From Belly to Brain: Targeting the Ghrelin Receptor in Appetite and Food Intake Regulation.
From Belly to Brain: Targeting the Ghrelin Receptor in Appetite and Food Intake Regulation.
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DOI：
10.3390/ijms18020273
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发表时间：
2017-01-27
影响因子：
5.6
通讯作者：
Schellekens H
中科院分区：
文献类型：
--
作者：
Howick K;Griffin BT;Cryan JF;Schellekens H
生长素释放肽是唯一已知的外周源性食欲激素，可增加食欲和随后的食物摄入量。因此，生长激素释放系统作为降低肥胖症食欲以及刺激厌食症、营养不良和恶病质情况下食物摄入的治疗靶点受到了相当多的关注。随着针对这种激素的治疗潜力变得更加清晰，很明显它的多效作用涵盖中枢神经系统和外周器官。尽管进行了大量的研究，但专门针对胃饥饿素系统进行食欲调节的治疗化合物仍然难以捉摸，尽管对代谢功能的一些有希望的作用正在出现。这是由于多种因素造成的，从生长激素释放肽受体（生长激素促分泌受体，GHSR-1a）内化和异二聚化的复杂性，到偏向的配体相互作用和补偿性神经内分泌输出。尤其重要的是 GHSR-1a 的普遍表达，这使得在不侵犯 ghrelin 的各种外周功能的情况下调节中枢介导的食欲调节变得不可能。越来越明显的是，生长素释放肽的中央信号传导对于其对食欲、体重调节和食物刺激显着性的影响至关重要。提高生长素释放肽配体穿透血脑屏障的能力将增强向表达 GHSR-1a 的大脑区域的中枢递送，特别是在中脑边缘奖励回路内。
Ghrelin is the only known peripherally-derived orexigenic hormone, increasing appetite and subsequent food intake. The ghrelinergic system has therefore received considerable attention as a therapeutic target to reduce appetite in obesity as well as to stimulate food intake in conditions of anorexia, malnutrition and cachexia. As the therapeutic potential of targeting this hormone becomes clearer, it is apparent that its pleiotropic actions span both the central nervous system and peripheral organs. Despite a wealth of research, a therapeutic compound specifically targeting the ghrelin system for appetite modulation remains elusive although some promising effects on metabolic function are emerging. This is due to many factors, ranging from the complexity of the ghrelin receptor (Growth Hormone Secretagogue Receptor, GHSR-1a) internalisation and heterodimerization, to biased ligand interactions and compensatory neuroendocrine outputs. Not least is the ubiquitous expression of the GHSR-1a, which makes it impossible to modulate centrally-mediated appetite regulation without encroaching on the various peripheral functions attributable to ghrelin. It is becoming clear that ghrelin’s central signalling is critical for its effects on appetite, body weight regulation and incentive salience of food. Improving the ability of ghrelin ligands to penetrate the blood brain barrier would enhance central delivery to GHSR-1a expressing brain regions, particularly within the mesolimbic reward circuitry.