Diabetes Research Group, The SAAD Centre for Pharmacy and Diabetes, School of Biomedical Sciences, University of Ulster, Coleraine, UK.
Int J Obes (Lond). 2013 May;37(5):678-84. doi: 10.1038/ijo.2012.91. Epub 2012 Jun 5.
Consumption of high-fat diet exerts adverse effects on learning and memory formation, which is linked to impaired hippocampal function. Activation of glucagon-like peptide-1 (GLP-1) signalling ameliorates detrimental effects of obesity-diabetes on cognitive function; however, mechanisms underlying these beneficial actions remain unclear. This study examined effects of daily subcutaneous treatment with GLP-1 mimetic, Liraglutide, on synaptic plasticity, hippocampal gene expression and metabolic control in adult obese diabetic (ob/ob) mice.
Long-term potentiation (LTP) induced by area CA1 was completely abolished in ob/ob mice compared with lean controls. Deleterious effects on LTP were rescued (P<0.001) with Liraglutide. Indeed, Liraglutide-treated mice exhibited superior LTP profile compared with lean controls (P<0.01). Expression of hippocampal brain-derived neurotropic factor and neurotrophic tyrosine kinase receptor-type 2 were not significantly different, but synaptophysin and Mash1 were decreased in ob/ob mice. Treatment with Liraglutide over 21 days increased expression of Mash1 in ob/ob mice (2.0-fold; P<0.01). These changes were associated with significantly reduced plasma glucose (21% reduction; P<0.05) and markedly improved plasma insulin concentrations (2.1- to 3.3-fold; P<0.05 to P<0.01). Liraglutide also significantly reduced the glycaemic excursion following an intraperitonal glucose load (area under curve (AUC) values: 22%; P<0.05) and markedly enhanced the insulin response to glucose (AUC values: 1.6-fold; P<0.05). O2 consumption, CO2 production, respiratory exchange ratio and energy expenditure were not altered by Liraglutide therapy. On day 21, accumulated food intake (32% reduction; P<0.05) and number of feeding bouts (32% reduction; P<0.05) were significantly reduced but simple energy restriction was not responsible for the beneficial actions of Liraglutide.
Liraglutide elicits beneficial effects on metabolic control and synaptic plasticity in mice with severe obesity and insulin resistance mediated in part through increased expression of Mash1 believed to improve hippocampal neurogenesis and cell survival.
高脂肪饮食的摄入对学习和记忆形成有不良影响，这与海马功能受损有关。胰高血糖素样肽-1（GLP-1）信号的激活可以改善肥胖型糖尿病对认知功能的不良影响；然而，这些有益作用的机制尚不清楚。本研究探讨了每日皮下给予 GLP-1 类似物利拉鲁肽对成年肥胖型糖尿病（ob/ob）小鼠突触可塑性、海马基因表达和代谢控制的影响。
与瘦对照组相比，ob/ob 小鼠 CA1 区的长时程增强（LTP）完全被消除。利拉鲁肽（Liraglutide）挽救了对 LTP 的有害影响（P<0.001）。事实上，与瘦对照组相比，利拉鲁肽治疗组的 LTP 表现更为优越（P<0.01）。海马脑源性神经营养因子和神经营养酪氨酸激酶受体 2 的表达没有显著差异，但 ob/ob 小鼠的突触小体和 Mash1 减少。利拉鲁肽治疗 21 天可增加 ob/ob 小鼠 Mash1 的表达（增加 2 倍；P<0.01）。这些变化与血糖显著降低（降低 21%；P<0.05）和血浆胰岛素浓度显著升高（2.1 至 3.3 倍；P<0.05 至 P<0.01）相关。利拉鲁肽还显著降低了腹腔内葡萄糖负荷后的血糖波动（曲线下面积（AUC）值：22%；P<0.05），并显著增强了葡萄糖对胰岛素的反应（AUC 值：增加 1.6 倍；P<0.05）。利拉鲁肽治疗并未改变 O2 消耗、CO2 产生、呼吸交换率和能量消耗。第 21 天，累积食物摄入量（降低 32%；P<0.05）和摄食次数（降低 32%；P<0.05）显著减少，但单纯的能量限制并不是利拉鲁肽有益作用的原因。
利拉鲁肽对严重肥胖和胰岛素抵抗的小鼠的代谢控制和突触可塑性产生有益影响，部分通过增加 Mash1 的表达来介导，这被认为可以改善海马神经发生和细胞存活。
