Department of Respiratory and Critical Care Medicine, Binzhou Medical University Hospital, Binzhou, Shangdong 256603, China; USDA-ARS Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
USDA-ARS Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
Mol Metab. 2017 Nov;6(11):1350-1359. doi: 10.1016/j.molmet.2017.08.009. Epub 2017 Sep 1.
Glucagon-like peptides are co-released from enteroendocrine L cells in the gut and preproglucagon (PPG) neurons in the brainstem. PPG-derived GLP-1/2 are probably key neuroendocrine signals for the control of energy balance and glucose homeostasis. The objective of this study was to determine whether activation of PPG neurons per se modulates glucose homeostasis and insulin sensitivity in vivo.
We generated glucagon (Gcg) promoter-driven Cre transgenic mice and injected excitatory hM3Dq-mCherry AAV into their brainstem NTS. We characterized the metabolic impact of PPG neuron activation on glucose homeostasis and insulin sensitivity using stable isotopic tracers coupled with hyperinsulinemic euglycemic clamp.
We showed that after ip injection of clozapine N-oxide, Gcg-Cre lean mice transduced with hM3Dq in the brainstem NTS downregulated basal endogenous glucose production and enhanced glucose tolerance following ip glucose tolerance test. Moreover, acute activation of PPG neurons enhanced whole-body insulin sensitivity as indicated by increased glucose infusion rate as well as augmented insulin-suppression of endogenous glucose production and gluconeogenesis. In contrast, insulin-stimulation of glucose disposal was not altered significantly.
We conclude that acute activation of PPG neurons in the brainstem reduces basal glucose production, enhances intraperitoneal glucose tolerance, and augments hepatic insulin sensitivity, suggesting an important physiological role of PPG neurons-mediated circuitry in promoting glycemic control and insulin sensitivity.
肠内分泌 L 细胞和脑桥前胰高血糖素原 (PPG) 神经元共同释放胰高血糖素样肽。PPG 衍生的 GLP-1/2 可能是控制能量平衡和葡萄糖稳态的关键神经内分泌信号。本研究的目的是确定 PPG 神经元的激活本身是否调节体内葡萄糖稳态和胰岛素敏感性。
我们生成了胰高血糖素 (Gcg) 启动子驱动的 Cre 转基因小鼠，并将兴奋性 hM3Dq-mCherry AAV 注入其脑桥 NTS。我们使用稳定同位素示踪剂和高胰岛素-正常血糖钳夹技术，研究了 PPG 神经元激活对葡萄糖稳态和胰岛素敏感性的代谢影响。
我们表明，在 ip 注射氯氮平 N-氧化物后，脑桥 NTS 中被 hM3Dq 转导的 Gcg-Cre 瘦小鼠下调了基础内源性葡萄糖产生，并增强了 ip 葡萄糖耐量试验后的葡萄糖耐量。此外，PPG 神经元的急性激活增强了全身胰岛素敏感性，表现为葡萄糖输注率增加，以及增强了胰岛素抑制内源性葡萄糖产生和糖异生的作用。相比之下，胰岛素刺激葡萄糖摄取没有明显改变。
我们得出结论，脑桥 PPG 神经元的急性激活降低了基础葡萄糖产生，增强了腹腔内葡萄糖耐量，并增强了肝胰岛素敏感性，这表明 PPG 神经元介导的回路在促进血糖控制和胰岛素敏感性方面具有重要的生理作用。
