Cell Signalling Research Group, School of Biomedical Sciences, The Medical School, Queen's Medical Centre, University of Nottingham Nottingham, UK.
Front Endocrinol (Lausanne). 2012 Jan 3;2:112. doi: 10.3389/fendo.2011.00112. eCollection 2011.
Discovery of G protein coupled receptors for long chain free fatty acids (FFAs), FFA1 (GPR40) and GPR120, has expanded our understanding of these nutrients as signaling molecules. These receptors have emerged as important sensors for FFA levels in the circulation or the gut lumen, based on evidence from in vitro and rodent models, and an increasing number of human studies. Here we consider their promise as therapeutic targets for metabolic disease, including type 2 diabetes and obesity. FFA1 directly mediates acute FFA-induced glucose-stimulated insulin secretion in pancreatic beta-cells, while GPR120 and FFA1 trigger release of incretins from intestinal endocrine cells, and so indirectly enhance insulin secretion and promote satiety. GPR120 signaling in adipocytes and macrophages also results in insulin sensitizing and beneficial anti-inflammatory effects. Drug discovery has focused on agonists to replicate acute benefits of FFA receptor signaling, with promising early results for FFA1 agonists in man. Controversy surrounding chronic effects of FFA1 on beta-cells illustrates that long term benefits of antagonists also need exploring. It has proved challenging to generate highly selective potent ligands for FFA1 or GPR120 subtypes, given that both receptors have hydrophobic orthosteric binding sites, which are not completely defined and have modest ligand affinity. Structure activity relationships are also reliant on functional read outs, in the absence of robust binding assays to provide direct affinity estimates. Nevertheless synthetic ligands have already helped dissect specific contributions of FFA1 and GPR120 signaling from the many possible cellular effects of FFAs. Approaches including use of fluorescent ligand binding assays, and targeting allosteric receptor sites, may improve further pre-clinical ligand development at these receptors, to exploit their unique potential to target multiple facets of diabetes.
长链游离脂肪酸（FFA）G 蛋白偶联受体（GPCR），即 FFA1（GPR40）和 GPR120 的发现，扩展了我们对这些作为信号分子的营养物质的理解。这些受体已成为循环或肠腔中 FFA 水平的重要传感器，这一观点基于体外和啮齿动物模型以及越来越多的人类研究。在此，我们考虑将其作为代谢疾病（包括 2 型糖尿病和肥胖症）治疗靶点的潜力。FFA1 可直接介导急性 FFA 诱导的胰岛β细胞葡萄糖刺激胰岛素分泌，而 GPR120 和 FFA1 则触发肠内分泌细胞分泌肠促胰岛素，从而间接增强胰岛素分泌并促进饱腹感。GPR120 在脂肪细胞和巨噬细胞中的信号转导也导致胰岛素增敏和有益的抗炎作用。药物发现的重点是复制 FFA 受体信号的急性作用的激动剂，FFA1 激动剂在人类中具有早期的良好结果。围绕 FFA1 对β细胞的慢性作用的争议表明，也需要探索拮抗剂的长期益处。鉴于这两个受体都具有疏水性的正位结合位点，其尚未完全定义且配体亲和力适中，因此为 FFA1 或 GPR120 亚型生成高选择性的强效配体一直具有挑战性。构效关系也依赖于功能读出，在缺乏强大的结合测定以提供直接亲和力估计的情况下。尽管如此，合成配体已经帮助我们从 FFA 的许多可能的细胞作用中分离出 FFA1 和 GPR120 信号的特定贡献。包括使用荧光配体结合测定和靶向变构受体部位的方法，可能会进一步改善这些受体的临床前配体开发，以利用其独特的潜力靶向糖尿病的多个方面。
