Discovery Chemistry, Janssen Research and Development , Spring House, PA, USA.
Expert Opin Ther Pat. 2020 Oct;30(10):729-742. doi: 10.1080/13543776.2020.1811852. Epub 2020 Aug 30.
G protein-coupled receptor 120 (GPR120) is a G coupled GPCR specifically activated by long-chain fatty acids (LCFAs). Functionally, it has been identified as a member of a family of lipid-binding free fatty acid receptors including GPR40, GPR41, and GPR43. Upon stimulation by LCFAs, GPR120 can directly or indirectly modulate hormone secretion from the gastrointestinal tract and pancreas, and regulate lipid and/or glucose metabolism in adipose, liver, and muscle tissues. Additionally, GPR120 is postulated to mediate anti-inflammatory and insulin-sensitizing effects in adipose and macrophages. These benefits suggest that GPR120 agonists have the potential to be an effective treatment for obesity, type 2 diabetes mellitus (T2DM), and other metabolic syndromes.
This article highlights and reviews research advances in this field that have been published in patent literature and peer-reviewed journals since 2014.
Current development has been hindered by species differences in GPR120 distribution, differences in GPR120-mediated signaling in distinct tissue types, and lack of available ligands with suitable selectivity for GPR120 over GPR40 in both human and rodents. The discovery of β-arrestin biased GPR120 agonists will help elucidate the potential of selective therapeutics that may discriminate between desirable and undesirable pharmacological effects.
ALA: α-linolenic acid; AUC: area under the curve; BRET: bioluminescence resonance energy transfer; CCK: cholecystokinin; CHO-K1 cell: Chinese hamster ovary-K1 cell; mouse: diabetic mouse; DHA: docosahexaenoic acid; DIO: diet-induced obesity; DMSO: dimethyl sulfoxide; DPP-4: dipeptidyl peptidase 4; EPA: eicosapentaenoic acid; FA(s): fatty acid(s); FFA(s): free fatty acid(s); FFAR: free fatty acid receptor; FLIPR: fluorescent imaging plate reader; GIR: glucose infusion rate; GLP-1: glucagon-like peptide 1; GP(C)R: G protein-coupled receptor; GSIS: glucose-stimulated insulin secretion; HEK293 cell: human embryonic kidney 293 cell; HOMA-IR: homeostatic measurement assessment of insulin resistance; IP1: inositol phosphate turnover; IPGTT: intraperitoneal glucose tolerance test; LCFA(s): long-chain fatty acid(s); MED: maximal efficacy; MIN6 cell: mouse insulin-secreting cell; NPY: neuropeptide Y; OGTT: oral glucose tolerance test; pERK: phosphorylated ERK; PPAR: peroxisome proliferator-activated receptor; QD: once daily; SAR: structure-activity relationship; siRNA: small interfering ribonucleic acid; STC-1: intestinal secretin tumor cell; T2DM: type 2 diabetes mellitus; U2OS cell: human bone osteosarcoma epithelial cell; uHTS: ultrahigh-throughput screening; ZDF: zucker diabetic fatty.
G 蛋白偶联受体 120（GPR120）是一种特定被长链脂肪酸（LCFAs）激活的 G 蛋白偶联 GPCR。从功能上讲，它被鉴定为脂质结合游离脂肪酸受体家族的一员，包括 GPR40、GPR41 和 GPR43。在 LCFAs 的刺激下，GPR120 可以直接或间接调节胃肠道和胰腺的激素分泌，并调节脂肪、肝脏和肌肉组织中的脂质和/或葡萄糖代谢。此外，GPR120 被假设在脂肪组织和巨噬细胞中介导抗炎和胰岛素增敏作用。这些益处表明，GPR120 激动剂有可能成为肥胖症、2 型糖尿病（T2DM）和其他代谢综合征的有效治疗方法。
本文重点介绍并回顾了自 2014 年以来在专利文献和同行评议期刊中发表的该领域的研究进展。
目前的发展受到 GPR120 分布的种属差异、不同组织类型中 GPR120 介导的信号转导差异以及缺乏对人和啮齿动物中 GPR40 具有合适选择性的可用配体的限制。β-arrestin 偏向性 GPR120 激动剂的发现将有助于阐明选择性治疗的潜力，这些治疗可能区分理想和不良的药理作用。
ALA：α-亚麻酸；AUC：曲线下面积；BRET：生物发光共振能量转移；CCK：胆囊收缩素；CHO-K1 细胞：中国仓鼠卵巢-K1 细胞；小鼠：糖尿病小鼠；DHA：二十二碳六烯酸；DIO：饮食诱导肥胖；DMSO：二甲基亚砜；DPP-4：二肽基肽酶 4；EPA：二十碳五烯酸；FA（s）：脂肪酸（s）；FFA（s）：游离脂肪酸（s）；FFAR：游离脂肪酸受体；FLIPR：荧光成像板读数器；GIR：葡萄糖输注率；GLP-1：胰高血糖素样肽 1；GP（C）R：G 蛋白偶联受体；GSIS：葡萄糖刺激胰岛素分泌；HEK293 细胞：人胚肾 293 细胞；HOMA-IR：胰岛素抵抗的稳态评估；IP1：肌醇磷酸化转换；IPGTT：腹腔葡萄糖耐量试验；LCFA（s）：长链脂肪酸（s）；MED：最大功效；MIN6 细胞：小鼠胰岛素分泌细胞；NPY：神经肽 Y；OGTT：口服葡萄糖耐量试验；pERK：磷酸化 ERK；PPAR：过氧化物酶体增殖物激活受体；QD：每日一次；SAR：结构-活性关系；siRNA：小干扰核糖核酸；STC-1：肠分泌素肿瘤细胞；T2DM：2 型糖尿病；U2OS 细胞：人骨肉瘤上皮细胞；uHTS：超高通量筛选；ZDF：zucker 糖尿病肥胖。
