synergistically enhance tanycytic endozepine expression and release. Finally, endozepines, which induce ERK activation necessary for leptin transport into the brain in cultured tanycytes, require tanycytic leptin receptor expression to promote STAT3 phosphorylation in the hypothalamus. Our data identify endozepines as potential anti-obesity compounds in part through the modulation of the LepR-ERK-dependent tanycytic leptin shuttle.

能量稳态的研究集中在神经元信号；然而，神经胶质细胞的作用仍然很少被探索。胶质内氮平通过仍然知之甚少的机制发挥厌食作用。在此背景下，本研究旨在破译内西平产生厌食作用的机制，并研究其对高脂饮食引起的肥胖的潜在疗效。我们进行了生理学、药理学和分子分析的结合，以剖析内西平诱导的吞咽不足的潜在机制。为了评估内西平的潜在抗肥胖作用，使用了不同的肥胖模型，即ob / ob和饮食诱导的肥胖小鼠。我们表明，内西平的脑内给药通过靶向厌食性脑回路并诱导 STAT3 磷酸化（瘦素信号传导的标志）来增强饱腹感。引人注目的是，在存在循环瘦素拮抗剂和瘦素缺陷小鼠（ob / ob) 但会增强这些动物中外源性瘦素给药引起的食物摄入量减少和体重减轻。Endozepines 通过减少食物摄入和恢复瘦素诱导的下丘脑 STAT3 磷酸化来逆转高脂饮食诱导的肥胖。有趣的是，我们观察到葡萄糖和胰岛素协同增强 tanycytic endozepine 的表达和释放。最后，在培养的 tanycytes 中诱导瘦素转运到大脑中所必需的 ERK 激活的 endozepines 需要 tanycytic 瘦素受体表达以促进下丘脑中的 STAT3 磷酸化。我们的数据部分通过调节 LepR-ERK 依赖性 tanycytic 瘦素穿梭，将 endozepines 确定为潜在的抗肥胖化合物。