Section of Experimental Animal Models, Department of Veterinary and Animal Science, Faculty of Health and Medical Sciences, University of Copenhagen, DK-1871, Frederiksberg C, Denmark; Obesity Pharmacology, Novo Nordisk A/S, 2760, Måløv, Denmark.
Obesity Pharmacology, Novo Nordisk A/S, 2760, Måløv, Denmark.
Neuropharmacology. 2020 May 1;167:107987. doi: 10.1016/j.neuropharm.2020.107987. Epub 2020 Feb 5.
The amylin receptor (AMY) and calcitonin receptor (CTR) agonists induce acute suppression of food intake in rodents by binding to receptors in the area postrema (AP) and potentially by targeting arcuate (ARC) neurons directly. Salmon calcitonin (sCT) induces more potent, longer lasting anorectic effects compared to amylin. We thus aimed to investigate whether AMY/CTR agonists target key neuronal populations in the ARC, and whether differing brain distribution patterns could mediate the observed differences in efficacy with sCT and amylin treatment. Brains were examined by whole brain 3D imaging and confocal microscopy following subcutaneous administration of fluorescently labelled peptides to mice. We found that sCT, but not amylin, internalizes into a subset of ARC NPY neurons, along with an unknown subset of ARC, AP and dorsal vagal motor nucleus cells. ARC POMC neurons were not targeted. Furthermore, amylin and sCT displayed similar distribution patterns binding to receptors in the AP, the organum vasculosum of the lamina terminalis (OVLT) and the ARC. Amylin distributed within the median eminence with only specs of sCT being present in this region, however amylin was only detectable 10 minutes after injection while sCT displayed a residence time of up to 2 hours post injection. We conclude that AMY/CTR agonists bind to receptors in a subset of ARC NPY neurons and in circumventricular organs. Furthermore, the more sustained and greater anorectic efficacy of sCT compared to rat amylin is not attributable to differences in brain distribution patterns but may more likely be explained by greater potency at both the CTR and AMY.
胰岛淀粉样多肽受体（AMY）和降钙素受体（CTR）激动剂通过与后穹窿（AP）中的受体结合，并且可能直接靶向弓状核（ARC）神经元，从而在啮齿动物中急性抑制食物摄入。鲑鱼降钙素（sCT）与胰岛淀粉样多肽相比，引起更有效、更持久的厌食作用。因此，我们旨在研究 AMY/CTR 激动剂是否靶向 ARC 中的关键神经元群体，以及不同的脑分布模式是否可以介导 sCT 和胰岛淀粉样多肽治疗中观察到的疗效差异。在向小鼠皮下给予荧光标记肽后，通过全脑 3D 成像和共聚焦显微镜检查大脑。我们发现，sCT 而不是胰岛淀粉样多肽，可内化到 ARC NPY 神经元的亚群中，以及未知的 ARC、AP 和背侧迷走运动核细胞的亚群中。ARC POMC 神经元未被靶向。此外，在 AP、终板血管器（OVLT）和 ARC 中，胰岛淀粉样多肽和 sCT 结合受体显示出相似的分布模式。胰岛淀粉样多肽在中脑上部分布，只有少量的 sCT 存在于该区域，然而，胰岛淀粉样多肽在注射后 10 分钟才被检测到，而 sCT 在注射后 2 小时内仍有存在。我们得出结论，AMY/CTR 激动剂结合到 ARC NPY 神经元和室周器官的受体上。此外，与大鼠胰岛淀粉样多肽相比，sCT 更持久和更有效的厌食作用并不是由于脑分布模式的差异，而是可能更归因于在 CTR 和 AMY 上的更高效力。
