Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana.
Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, Indiana.
Endocrinology. 2019 Sep 1;160(9):2038-2048. doi: 10.1210/en.2019-00341.
Insulin signaling in the central nervous system influences satiety, counterregulation, and peripheral insulin sensitivity. Neurons expressing the Glut4 glucose transporter influence peripheral insulin sensitivity. Here, we analyzed the effects of insulin receptor (IR) signaling in hypothalamic Glut4 neurons on glucose sensing as well as leptin and amino acid signaling. By measuring electrophysiological responses to low glucose conditions, we found that the majority of Glut4 neurons in the ventromedial hypothalamus (VMH) were glucose excitatory neurons. GLUT4-Cre-driven insulin receptor knockout mice with a combined ablation of IR in Glut4-expressing tissues showed increased counterregulatory response to either 2-deoxyglucose-induced neuroglycopenia or systemic insulin-induced hypoglycemia. The latter response was recapitulated in mice with decreased VMH IR expression, suggesting that the effects on the counterregulatory response are likely mediated through the deletion of IRs on Glut4 neurons in the VMH. Using immunohistochemistry in fluorescently labeled hypothalamic Glut4 neurons, we showed that IR signaling promoted hypothalamic cellular signaling responses to the rise of insulin, leptin, and amino acids associated with feeding. We concluded that hypothalamic Glut4 neurons modulated the glucagon counterregulatory response and that IR signaling in Glut4 neurons was required to integrate hormonal and nutritional cues for the regulation of glucose metabolism.
中枢神经系统中的胰岛素信号影响饱腹感、代偿性和外周胰岛素敏感性。表达葡萄糖转运蛋白 4 (Glut4) 的神经元影响外周胰岛素敏感性。在这里，我们分析了下丘脑 Glut4 神经元中胰岛素受体 (IR) 信号对葡萄糖感应以及瘦素和氨基酸信号的影响。通过测量对低血糖条件的电生理反应，我们发现，腹内侧下丘脑 (VMH) 中的大多数 Glut4 神经元是葡萄糖兴奋神经元。在表达 Glut4 的组织中，GLUT4-Cre 驱动的胰岛素受体敲除小鼠，其 IR 在 Glut4 表达组织中的联合缺失，表现出对 2-脱氧葡萄糖诱导的神经低血糖或全身胰岛素诱导的低血糖的代偿性反应增强。后者的反应在 VMH IR 表达降低的小鼠中得到再现，表明对代偿性反应的影响可能是通过 VMH 中 Glut4 神经元上的 IR 缺失介导的。通过对荧光标记的下丘脑 Glut4 神经元进行免疫组织化学染色，我们发现，IR 信号促进了与进食相关的胰岛素、瘦素和氨基酸升高的下丘脑细胞信号反应。我们得出结论，下丘脑 Glut4 神经元调节胰高血糖素的代偿性反应，而 Glut4 神经元中的 IR 信号对于整合激素和营养信号以调节葡萄糖代谢是必需的。
