University of Bordeaux, INSERM, Neurocentre Magendie, U1215, 3300, Bordeaux, France.
Basic Sciences Department, Faculty of Medicine and Health Sciences, Universitat Internacional de Catalunya, Josep Trueta S/N, 08195, Sant Cugat del Vallès, Spain.
Cell Mol Life Sci. 2021 Dec;78(23):7469-7490. doi: 10.1007/s00018-021-04002-6. Epub 2021 Oct 31.
The crucial role of the hypothalamus in the pathogenesis of obesity is widely recognized, while the precise molecular and cellular mechanisms involved are the focus of intense research. A disrupted endocannabinoid system, which critically modulates feeding and metabolic functions, through central and peripheral mechanisms, is a landmark indicator of obesity, as corroborated by investigations centered on the cannabinoid receptor CB1, considered to offer promise in terms of pharmacologically targeted treatment for obesity. In recent years, novel insights have been obtained, not only into relation to the mode of action of CB receptors, but also CB ligands, non-CB receptors, and metabolizing enzymes considered to be part of the endocannabinoid system (particularly the hypothalamus). The outcome has been a substantial expansion in knowledge of this complex signaling system and in drug development. Here we review recent literature, providing further evidence on the role of hypothalamic endocannabinoids in regulating energy balance and the implication for the pathophysiology of obesity. We discuss how these lipids are dynamically regulated in obesity onset, by diet and metabolic hormones in specific hypothalamic neurons, the impact of gender, and the role of endocannabinoid metabolizing enzymes as promising targets for tackling obesity and related diseases.
下丘脑在肥胖症发病机制中的关键作用已得到广泛认可，而涉及的精确分子和细胞机制则是密集研究的焦点。一个紊乱的内源性大麻素系统通过中枢和外周机制，对摄食和代谢功能进行关键调节，是肥胖的一个重要标志，这一点得到了以大麻素受体 CB1 为中心的研究的证实，被认为在肥胖的药物靶向治疗方面具有潜力。近年来，不仅获得了关于 CB 受体作用模式的新见解，而且还获得了内源性大麻素系统（特别是下丘脑）的 CB 配体、非 CB 受体和代谢酶的新见解。这导致了对这个复杂信号系统和药物开发的知识的大量扩展。在这里，我们回顾了最近的文献，提供了更多关于下丘脑内源性大麻素在调节能量平衡中的作用的证据，以及这些脂质在肥胖症发病机制中的意义。我们讨论了这些脂质在肥胖症发生过程中是如何被饮食和代谢激素在特定的下丘脑神经元中动态调节的，讨论了性别差异的影响，以及内源性大麻素代谢酶作为解决肥胖症和相关疾病的有前途的靶点的作用。
