Laboratory of Molecular Biology of Exercise (LaBMEx). School of Applied Science, University of Campinas (UNICAMP), Rua Pedro Zaccarias, 1300, CEP 13484-350 Limeira, São Paulo, Brazil.
Faculty of Medical Sciences, Department of Internal Medicine, University of Campinas (UNICAMP), CEP 13083-887 Campinas, São Paulo, Brazil.
Nat Commun. 2014 Sep 25;5:4859. doi: 10.1038/ncomms5859.
Sphingosine 1-phosphate receptor 1 (S1PR1) is a G-protein-coupled receptor for sphingosine-1-phosphate (S1P) that has a role in many physiological and pathophysiological processes. Here we show that the S1P/S1PR1 signalling pathway in hypothalamic neurons regulates energy homeostasis in rodents. We demonstrate that S1PR1 protein is highly enriched in hypothalamic POMC neurons of rats. Intracerebroventricular injections of the bioactive lipid, S1P, reduce food consumption and increase rat energy expenditure through persistent activation of STAT3 and the melanocortin system. Similarly, the selective disruption of hypothalamic S1PR1 increases food intake and reduces the respiratory exchange ratio. We further show that STAT3 controls S1PR1 expression in neurons via a positive feedback mechanism. Interestingly, several models of obesity and cancer anorexia display an imbalance of hypothalamic S1P/S1PR1/STAT3 axis, whereas pharmacological intervention ameliorates these phenotypes. Taken together, our data demonstrate that the neuronal S1P/S1PR1/STAT3 signalling axis plays a critical role in the control of energy homeostasis in rats.
鞘氨醇 1-磷酸受体 1（S1PR1）是鞘氨醇 1-磷酸（S1P）的 G 蛋白偶联受体，在许多生理和病理生理过程中发挥作用。在这里，我们表明下丘脑神经元中的 S1P/S1PR1 信号通路调节啮齿动物的能量平衡。我们证明 S1PR1 蛋白在大鼠下丘脑 POMC 神经元中高度富集。脑室内注射生物活性脂质 S1P 通过持续激活 STAT3 和黑皮质素系统，减少食物摄入并增加大鼠能量消耗。同样，选择性破坏下丘脑 S1PR1 会增加食物摄入并降低呼吸交换率。我们进一步表明，STAT3 通过正反馈机制控制神经元中的 S1PR1 表达。有趣的是，几种肥胖症和癌症厌食症模型显示下丘脑 S1P/S1PR1/STAT3 轴失衡，而药物干预可改善这些表型。总之，我们的数据表明神经元 S1P/S1PR1/STAT3 信号轴在控制大鼠能量平衡中起着关键作用。
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