Wang Zixuan, Hou Lin, Huang Lanhui, Guo Jun, Zhou Xinli
Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong University, Shandong Clinical Medical Center of Endocrinology and Metabolism, Institute of Endocrinology and Metabolism, Shandong Academy of Clinical Medicine, China.
Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong University, Shandong Clinical Medical Center of Endocrinology and Metabolism, Institute of Endocrinology and Metabolism, Shandong Academy of Clinical Medicine, China.
Biochem Biophys Res Commun. 2017 Apr 22;486(1):116-123. doi: 10.1016/j.bbrc.2017.03.010. Epub 2017 Mar 6.
Oxidative stress is associated with obesity and may be accompanied by liver insulin resistance and mitochondrial dysfunction. Decreased mitochondrial respiratory chain enzymatic activities and decreased insulin metabolic signaling may promote these maladaptive changes. In this context, exenatide has been reported to reduce hepatic lipid deposition, improve insulin sensitivity and improve mitochondrial dysfunction. We hypothesized that exenatide would attenuate mitochondrial dysfunction by reducing hepatic lipid deposition, blunting oxidant stress and promoting insulin metabolic signaling in a high fat diet-induced model of obesity and insulin resistance. Sixteen-week-old male C57BL/6 diet-induced obese (DIO) mices and age-matched standard diet (STD) mices were treated with exenatide (10 μg/kg twice a day) for 28 days. Compared with untreated STD mice, untreated DIO mice exhibited deposited excessive lipid in liver and produced the oxidative stress in conjunction with insulin resistance, abnormal hepatic cells and mitochondrial histoarchitecture, mitochondrial dysfunction and reduced organism metabolism. Exenatide reduced hepatic steatosis, decreased oxidative stress, and improved insulin resistance in DIO mice, in concert with improvements in the insulin metabolic signaling, mitochondrial respiratory chain enzymatic activation, adenine nucleotide production, organism metabolism and weight gain. Results support the hypothesis that exenatide reduces hepatic cells and mitochondrial structural anomaly and improves insulin resistance in concert with improvements in insulin sensitivity and mitochondrial function activation, concomitantly with reductions in oxidative stress.
氧化应激与肥胖相关，可能伴有肝脏胰岛素抵抗和线粒体功能障碍。线粒体呼吸链酶活性降低和胰岛素代谢信号减弱可能会促进这些适应性不良变化。在此背景下，已有报道称艾塞那肽可减少肝脏脂质沉积、改善胰岛素敏感性并改善线粒体功能障碍。我们推测，在高脂饮食诱导的肥胖和胰岛素抵抗模型中，艾塞那肽可通过减少肝脏脂质沉积、减轻氧化应激和促进胰岛素代谢信号来减轻线粒体功能障碍。16周龄雄性C57BL/6饮食诱导肥胖（DIO）小鼠和年龄匹配的标准饮食（STD）小鼠接受艾塞那肽（10μg/kg，每日两次）治疗28天。与未治疗的STD小鼠相比，未治疗的DIO小鼠肝脏中脂质过度沉积，产生氧化应激，同时伴有胰岛素抵抗、肝细胞和线粒体组织结构异常、线粒体功能障碍以及机体代谢降低。艾塞那肽可减轻DIO小鼠的肝脏脂肪变性，降低氧化应激，并改善胰岛素抵抗，同时改善胰岛素代谢信号、线粒体呼吸链酶激活、腺嘌呤核苷酸生成、机体代谢和体重增加。结果支持以下假设：艾塞那肽可减少肝细胞和线粒体结构异常，改善胰岛素抵抗，同时改善胰岛素敏感性和线粒体功能激活，同时降低氧化应激。
