The peroxisome proliferator-activated receptors (PPARs) exert vital function in the regulation of energy metabolism, which were considered as promising targets of metabolic syndrome. Until now, PPARδ/γ dual agonist is rarely reported, and thereby the pharmacologic action of PPARδ/γ dual agonist is still unclear. In this study, we identified a dual PPARδ/γ partial agonist 6 (ZLY06) based on the cyclization strategy of PPARα/δ dual agonist GFT505. ZLY06 revealed excellent pharmacokinetic profiles suitable for oral medication. Moreover, ZLY06 markedly improved glucolipid metabolism without weight gain, and alleviated fatty liver by promoting the β-oxidation of fatty acid and inhibiting hepatic lipogenesis. In contrast, weight gain and hepatic steatosis were observed in Rosiglitazone, a widely used PPARγ full agonist. All of these results indicated that ZLY06 exhibits potential benefits on metabolic syndrome, while no adverse effects related to PPARγ full agonist.

过氧化物酶体增殖物激活受体 (PPAR) 在能量代谢的调节中发挥重要作用，被认为是代谢综合征的有希望的靶点。迄今为止，PPARδ/γ双重激动剂的报道很少，因此PPARδ/γ双重激动剂的药理作用尚不清楚。在这项研究中，我们确定了一种双重 PPARδ/γ 部分激动剂6(ZLY06)基于PPARα/δ双重激动剂GFT505的环化策略。ZLY06 揭示了适用于口服药物的出色药代动力学特征。此外，ZLY06 显着改善了糖脂代谢而不会增加体重，并通过促进脂肪酸的 β 氧化和抑制肝脏脂肪生成来缓解脂肪肝。相比之下，在广泛使用的 PPARγ 完全激动剂罗格列酮中观察到体重增加和肝脂肪变性。所有这些结果表明，ZLY06 对代谢综合征表现出潜在的益处，而与 PPARγ 完全激动剂无关。