Neurophysiology Unit, Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand; Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.
School of Pharmaceutical Sciences, Wenzhou Medical University, University-Town, Wenzhou, Zhejiang, China.
Biomed Pharmacother. 2018 Jan;97:1663-1672. doi: 10.1016/j.biopha.2017.12.021. Epub 2017 Dec 8.
The beneficial effects of Fibroblast Growth Factor 21 (FGF21) on metabolic function and neuroprotection have been shown in earlier research. We have previously shown that the Dipeptidyl Peptidase 4 inhibitor, vildagliptin, also led to improved insulin sensitivity and brain function in the obese-insulin resistant condition. However, the comparative efficacy on the improvement of metabolic function and neuroprotection between FGF21 and vildagliptin in the obese-insulin resistant condition has never been investigated. Twenty-four male Wistar rats were divided into two groups, and received either a normal diet (ND, n=6) or a high fat diet (HFD, n=18) for 16 weeks. At week 13, the HFD-fed rats were divided into three subgroups (n=6/subgroup) to receive either a vehicle, recombinant human FGF21 (0.1mg/kg/day) or vildagliptin (3mg/kg/day), for four weeks. ND-fed rats were given a vehicle for four weeks. The metabolic parameters and brain function were subsequently investigated. The results demonstrated that the rats fed on HFD had obese-insulin resistance, increased systemic inflammation, brain mitochondrial dysfunction, increased brain apoptosis, impaired hippocampal plasticity, and demonstrated cognitive decline. FGF21 and vildagliptin effectively attenuated peripheral insulin resistance, brain mitochondrial dysfunction, brain apoptosis and cognitive decline. However, only FGF21 treatment led to significantly reduced body weight gain, visceral fat, systemic inflammation, improved hippocampal synaptic plasticity, enhanced FGF21 mediated signaling in the brain leading to prevention of early cognitive decline. These findings suggest that FGF21 exerts greater efficacy than vildagliptin in restoring metabolic function as well as brain function in cases of obese-insulin resistant rats.
成纤维细胞生长因子 21（FGF21）对代谢功能和神经保护的有益作用在早期研究中已得到证实。我们之前已经表明，二肽基肽酶 4 抑制剂维达格列汀也能改善肥胖-胰岛素抵抗状态下的胰岛素敏感性和大脑功能。然而，FGF21 和维达格列汀在肥胖-胰岛素抵抗状态下改善代谢功能和神经保护的相对疗效尚未被研究。24 只雄性 Wistar 大鼠被分为两组，分别给予正常饮食（ND，n=6）或高脂肪饮食（HFD，n=18）16 周。在第 13 周，HFD 喂养的大鼠被分为三组（n=6/组），分别给予载体、重组人 FGF21（0.1mg/kg/天）或维达格列汀（3mg/kg/天），持续 4 周。ND 喂养的大鼠给予载体 4 周。随后检测代谢参数和大脑功能。结果表明，HFD 喂养的大鼠表现出肥胖-胰岛素抵抗、全身炎症增加、脑线粒体功能障碍、脑凋亡增加、海马可塑性受损和认知能力下降。FGF21 和维达格列汀能有效减轻外周胰岛素抵抗、脑线粒体功能障碍、脑凋亡和认知下降。然而，只有 FGF21 治疗能显著减轻体重增加、内脏脂肪、全身炎症、改善海马突触可塑性、增强大脑中 FGF21 介导的信号转导，从而预防早期认知能力下降。这些发现表明，在肥胖-胰岛素抵抗大鼠中，FGF21 在恢复代谢功能和大脑功能方面比维达格列汀更有效。
