Howick Ken, Griffin Brendan T, Cryan John F, Schellekens Harriët
Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland.
School of Pharmacy, University College Cork, Cork, Ireland.
Int J Mol Sci. 2017 Jan 27;18(2):273. doi: 10.3390/ijms18020273.
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 centrallymediated 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.
胃饥饿素是唯一已知的由外周产生的促食欲激素，可增加食欲及随后的食物摄入量。因此，胃饥饿素能系统作为减少肥胖患者食欲以及刺激厌食、营养不良和恶病质患者食物摄入的治疗靶点，受到了广泛关注。随着靶向该激素的治疗潜力日益清晰，显然其多效性作用涉及中枢神经系统和外周器官。尽管进行了大量研究，但一种专门靶向胃饥饿素系统以调节食欲的治疗化合物仍难以捉摸，不过对代谢功能已出现了一些有前景的作用。这是由多种因素导致的，从胃饥饿素受体（生长激素促分泌素受体，GHSR-1a）内化和异二聚化的复杂性，到偏向性配体相互作用和代偿性神经内分泌输出。尤其重要的是GHSR-1a的广泛表达，这使得在不影响胃饥饿素的各种外周功能的情况下，不可能调节中枢介导的食欲调节。越来越明显的是，胃饥饿素的中枢信号传导对其在食欲、体重调节和食物激励显著性方面的作用至关重要。提高胃饥饿素配体穿透血脑屏障的能力，将增强向表达GHSR-1a的脑区的中枢递送，特别是在中脑边缘奖赏回路内。
