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'.

中文翻译：

---

ghrelin配体，anamorelin和HM01的行为表征：啮齿动物的食欲和奖励动机。

ghrelinergic系统已作为代谢性疾病和食欲调节的治疗靶标进行了稳步研究。虽然内源性生长素释放肽激活了生长激素促分泌素受体（GHSR-1a）途径的全部补体，但合成的GHSR-1a配体显示出偏向的信号传导和功能选择性，这对预期的和确实的，非预期的治疗效果产生了重大影响。GHSR-1a受体在体内的广泛表达还必须考虑GHSR-1a配体的生物分布。在这里，我们研究了anamorelin和HM01，这两个最近描述的合成GHSR-1a配体在临床前和临床研究中已显示出对食物摄入的良好影响。我们在细胞体外测定中比较下游信号通路，包括钙动员，IP-one，内在化和β-arrestin募集试验。我们描述了新的发散激活的中央奖励电路，由anamorelin和HM01使用c-Fos免疫染色以及在食物摄取和奖励范例中的行为影响。有趣的是，在我们选择的范例中，我们发现在与anamorelin和HM01处理的动物中，与奖赏相关的行为呈反常下降。这项工作强调了考虑与未来基于生长素释放肽的疗法有关的信号偏倚的至关重要性。此外，GHSR-1a配体的中心通路，特别是对大脑区域的奖赏，仍然是引起强烈食欲刺激作用的关键因素。新型GHSR-1a配体的下游ghrelinergic信号传导和生物分布的精确表征将对它们的成功开发起决定性作用，并将为未来的合成配体进行预测性建模和设计，以对抗涉及ghrelinergic系统的代谢和食欲障碍。本文是有关“神经肽”的特刊的一部分。