Knockdown of GLP-1 Receptors in Vagal Afferents Affects Normal Food Intake and Glycemia
Knockdown of GLP-1 Receptors in Vagal Afferents Affects Normal Food Intake and Glycemia
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DOI：
10.2337/db15-0973
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发表时间：
2016-01-01
期刊：
影响因子：
7.7
通讯作者：
Lee, Shin J.
中科院分区：
文献类型：
--
作者：
Krieger, Jean-Philippe;Arnold, Myrtha;Lee, Shin J.
肠内分泌L细胞的营养刺激诱导肠促胰岛素和饱腹肽胰高血糖素样肽1（GLP-1）的释放。迷走神经支配内脏器官，可能有助于介导肠源性GLP-1对摄食量、能量稳态和血糖控制的影响。为了检验迷走神经传入神经元（货车）GLP-1受体（GLP-1 R）是内源性GLP-1的这些作用所必需的假设，我们建立了一种新的双侧结状神经节注射技术，以递送慢病毒载体并敲低雄性Sprague道利大鼠中的货车GLP-1 R。我们发现，在正常饮食条件下，货车GLP-1 Rs的完全表达对于维持长期能量平衡是不必要的。然而，货车GLP-1 R敲低（kd）确实增加了膳食量并加速了胃排空。此外，GLP-1 R kd大鼠餐后血糖升高，胰岛素释放减弱，表明货车GLP-1 R是餐后神经肠促胰岛素效应的生理贡献者。总的来说，我们的研究结果强调了VAN在介导内源性GLP-1对食物摄入和食欲的影响方面的关键作用，并可能促进基于GLP-1的治疗的进一步发展。
Nutrient stimulation of enteroendocrine L cells induces the release of the incretin and satiating peptide glucagon-like peptide 1 (GLP-1). The vagus nerve innervates visceral organs and may contribute to the mediation of gut-derived GLP-1's effects on food intake, energy homeostasis, and glycemic control. To test the hypothesis that vagal afferent neuron (VAN) GLP-1 receptors (GLP-1Rs) are necessary for these effects of endogenous GLP-1, we established a novel bilateral nodose ganglia injection technique to deliver a lentiviral vector and to knock down VAN GLP-1Rs in male Sprague Dawley rats. We found that a full expression of VAN GLP-1Rs is not necessary for the maintenance of long-term energy balance in normal eating conditions. VAN GLP-1R knockdown (kd) did, however, increase meal size and accelerated gastric emptying. Moreover, postmeal glycemia was elevated and insulin release was blunted in GLP-1R kd rats, suggesting that VAN GLP-1Rs are physiological contributors to the neuroincretin effect after a meal. Collectively, our results highlight a crucial role for the VANs in mediating the effects of endogenous GLP-1 on food intake and glycemia and may promote the further development of GLP-1-based therapies.