HWL-088, a new potent free fatty acid receptor 1 (FFAR1) agonist, improves glucolipid metabolism and acts additively with metformin in ob/ob diabetic mice
HWL-088, a new potent free fatty acid receptor 1 (FFAR1) agonist, improves glucolipid metabolism and acts additively with metformin in ob/ob diabetic mice
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HWL-088 是一种新型强效游离脂肪酸受体 1 (FFAR1) 激动剂，可改善 ob/ob 糖尿病小鼠的糖脂代谢，并与二甲双胍联合作用
DOI：
10.1111/bph.14980
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发表时间：
2020-02-08
影响因子：
7.3
通讯作者：
Li, Zheng
中科院分区：
文献类型：
--
作者：
Chen, Yueming;Ren, Qiang;Li, Zheng
背景和目的游离脂肪酸受体 1 (FFAR1) 在葡萄糖刺激的胰岛素分泌中发挥重要作用，使其成为有吸引力的抗糖尿病靶点。本研究描述了 HWL-088（2-（2-氟-4-（（2'-甲基-[1,1'-联苯]-3-基）甲氧基）苯氧基）乙酸）的药理学特征，HWL-088 是一种新型高效 FFAR1 激动剂的体外和体内活性。此外，我们还研究了 HWL-088 单独使用以及与二甲双胍联合使用对糖尿病小鼠的长期影响。 实验方法 在基于细胞的测定中研究了 HWL-088 对 FFAR1 和 PPAR α/γ/δ 的体外影响。在 MIN6 细胞系和大鼠中评估了葡萄糖依赖性促胰岛素作用。在 ob/ob 小鼠中研究了对葡萄糖和脂质代谢的长期影响。 主要结果 HWL-088 是一种高效 FFAR1 激动剂 (EC50 = 18.9 nM)，具有中等 PPAR δ 活性 (EC50 = 570.9 nM)，可在体外和体内促进葡萄糖依赖性胰岛素分泌。长期服用 HWL-088 比另一种 FFAR1 激动剂 TAK-875 表现出更好的血糖控制和血浆脂质分布，并且与二甲双胍联合使用时观察到协同改善。此外，HWL-088和联合疗法通过上调胰腺十二指肠同源盒-1来改善β细胞功能，减少脂肪组织中的脂肪积累并减轻ob/ob小鼠的脂肪肝。 HWL-088 的作用包括减少肝脏脂肪生成和氧化应激，增加脂蛋白脂解、葡萄糖摄取、线粒体功能和脂肪酸 β-氧化。 结论和意义 这些数据表明，长期使用 HWL-088（一种高效 FFAR1 激动剂）治疗可改善葡萄糖和脂质代谢，可能有助于通过单一疗法或与二甲双胍联合治疗糖尿病。
Background and Purpose The free fatty acid receptor 1 (FFAR1) plays an important role in glucose-stimulated insulin secretion making it an attractive anti-diabetic target. This study characterizes the pharmacological profile of HWL-088 (2-(2-fluoro-4-((2 '-methyl-[1,1 '- biphenyl]-3-yl)methoxy)phenoxy)acetic acid), a novel highly potent FFAR1 agonist in vitro and in vivo. Moreover, we investigated the long-term effects of HWL-088 alone and in combination with metformin in diabetic mice.Experimental Approach In vitro effects of HWL-088 on FFAR1 and PPAR alpha/gamma/delta were studied in cell-based assays. Glucose-dependent insulinotropic effects were evaluated in MIN6 cell line and in rats. Long-term effects on glucose and lipid metabolism were investigated in ob/ob mice.Key Results HWL-088 is a highly potent FFAR1 agonist (EC50 = 18.9 nM) with moderate PPAR delta activity (EC50 = 570.9 nM) and promotes glucose-dependent insulin secretion in vitro and in vivo. Long-term administration of HWL-088 exhibited better glucose control and plasma lipid profiles than those of another FFAR1 agonist, TAK-875, and synergistic improvements were observed when combined with metformin. Moreover, HWL-088 and combination therapy improved beta-cell function by up-regulation of pancreas duodenum homeobox-1, reduced fat accumulation in adipose tissue and alleviated fatty liver in ob/ob mice. The effect of HWL-088 involves a reduction in hepatic lipogenesis and oxidative stress, increased lipoprotein lipolysis, glucose uptake, mitochondrial function and fatty acid beta-oxidation.Conclusion and Implications These data indicate that long-term treatment with HWL-088, a highly potent FFAR1 agonist, improves glucose and lipid metabolism and may be useful for the treatment of diabetes mellitus by mono-therapy or combination with metformin.