The free fatty acid receptor 1 (FFA1) and peroxisome proliferator-activated receptor δ (PPARδ) are considered as anti-diabetic targets based on their role in improving insulin secretion and resistance. Based on their synergetic mechanisms, we have previously identified the first-in-class dual FFA1/PPARδ agonist ZLY032. After long-term treatment, ZLY032 significantly improved glucolipid metabolism and alleviated fatty liver in ob/ob mice and methionine choline-deficient diet-fed db/db mice, mainly by regulating triglyceride metabolism, fatty acid β-oxidation, lipid synthesis, inflammation, oxidative stress and mitochondrial function. Notably, ZLY032 exhibited greater advantages on lipid metabolism, insulin sensitivity and pancreatic β-cell function than TAK-875, the most advanced candidate of FFA1 agonists. Moreover, ZLY032 prevented CCl4-induced liver fibrosis by reducing the expressions of genes involved in inflammation and fibrosis development. These results suggest that the dual FFA1/PPARδ agonists such as ZLY032 may be useful for the treatment of metabolic disorders.

中文翻译：

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ZLY032 是一流的双 FFA1/PPARδ 激动剂，可改善糖脂代谢并缓解肝纤维化。

游离脂肪酸受体 1 (FFA1) 和过氧化物酶体增殖物激活受体 δ (PPARδ) 被认为是抗糖尿病靶点，因为它们在改善胰岛素分泌和抵抗方面的作用。基于它们的协同机制，我们之前已经确定了一流的双 FFA1/PPARδ 激动剂 ZLY032。长期治疗后，ZLY032显着改善了ob/ob小鼠和缺乏蛋氨酸胆碱饮食喂养的db/db小鼠的糖脂代谢和脂肪肝，主要通过调节甘油三酯代谢、脂肪酸β-氧化、脂质合成、炎症、氧化应激和线粒体功能。值得注意的是，与最先进的 FFA1 激动剂候选物 TAK-875 相比，ZLY032 在脂质代谢、胰岛素敏感性和胰腺 β 细胞功能方面表现出更大的优势。而且，ZLY032 通过降低参与炎症和纤维化发展的基因的表达来预防 CCl4 诱导的肝纤维化。这些结果表明双 FFA1/PPARδ 激动剂如 ZLY032 可用于治疗代谢紊乱。