Enteroendocrine cell-derived peptide YY signalling is stimulated by pinolenic acid or Intralipid and involves coactivation of fatty acid receptors FFA1, FFA4 and GPR119

IF 2.5 3区医学 Q3 ENDOCRINOLOGY & METABOLISM Neuropeptides Pub Date : 2024-10-11 DOI:10.1016/j.npep.2024.102477

Iain R. Tough, Runisha Moodaley, Helen M. Cox

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Abstract

Long chain fatty acids are sensed by enteroendocrine L cells that express free-fatty acid receptors, including FFA1, FFA4 and the acylethanolamine receptor GPR119. Here we investigated the acute effects of single or multiple agonism at these G protein-coupled receptors in intestinal mucosae where L cell-derived peptide YY (PYY) is anti-secretory and acts via epithelial Y₁ receptors. Mouse ileal or colonic mucosae were mounted in Ussing chambers, voltage-clamped and the resultant short-circuit current (I_sc) recorded continuously. The agonists used were; FFA1, TAK-875 or AM-1638; for FFA4, Merck A; or for GPR119, AR231453, PSN632408 or AR440006. Their responses were compared with those of pinolenic acid (PA, a presumed dual FFA1/FFA4 agonist) and the lipid emulsion, Intralipid. The FFA1 agonist AM-1638 (EC₅₀ = 38.2 nM) was more potent than TAK-875 (EC₅₀ = 203.1 nM) but exhibited similar efficacy. GPR119 agonism (AR231453) pretreatment enhanced subsequent FFA1 (AM-1638 or TAK-875) and FFA4 (Merck A) signalling. PA (EC₅₀ = 298.2 nM) co-activated epithelial FFA1 and FFA4 and involved endogenous PYY Y₁/Y₂-receptor mechanisms but desensitisation was observed between PA and high GPR119 agonist concentrations. Apical Intralipid co-activated FFA1, FFA4 and GPR119 with a residual component not being attributable to PYY, or this trio of fatty acid receptors.

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蒎烯酸或 Intralipid 可刺激肠内分泌细胞衍生的肽 YY 信号，并涉及脂肪酸受体 FFA1、FFA4 和 GPR119 的协同激活。

长链脂肪酸由表达游离脂肪酸受体（包括 FFA1、FFA4 和酰乙醇胺受体 GPR119）的肠内分泌 L 细胞感知。在此，我们研究了单次或多次激动这些 G 蛋白偶联受体对肠粘膜的急性影响，其中 L 细胞衍生的肽 YY（PYY）具有抗分泌作用，并通过上皮 Y1 受体发挥作用。将小鼠回肠或结肠粘膜装入乌星室，进行电压钳夹，并连续记录由此产生的短路电流（Isc）。使用的激动剂有：FFA1，TAK-875 或 AM-1638；FFA4，默克 A；或 GPR119，AR231453、PSN632408 或 AR440006。将它们的反应与松脂酸（PA，一种假定的 FFA1/FFA4 双激动剂）和脂质乳液 Intralipid 的反应进行了比较。FFA1激动剂AM-1638（EC50 = 38.2 nM）比TAK-875（EC50 = 203.1 nM）更有效，但药效相似。GPR119 激动剂（AR231453）预处理增强了随后的 FFA1（AM-1638 或 TAK-875）和 FFA4（默克 A）信号传导。PA（EC50 = 298.2 nM）共同激活上皮 FFA1 和 FFA4，并涉及内源性PYY Y1/Y2 受体机制，但在 PA 和高浓度 GPR119 激动剂之间观察到脱敏现象。Apical Intralipid 可共同激活 FFA1、FFA4 和 GPR119，其残余部分不归因于PYY 或这三种脂肪酸受体。

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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.