The pleiotropic action of adiponectin in improving cell survival and metabolism has motivated the development of small molecule therapeutic agents for treating diabetes and lipotoxicity. AdipoRon is a synthetic agonist of adiponectin receptor yet is limited by its poor solubility and bioavailability. In this work, we expand on the protective effects of AdipoRon in pancreatic β-cells and examine how structural modifications could affect the activity, pharmacokinetics, and bioavailability of this small molecule. We describe a series of AdipoRon analogs containing amphiphilic ethylene glycol (PEG) chains. Among these, AdipoRonPEG5 induced pleiotropic effects in mice under insulinopenic and high fat diet (HFD) conditions. While both AdipoRon and AdipoRonPEG5 substantially attenuate palmitate-induced lipotoxicity in INS-1 cells, only AdipoRonPEG5 treatment is accompanied by a significant reduction in cytotoxic ceramides. In vivo, AdipoRonPEG5 can substantially reduce pancreatic, hepatic, and serum ceramide species, with a concomitant increase in the corresponding sphingoid bases, and improves insulin sensitivity of mice under HFD feeding conditions. Furthermore, hyperglycemia in streptozotocin (STZ)-induced insulinopenic adiponectin-null mice is also attenuated upon AdipoRonPEG5 treatment. Our results suggest that AdipoRonPEG5 is more effective in reducing ceramides and dihydroceramides in the liver of HFD-fed mice than AdipoRon, consistent with its potent activity in activating ceramidase in vitro in INS-1 cells. Additionally, these results indicate that the beneficial effects of AdipoRonPEG5 can be partially attributed to improved pharmacokinetics as compared to AdipoRon, thus suggesting that further derivatization may improve affinity and tissue-specific targeting.

中文翻译：

---

聚乙二醇化的 AdipoRon 衍生物可改善胰岛素缺乏和高脂肪饮食条件下的葡萄糖和脂质代谢。

脂联素在改善细胞存活和新陈代谢方面的多效作用推动了用于治疗糖尿病和脂毒性的小分子治疗剂的开发。AdipoRon 是一种合成的脂联素受体激动剂，但受限于其较差的溶解度和生物利用度。在这项工作中，我们扩展了 AdipoRon 在胰腺 β 细胞中的保护作用，并研究了结构修饰如何影响这种小分子的活性、药代动力学和生物利用度。我们描述了一系列含有两亲乙二醇 (PEG) 链的 AdipoRon 类似物。其中，AdipoRonPEG5 在胰岛素缺乏和高脂饮食 (HFD) 条件下诱导小鼠的多效性。虽然 AdipoRon 和 AdipoRonPEG5 都大大减弱了 INS-1 细胞中棕榈酸酯诱导的脂毒性，只有 AdipoRonPEG5 处理伴随着细胞毒性神经酰胺的显着减少。在体内，AdipoRonPEG5 可以显着减少胰腺、肝脏和血清神经酰胺种类，同时增加相应的鞘氨醇碱基，并提高 HFD 喂养条件下小鼠的胰岛素敏感性。此外，在 AdipoRonPEG5 治疗后，链脲佐菌素 (STZ) 诱导的胰岛素缺乏性脂联素缺失小鼠的高血糖症也得到了缓解。我们的结果表明，AdipoRonPEG5 在减少 HFD 喂养小鼠肝脏中的神经酰胺和二氢神经酰胺方面比 AdipoRon 更有效，这与其在 INS-1 细胞体外激活神经酰胺酶的有效活性一致。此外，