Key Laboratory of Endocrinology of National Health Commission, Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100730, China.
Endocr J. 2022 Oct 28;69(10):1233-1244. doi: 10.1507/endocrj.EJ21-0802. Epub 2022 Jul 16.
Liraglutide has been approved for the treatment of obesity in the past few years. Both oxidative stress and leptin resistance are the critical drivers of obesity. The present study investigated the mechanism of liraglutide protection against obesity by ameliorating leptin resistance and oxidative stress. Male C57BL/6J mice were fed a high-fat diet (HFD) and subcutaneously injected with 200 μg/kg/d liraglutide for 20 weeks. Body weight, fat mass, serum levels of leptin, insulin, and superoxide dismutase (SOD) activities were measured. In addition, glucose and insulin tolerance tests were performed. The expressions of leptin, its signaling genes, and antioxidant enzymes were detected using RT-qPCR and western blot methods in liver and white adipose tissue (WAT) of mice. The results depicted that liraglutide treatment significantly slowed weight gain of body, reduced the fat mass, ameliorated glucose and lipid metabolism, and hepatic steatosis in HFD-fed obese mice. Further study demonstrated that liraglutide treatment resulted in decreased serum levels and the transcript levels of leptin as well as leptin signaling inhibitory regulators. However, it increased leptin receptor expression and the phosphorylation of signal transducer and activator of transcription 3 (p-STAT3) in WAT (p < 0.05). In addition, the antioxidant enzyme expression was elevated in both liver and WAT of liraglutide-treated mice (p < 0.05). In conclusion, liraglutide conspicuously prevented obesity and ameliorated glucose and lipid metabolism in obese mice through a novel mechanism that improves peripheral leptin resistance in WAT and enhance the antioxidant enzyme expression in both liver and WAT.
利拉鲁肽在过去几年中已被批准用于肥胖症的治疗。氧化应激和瘦素抵抗都是肥胖的关键驱动因素。本研究通过改善瘦素抵抗和氧化应激来探讨利拉鲁肽保护肥胖的机制。雄性 C57BL/6J 小鼠喂食高脂肪饮食（HFD）并皮下注射 200μg/kg/d 利拉鲁肽 20 周。测量体重、脂肪量、血清瘦素、胰岛素和超氧化物歧化酶（SOD）活性水平。此外，还进行了葡萄糖和胰岛素耐量测试。使用 RT-qPCR 和 Western blot 方法检测肝脏和白色脂肪组织（WAT）中小鼠瘦素、其信号基因和抗氧化酶的表达。结果表明，利拉鲁肽治疗显著减缓了肥胖 HFD 喂养小鼠的体重增加，减少了脂肪量，改善了葡萄糖和脂质代谢以及肝脂肪变性。进一步的研究表明，利拉鲁肽治疗导致血清瘦素水平和转录水平降低以及瘦素信号抑制调节剂增加。然而，它增加了 WAT 中瘦素受体表达和信号转导和转录激活因子 3（p-STAT3）的磷酸化（p<0.05）。此外，利拉鲁肽治疗的小鼠肝脏和 WAT 中的抗氧化酶表达增加（p<0.05）。总之，利拉鲁肽通过改善 WAT 外周瘦素抵抗和增强肝脏和 WAT 中抗氧化酶表达的新机制，显著预防肥胖症并改善肥胖小鼠的葡萄糖和脂质代谢。
