Carvas Alexandra Oliveira, Leuthardt Andrea, Kulka Patricia, Lommi Greta, Hassan Shad, Coester Bernd, Lundh Sofia, Pers Tune, Secher Anna, Raun Kirsten, Lutz Thomas A, Le Foll Christelle
Institute of Veterinary Physiology, University of Zurich, Switzerland.
Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark.
EBioMedicine. 2025 Jul 2;118:105836. doi: 10.1016/j.ebiom.2025.105836.
Amylin (AmyR) and calcitonin (CTR) receptor co-agonists are currently in Phase II/III clinical trials for obesity treatment. Amylin binds to a heterodimeric receptor composed of CTR and the receptor activity modifying proteins 1, 2 or 3 (RAMP1-3).
We investigated the role of amylin 1 and 3 (AMYR, AMYR) receptors in modulating the pharmacological effects of the dual amylin-calcitonin receptor agonists, cagrilintide and salmon calcitonin (sCT), in RAMP1/3 knockout (KO) mice. Male wild-type (WT) and KO littermate mice were fed high-fat diet for 23 weeks prior to the 3-week treatment period with vehicle, 150 nmol/kg sCT or 3 nmol/kg cagrilintide (subcutaneously, SID).
Body weight loss was observed in WT cagrilintide-treated mice (-3.4 ± 0.51 g, P < 0.005; n = 8/group), whereas sCT rather increased it (0.60 ± 0.38 g, P < 0.01; n = 8/group). The absence of RAMP1 and RAMP3 impeded cagrilintide's potency but improved sCT's efficacy on weight loss. Cagrilintide and sCT both decreased food intake during the first few days of treatment in WT mice only (Day 1: vehicle 2.7 ± 0.2 g; cagrilintide 1.2 ± 0.1 g, P < 0.0001; sCT 1.5 ± 0.2 g, P < 0.0021; n = 7-8/group). Both peptides activated cFos signal in neurons of the dorsal vagal complex (DVC) and lateral parabrachial nucleus (LPBN) of WT mice while AP cFos signal was decreased in cagrilintide-treated RAMP1/3 KO mice by 57% compared to WT cagrilintide-injected mice (P < 0.001, n = 5-6/group). Differential gene expression was analysed in the DVC, LPBN and mediobasal hypothalamic area of WT and RAMP1/3 KO mice. After 3 weeks of treatment, neither sCT nor cagrilintide significantly altered gene expression in the DVC or LPBN in WT mice. However, mRNA bulk sequencing points to a role of RAMP1/3 in synaptic function and receptor trafficking.
Altogether, these results demonstrate the dependency of cagrilintide on AMYR and AMYR to lower body weight.
This work was supported by an investigator led Novo Nordisk Consortium grant, Swiss National Foundation and the University of Zurich.
胰淀素（AmyR）和降钙素（CTR）受体共同激动剂目前正处于治疗肥胖症的II/III期临床试验阶段。胰淀素与由CTR和受体活性修饰蛋白1、2或3（RAMP1 - 3）组成的异二聚体受体结合。
我们研究了胰淀素1型和3型（AMYR、AMYR）受体在调节双重胰淀素 - 降钙素受体激动剂卡格列肽和鲑鱼降钙素（sCT）对RAMP1/3基因敲除（KO）小鼠药理作用中的作用。雄性野生型（WT）和基因敲除同窝小鼠在接受为期3周的赋形剂、150 nmol/kg sCT或3 nmol/kg卡格列肽（皮下注射，每日一次）治疗前，先高脂饮食23周。
接受卡格列肽治疗的WT小鼠体重减轻（-3.4±0.51 g，P<0.005；每组n = 8），而sCT反而使其体重增加（0.60±0.38 g，P<0.01；每组n = 8）。RAMP1和RAMP3的缺失阻碍了卡格列肽的效力，但提高了sCT在体重减轻方面的疗效。仅在治疗的头几天，卡格列肽和sCT均使WT小鼠的食物摄入量减少（第1天：赋形剂组2.7±0.2 g；卡格列肽组1.2±0.1 g，P<0.0001；sCT组1.5±0.2 g，P<0.0021；每组n = 7 - 8）。两种肽均激活WT小鼠背迷走神经复合体（DVC）和外侧臂旁核（LPBN）神经元中的cFos信号，而与注射卡格列肽的WT小鼠相比，接受卡格列肽治疗的RAMP1/3基因敲除小鼠中AP cFos信号减少了57%（P<0.001，每组n = 5 - 6）。对WT和RAMP1/3基因敲除小鼠的DVC、LPBN和下丘脑内侧基底部区域进行了差异基因表达分析。治疗3周后，sCT和卡格列肽均未显著改变WT小鼠DVC或LPBN中的基因表达。然而，mRNA高通量测序表明RAMP1/3在突触功能和受体运输中起作用。
总之，这些结果证明了卡格列肽降低体重对AMYR和AMYR的依赖性。
这项工作得到了由研究人员主导的诺和诺德财团资助、瑞士国家基金会和苏黎世大学的支持。
