School of Pharmacy, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Food for Health Ireland, University College Cork, Cork, Ireland.
Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; APC Microbiome Ireland, University College Cork, Cork, Ireland.
Neuropharmacology. 2020 May 15;168:108011. doi: 10.1016/j.neuropharm.2020.108011. Epub 2020 Feb 14.
The ghrelinergic system has been steadily investigated as a therapeutic target in the treatment of metabolic disorders and modulation of appetite. While endogenous ghrelin activates the full complement of the growth hormone secretagogue receptor (GHSR-1a) pathways, synthetic GHSR-1a ligands display biased signalling and functional selectivity, which have a significant impact on the intended and indeed, unintended, therapeutic effects. The widespread expression of the GHSR-1a receptor in vivo also necessitates an imperative consideration of the biodistribution of GHSR-1a ligands. Here, we investigate anamorelin and HM01, two recently described synthetic GHSR-1a ligands which have shown promising effects on food intake in preclinical and clinical studies. We compare the downstream signalling pathways in cellular in vitro assays, including calcium mobilization, IP-one, internalization and β-arrestin recruitment assays. We describe a novel divergent activation of central reward circuitry by anamorelin and HM01 using c-Fos immunostaining as well as behavioural effects in food intake and reward paradigms. Interestingly, we found a paradoxical reduction in reward-related behaviour for anamorelin and HM01 treated animals in our chosen paradigms. The work highlights the critical importance to consider signalling bias in relation to future ghrelin-based therapies. In addition, central access of GHSR-1a ligands, particularly to reward areas of the brain, remains a crucial factor in eliciting potent appetite-stimulating effects. The precise characterization of downstream ghrelinergic signalling and biodistribution of novel GHSR-1a ligands will be decisive in their successful development and will allow predictive modelling and design of future synthetic ligands to combat metabolic and appetite disorders involving the ghrelinergic system. This article is part of the special issue on 'Neuropeptides'.
胃饥饿素能系统一直被作为治疗代谢紊乱和调节食欲的治疗靶点进行深入研究。虽然内源性胃饥饿素激活了生长激素促分泌素受体（GHSR-1a）途径的全套信号通路，但合成的 GHSR-1a 配体显示出偏向信号和功能选择性，这对预期的甚至非预期的治疗效果都有重大影响。GHSR-1a 受体在体内的广泛表达也需要对 GHSR-1a 配体的生物分布进行强制性考虑。在这里，我们研究了两种最近描述的合成 GHSR-1a 配体，即 anamorelin 和 HM01，它们在临床前和临床研究中显示出对食物摄入有良好的效果。我们比较了这两种配体在细胞体外测定中的下游信号通路，包括钙动员、IP-1、内化和β-arrestin 招募测定。我们描述了 anamorelin 和 HM01 通过 c-Fos 免疫染色对中枢奖赏回路的新型发散激活，以及在食物摄入和奖赏范式中的行为效应。有趣的是，我们发现 anamorelin 和 HM01 处理的动物在我们选择的范式中表现出奖励相关行为的反常减少。这项工作强调了在未来的胃饥饿素治疗中考虑信号偏向的重要性。此外，GHSR-1a 配体进入中枢，特别是进入大脑的奖励区域，仍然是产生强烈的食欲刺激作用的关键因素。新型 GHSR-1a 配体的下游胃饥饿素能信号和生物分布的精确特征将对其成功开发具有决定性意义，并允许对未来涉及胃饥饿素能系统的代谢和食欲障碍的合成配体进行预测建模和设计。本文是“神经肽”特刊的一部分。
