Peripheral administration of lipidized NPAF and NPFF analogs does not influence central food intake regulation but induces anxiety-like behavior

IF 2.5 3区医学 Q3 ENDOCRINOLOGY & METABOLISM Neuropeptides Pub Date : 2024-02-23 DOI:10.1016/j.npep.2024.102417

Veronika Strnadová , Alena Morgan , Magdalena Škrlová , Eliška Haasová , Kristina Bardová , Aneta Myšková , David Sýkora , Jaroslav Kuneš , Blanka Železná , Lenka Maletínská

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Abstract

RF-amide peptides influence multiple physiological processes, including the regulation of appetite, stress responses, behavior, and reproductive and endocrine functions. In this study, we examined the roles of neuropeptide FF receptors (NPFFR1 and NPFFR2) by generating several lipidized analogs of neuropeptide AF (NPAF) and 1DMe, a stable analog of neuropeptide FF (NPFF). These analogs were administered peripherally for the first time to investigate their effects on food intake and other potential physiological outcomes. Lipidized NPAF and 1DMe analogs exhibited enhanced stability and increased pharmacokinetics. These analogs demonstrated preserved high affinity for NPFFR2 in the nanomolar range, while the binding affinity for NPFFR1 was tens of nanomoles. They activated the ERK and Akt signaling pathways in cells overexpressing the NPFFR1 and NPFFR2 receptors.

Acute food intake in fasted mice decreased after the peripheral administration of oct-NPAF or oct-1DMe. However, this effect was not as pronounced as that observed after the injection of palm¹¹-PrRP31, a potent anorexigenic compound used as a comparator that binds to GPR10 and the NPFFR2 receptor with high affinity. Neither oct-1DMe nor oct-NPAF decreased food intake or body weight in mice with diet-induced obesity during long-term treatment. In mice treated with oct-1DMe, we observed decreased activity in the central zone during the open field test and decreased activity in the open arms of the elevated plus maze. Furthermore, we observed a decrease in plasma noradrenaline levels and an increase in plasma corticosterone levels, as well as an increase in Crh expression in the hypothalamus. Moreover, neuronal activity in the hypothalamus was increased after treatment with oct-1DMe.

In this study, we report that oct-1DMe did not have any long-term effects on the central regulation of food intake; however, it caused anxiety-like behavior.

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外周给药脂化 NPAF 和 NPFF 类似物不会影响中枢食物摄入调节，但会诱发焦虑样行为

RF-酰胺肽影响多种生理过程，包括调节食欲、应激反应、行为以及生殖和内分泌功能。在这项研究中，我们通过生成几种神经肽 AF（NPAF）的脂质化类似物和神经肽 FF（NPFF）的稳定类似物 1DMe，研究了神经肽 FF 受体（NPFFR1 和 NPFFR2）的作用。这些类似物首次在外周给药，以研究它们对食物摄入量和其他潜在生理结果的影响。脂质化的 NPAF 和 1DMe 类似物表现出更高的稳定性和更强的药代动力学。这些类似物与 NPFFR2 的结合亲和力保持在纳摩尔范围内，而与 NPFFR1 的结合亲和力仅为数十纳摩尔。在过量表达 NPFFR1 和 NPFFR2 受体的细胞中，它们激活了 ERK 和 Akt 信号通路。在外周给药 oct-NPAF 或 oct-1DMe 后，禁食小鼠的急性食物摄入量下降。然而，这种效应不如注射palm11-PrRP31后观察到的效应明显，palm11-PrRP31是一种强效厌食化合物，可与GPR10和NPFFR2受体高亲和力结合。在长期治疗过程中，oct-1DMe和oct-NPAF都不会减少饮食诱发肥胖小鼠的食物摄入量或体重。在使用辛-1DMe治疗的小鼠中，我们观察到小鼠在开阔地试验中中心区的活动减少，在高架加迷宫的开阔臂中的活动减少。此外，我们还观察到血浆去甲肾上腺素水平降低，血浆皮质酮水平升高，以及下丘脑中 Crh 表达增加。在这项研究中，我们报告了oct-1DMe对食物摄入的中枢调节没有任何长期影响；但它会引起焦虑样行为。

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来源期刊

Neuropeptides 医学-内分泌学与代谢

CiteScore

5.40

自引率

6.90%

发文量

审稿时长

>12 weeks

期刊介绍： The aim of Neuropeptides is the rapid publication of original research and review articles, dealing with the structure, distribution, actions and functions of peptides in the central and peripheral nervous systems. The explosion of research activity in this field has led to the identification of numerous naturally occurring endogenous peptides which act as neurotransmitters, neuromodulators, or trophic factors, to mediate nervous system functions. Increasing numbers of non-peptide ligands of neuropeptide receptors have been developed, which act as agonists or antagonists in peptidergic systems. The journal provides a unique opportunity of integrating the many disciplines involved in all neuropeptide research. The journal publishes articles on all aspects of the neuropeptide field, with particular emphasis on gene regulation of peptide expression, peptide receptor subtypes, transgenic and knockout mice with mutations in genes for neuropeptides and peptide receptors, neuroanatomy, physiology, behaviour, neurotrophic factors, preclinical drug evaluation, clinical studies, and clinical trials.