Obesity and Metabolism Laboratory, Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 9112001, Israel.
Toxins (Basel). 2019 May 15;11(5):275. doi: 10.3390/toxins11050275.
In this review, we discuss the role of the endocannabinoid (eCB) system in regulating energy and metabolic homeostasis. Endocannabinoids, via activating the cannabinoid type-1 receptor (CBR), are commonly known as mediators of the thrifty phenotype hypothesis due to their activity in the central nervous system, which in turn regulates food intake and underlies the development of metabolic syndrome. Indeed, these findings led to the clinical testing of globally acting CBR blockers for obesity and various metabolic complications. However, their therapeutic potential was halted due to centrally mediated adverse effects. Recent observations that highlighted the key role of the peripheral eCB system in metabolic regulation led to the preclinical development of various novel compounds that block CBR only in peripheral organs with very limited brain penetration and without causing behavioral side effects. These unique molecules, which effectively ameliorate obesity, type II diabetes, fatty liver, insulin resistance, and chronic kidney disease in several animal models, are likely to be further developed in the clinic and may revive the therapeutic potential of blocking CBR once again.
在这篇综述中，我们讨论了内源性大麻素（eCB）系统在调节能量和代谢平衡中的作用。内源性大麻素通过激活大麻素受体 1（CBR1），因其在中枢神经系统中的活性而被普遍认为是节俭表型假说的介导物，而中枢神经系统反过来又调节食物摄入，是代谢综合征发展的基础。事实上，这些发现促使人们对全球作用的 CBR1 阻滞剂进行肥胖和各种代谢并发症的临床试验。然而，由于中枢介导的不良反应，它们的治疗潜力被停止。最近的观察结果强调了外周 eCB 系统在代谢调节中的关键作用，这导致了各种新型化合物的临床前开发，这些化合物仅在外周器官中阻断 CBR，而对大脑的穿透性非常有限，且不会引起行为副作用。这些独特的分子有效地改善了肥胖、二型糖尿病、脂肪肝、胰岛素抵抗和慢性肾病等多种动物模型，很可能在临床上进一步开发，并可能再次恢复阻断 CBR 的治疗潜力。
