J Clin Invest. 2014 Jun;124(6):2456-63. doi: 10.1172/JCI72434. Epub 2014 Apr 24.
Glucose control and weight loss are cornerstones of type 2 diabetes treatment. Currently, only glucagon-like peptide-1 (GLP1) analogs are able to achieve both weight loss and glucose tolerance. Both glucose and body weight are regulated by the brain, which contains GLP1 receptors (GLP1R). Even though the brain is poised to mediate the effects of GLP1 analogs, it remains unclear whether the glucose- and body weight-lowering effects of long-acting GLP1R agonists are via direct action on CNS GLP1R or the result of downstream activation of afferent neuronal GLP1R. We generated mice with either neuronal or visceral nerve-specific deletion of Glp1r and then administered liraglutide, a long-acting GLP1R agonist. We found that neither reduction of GLP1R in the CNS nor in the visceral nerves resulted in alterations in body weight or food intake in animals fed normal chow or a high-fat diet. Liraglutide treatment provided beneficial glucose-lowering effects in both chow- and high-fat-fed mice lacking GLP1R in the CNS or visceral nerves; however, liraglutide was ineffective at altering food intake, body weight, or causing a conditioned taste aversion in mice lacking neuronal GLP1R. These data indicate that neuronal GLP1Rs mediate body weight and anorectic effects of liraglutide, but are not required for glucose-lowering effects.
血糖控制和体重减轻是 2 型糖尿病治疗的基石。目前，只有胰高血糖素样肽-1（GLP1）类似物能够同时实现体重减轻和葡萄糖耐量。血糖和体重都受大脑调节，大脑中含有 GLP1 受体（GLP1R）。尽管大脑准备介导 GLP1 类似物的作用，但尚不清楚长效 GLP1R 激动剂的降血糖和体重作用是通过对中枢神经系统 GLP1R 的直接作用还是通过内脏神经 GLP1R 的下游激活来实现的。我们生成了神经元或内脏神经特异性缺失 Glp1r 的小鼠，然后给予利拉鲁肽，一种长效 GLP1R 激动剂。我们发现，无论是中枢神经系统还是内脏神经中 GLP1R 的减少，都不会导致正常饮食或高脂肪饮食喂养的动物体重或食物摄入量发生变化。利拉鲁肽治疗在缺乏中枢神经系统或内脏神经 GLP1R 的正常饮食和高脂肪饮食喂养的小鼠中均提供了有益的降血糖作用；然而，利拉鲁肽在缺乏神经元 GLP1R 的小鼠中不能改变食物摄入量、体重或引起条件性味觉厌恶。这些数据表明，神经元 GLP1R 介导利拉鲁肽的体重和厌食作用，但对降血糖作用不是必需的。
