Department of Cellular and Molecular Pathology, German Cancer Research Center, Heidelberg, Germany.
PLoS Biol. 2013;11(3):e1001506. doi: 10.1371/journal.pbio.1001506. Epub 2013 Mar 12.
Hypothalamic neurons are main regulators of energy homeostasis. Neuronal function essentially depends on plasma membrane-located gangliosides. The present work demonstrates that hypothalamic integration of metabolic signals requires neuronal expression of glucosylceramide synthase (GCS; UDP-glucose:ceramide glucosyltransferase). As a major mechanism of central nervous system (CNS) metabolic control, we demonstrate that GCS-derived gangliosides interacting with leptin receptors (ObR) in the neuronal membrane modulate leptin-stimulated formation of signaling metabolites in hypothalamic neurons. Furthermore, ganglioside-depleted hypothalamic neurons fail to adapt their activity (c-Fos) in response to alterations in peripheral energy signals. Consequently, mice with inducible forebrain neuron-specific deletion of the UDP-glucose:ceramide glucosyltransferase gene (Ugcg) display obesity, hypothermia, and lower sympathetic activity. Recombinant adeno-associated virus (rAAV)-mediated Ugcg delivery to the arcuate nucleus (Arc) significantly ameliorated obesity, specifying gangliosides as seminal components for hypothalamic regulation of body energy homeostasis.
下丘脑神经元是能量平衡的主要调节者。神经元的功能本质上取决于位于质膜上的神经节苷脂。本工作表明，代谢信号在下丘脑的整合需要神经元表达葡萄糖神经酰胺合酶（GCS；UDP-葡萄糖：神经酰胺葡萄糖基转移酶）。作为中枢神经系统（CNS）代谢控制的主要机制，我们证明 GCS 衍生的神经节苷脂与神经元膜中的瘦素受体（ObR）相互作用，调节瘦素刺激的信号代谢物在下丘脑神经元中的形成。此外，神经节苷脂耗竭的下丘脑神经元无法响应外周能量信号的改变来调整其活性（c-Fos）。因此，诱导性大脑前神经元特异性 Ugcg 基因（UDP-葡萄糖：神经酰胺葡萄糖基转移酶基因）缺失的小鼠表现出肥胖、体温过低和交感神经活动降低。重组腺相关病毒（rAAV）介导的 Ugcg 递送至弓状核（Arc）显著改善了肥胖，表明神经节苷脂是下丘脑调节身体能量平衡的重要组成部分。
