Wang Dongmei, Yan Junqiang, Chen Jing, Wu Wenlan, Zhu Xiaoying, Wang Yong
Department of Pathogen Biology, Medical College, Henan University of Science and Technology, No.6, Anhui Road, Jianxi District, Luoyang, 471003, China.
Department of Neurology, The First Affiliated Hospital of Henan University of Science and Technology, Jinghua Road 24, Luoyang, 471003, China.
Cell Mol Neurobiol. 2015 Oct;35(7):1061-71. doi: 10.1007/s10571-015-0201-y. Epub 2015 May 5.
The epidemic and experimental studies have confirmed that the obesity induced by high-fat diet not only caused neuronal insulin resistance, but also induced brain mitochondrial dysfunction as well as learning impairment in mice. Naringin has been reported to posses biological functions which are beneficial to human cognitions, but its protective effects on HFD-induced cognitive deficits and underlying mechanisms have not been well characterized. In the present study Male C57BL/6 J mice were fed either a control or high-fat diet for 20 weeks and then randomized into four groups treated with their respective diets including control diet, control diet + naringin, high-fat diet (HFD), and high-fat diet + naringin (HFDN). The behavioral performance was assessed by using novel object recognition test and Morris water maze test. Hippocampal mitochondrial parameters were analyzed. Then the protein levels of insulin signaling pathway and the AMP-activated protein kinase (AMPK) in the hippocampus were detected by Western blot method. Our results showed that oral administration of naringin significantly improved the learning and memory abilities as evidenced by increasing recognition index by 52.5% in the novel object recognition test and inducing a 1.05-fold increase in the crossing-target number in the probe test, and ameliorated mitochondrial dysfunction in mice caused by HFD consumption. Moreover, naringin significantly enhanced insulin signaling pathway as indicated by a 34.5% increase in the expression levels of IRS-1, a 47.8% decrease in the p-IRS-1, a 1.43-fold increase in the p-Akt, and a 1.89-fold increase in the p-GSK-3β in the hippocampus of the HFDN mice versus HFD mice. Furthermore, the AMPK activity significantly increased in the naringin-treated (100 mg kg(-1) d(-1)) group. These findings suggest that an enhancement in insulin signaling and a decrease in mitochondrial dysfunction through the activation of AMPK may be one of the mechanisms that naringin improves cognitive functions in HFD-induced obese mice.
流行病学和实验研究证实，高脂饮食诱导的肥胖不仅会导致神经元胰岛素抵抗，还会引起小鼠脑线粒体功能障碍以及学习障碍。据报道，柚皮苷具有对人类认知有益的生物学功能，但其对高脂饮食诱导的认知缺陷的保护作用及其潜在机制尚未得到充分阐明。在本研究中，雄性C57BL/6 J小鼠分别给予对照饮食或高脂饮食20周，然后随机分为四组，分别给予各自的饮食，包括对照饮食、对照饮食+柚皮苷、高脂饮食（HFD）和高脂饮食+柚皮苷（HFDN）。通过新颖物体识别测试和莫里斯水迷宫测试评估行为表现。分析海马体线粒体参数。然后通过蛋白质印迹法检测海马体中胰岛素信号通路和AMP激活蛋白激酶（AMPK）的蛋白质水平。我们的结果表明，口服柚皮苷显著改善了学习和记忆能力，在新颖物体识别测试中识别指数增加了52.5%，在探针测试中穿越目标次数增加了1.05倍，证明了这一点，并且改善了由高脂饮食引起的小鼠线粒体功能障碍。此外，与高脂饮食小鼠相比，HFDN小鼠海马体中IRS-1表达水平增加34.5%、p-IRS-1降低47.8%、p-Akt增加1.43倍、p-GSK-3β增加1.89倍，表明柚皮苷显著增强了胰岛素信号通路。此外，在柚皮苷处理组（100 mg kg(-1) d(-1)）中，AMPK活性显著增加。这些发现表明，通过激活AMPK增强胰岛素信号和减少线粒体功能障碍可能是柚皮苷改善高脂饮食诱导的肥胖小鼠认知功能的机制之一。
