Department of Biology, University of Pennsylvania, Philadelphia, PA 19104, USA.
Monell Chemical Senses Center, Philadelphia, PA 19104, USA; Department of Neuroscience, University of Pennsylvania, Philadelphia, PA 19104, USA.
Cell Metab. 2021 Mar 2;33(3):676-687.e5. doi: 10.1016/j.cmet.2020.12.018. Epub 2021 Jan 14.
Food intake is tightly regulated by complex and coordinated gut-brain interactions. Nutrients rapidly modulate activity in key populations of hypothalamic neurons that regulate food intake, including hunger-sensitive agouti-related protein (AgRP)-expressing neurons. Because individual macronutrients engage specific receptors in the gut to communicate with the brain, we reasoned that macronutrients may utilize different pathways to reduce activity in AgRP neurons. Here, we revealed that AgRP neuron activity in hungry mice is inhibited by site-specific intestinal detection of different macronutrients. We showed that vagal gut-brain signaling is required for AgRP neuron inhibition by fat. In contrast, spinal gut-brain signaling relays the presence of intestinal glucose. Further, we identified glucose sensors in the intestine and hepatic portal vein that mediate glucose-dependent AgRP neuron inhibition. Therefore, distinct pathways are activated by individual macronutrients to inhibit AgRP neuron activity.
食物摄入受复杂且协调的肠道-大脑相互作用的严格调节。营养物质迅速调节下丘脑神经元中调节食物摄入的关键神经元群的活动，包括饥饿敏感的 AgRP 表达神经元。由于个体宏量营养素在肠道中与大脑通讯时会利用特定的受体，我们推断宏量营养素可能利用不同的途径来降低 AgRP 神经元的活性。在这里，我们揭示了饥饿小鼠的 AgRP 神经元活性受到肠道中不同宏量营养素的特异性检测的抑制。我们表明，迷走神经肠道-大脑信号传导是脂肪抑制 AgRP 神经元所必需的。相比之下，脊髓肠道-大脑信号传导传递肠道葡萄糖的存在。此外，我们鉴定出肠道和肝门静脉中的葡萄糖传感器，介导葡萄糖依赖性 AgRP 神经元抑制。因此，不同的途径被个体宏量营养素激活以抑制 AgRP 神经元活性。
