Communication of gut hormones with the central nervous system is important to regulate systemic glucose homeostasis, but the precise underlying mechanism involved remain little understood. Nesfatin-1, encoded by nucleobindin-2 (NUCB2), a potent anorexigenic peptide hormone, was found to be released from the gastrointestinal tract, but its specific function in this context remains unclear. Herein, we found that gut nesfatin-1 can sense nutrients such as glucose and lipids and subsequently decreases hepatic glucose production. Nesfatin-1 infusion in the small intestine of NUCB2-knockout rats reduced hepatic glucose production via a gut - brain - liver circuit. Mechanistically, NUCB2/nesfatin-1 interacted directly with melanocortin 4 receptor (MC4R) through its H-F-R domain and increased cyclic adenosine monophosphate (cAMP) levels and glucagon-like peptide 1 (GLP-1) secretion in the intestinal epithelium, thus inhibiting hepatic glucose production. The intestinal nesfatin-1 -MC4R-cAMP-GLP-1 pathway and systemic gut-brain communication are required for nesfatin-1 - mediated regulation of liver energy metabolism. These findings reveal a novel mechanism of hepatic glucose production control by gut hormones through the central nervous system.

中文翻译：

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肠道 NUCB2/nesfatin-1 通过 MC4R-cAMP-GLP-1 通路调节肝脏葡萄糖的产生。


肠道激素与中枢神经系统的通讯对于调节全身葡萄糖稳态很重要，但所涉及的确切潜在机制仍知之甚少。由核结合蛋白-2 （NUCB2） 编码的 Nesfatin-1 是一种有效的厌食肽激素，被发现从胃肠道释放，但其在这种情况下的具体功能仍不清楚。在此，我们发现肠道 nesfatin-1 可以感知葡萄糖和脂质等营养物质，从而减少肝脏葡萄糖的产生。在 NUCB2 敲除大鼠的小肠中输注 Nesfatin-1 减少了通过肠道 - 大脑 - 肝脏回路的肝葡萄糖产生。从机制上讲，NUCB2/nesfatin-1 通过其 H-F-R 结构域直接与黑皮质素 4 受体 （MC4R） 相互作用，并增加肠上皮中环磷酸腺苷 （cAMP） 水平和胰高血糖素样肽 1 （GLP-1） 的分泌，从而抑制肝葡萄糖的产生。肠道 nesfatin-1 -MC4R-cAMP-GLP-1 通路和全身肠脑通讯是 nesfatin-1 介导的肝能量代谢调节所必需的。这些发现揭示了肠道激素通过中枢神经系统控制肝葡萄糖产生的新机制。