Rosiglitazone, a specific agonist of peroxisome proliferator-activated receptor-γ (PPAR-γ), displays a robust hypoglycemic action in patients with type 2 diabetes mellitus (T2DM) and elicits serious adverse reactions, especially hepatotoxicity and cardiotoxicity. Here, we aims to find a new natural PPAR-γ agonist with less adverse reactions than rosiglitazone in db/db mice. The method of virtual screening was used to identify a PPAR-γ agonist 18:0 Lyso PC from an in-house natural product library. We verified its pharmacological effects and adverse reactions comparing with rosiglitazone in vivo and in vitro. 18:0 Lyso PC exhibited pharmacological effects similar to those of rosiglitazone in db/db mice. Moreover, 18:0 Lyso PC showed a lower extent of liver injury and cardiotoxicity in db/db mice. The mechanism, by which this natural compound alleviates metabolic syndrome, involves a reduction in fatty acid synthesis mediated by activation of the phosphorylation of adenosine 5′-monophosphate (AMP)-activated protein kinase-alpha (AMPKα) and acetyl-CoA carboxylase (ACC) and an increase expression of uncoupled protein 1 (UCP1) and PPAR-γ coactivator-1 alpha (PGC1-α). 18:0 Lyso PC, a natural compound, can show a similar hypoglycemic effect to rosiglitazone by activating PPAR-γ, while eliciting markedly fewer adverse reactions than rosiglitazone.

罗格列酮是一种过氧化物酶体增殖物激活受体-γ (PPAR-γ) 的特异性激动剂，在 2 型糖尿病 (T2DM) 患者中显示出强烈的降血糖作用，并引起严重的不良反应，尤其是肝毒性和心脏毒性。在这里，我们的目标是在db/db小鼠中找到一种新的天然 PPAR-γ 激动剂，其不良反应比罗格列酮少。虚拟筛选方法用于从内部天然产物库中鉴定 PPAR-γ 激动剂 18:0 Lyso PC。我们在体内外验证了其与罗格列酮相比的药理作用和不良反应。18:0 Lyso PC 在db/db小鼠中表现出与罗格列酮相似的药理作用。此外，18:0 Lyso PC 显示出较低程度的肝损伤和心脏毒性db/db小鼠。这种天然化合物减轻代谢综合征的机制涉及通过激活腺苷 5'-单磷酸 (AMP) 活化蛋白激酶-α (AMPKα) 和乙酰辅酶 A 羧化酶 (ACC) 的磷酸化介导的脂肪酸合成减少) 和未偶联蛋白 1 (UCP1) 和 PPAR-γ 辅激活因子-1 α (PGC1-α) 的表达增加。18:0 Lyso PC 是一种天然化合物，可通过激活 PPAR-γ 显示出与罗格列酮相似的降血糖作用，同时引起的不良反应明显少于罗格列酮。