Kubo Haremaru, Imai Junta, Izumi Tomohito, Kohata Masato, Kawana Yohei, Endo Akira, Sugawara Hiroto, Seike Junro, Horiuchi Takahiro, Komamura Hiroshi, Sato Toshihiro, Hosaka Shinichiro, Asai Yoichiro, Kodama Shinjiro, Takahashi Kei, Kaneko Keizo, Katagiri Hideki
JCI Insight. 2025 May 8;10(9). doi: 10.1172/jci.insight.183864.
Under insulin-resistant conditions, such as obesity, pancreatic β cells adaptively proliferate and secrete more insulin to prevent blood glucose elevation. We previously reported hepatic ERK activation during obesity development to stimulate a neuronal relay system, consisting of afferent splanchnic nerves from the liver and efferent vagal nerves to the pancreas, thereby triggering adaptive β cell proliferation. However, the mechanism linking obesity with the interorgan system originating in hepatic ERK activation remains unclear. Herein, we clarified that colonic inflammation promotes β cell proliferation through this interorgan system from the liver to the pancreas. First, dextran sodium sulfate (DSS) treatment induced colonic inflammation and hepatic ERK activation as well as β cell proliferation, all of which were suppressed by blockades of the neuronal relay system by several approaches. In addition, treatment with anti-lymphocyte Peyer's patch adhesion molecule-1 (anti-LPAM1) antibody suppressed β cell proliferation induced by DSS treatment. Importantly, high-fat diet (HFD) feeding also elicited colonic inflammation, and its inhibition by anti-LPAM1 antibody administration suppressed hepatic ERK activation and β cell proliferation induced by HFD. Thus, colonic inflammation triggers adaptive β cell proliferation via the interorgan mechanism originating in hepatic ERK activation. The present study revealed a potentially novel role of the gastrointestinal tract in the maintenance of β cell regulation.
在胰岛素抵抗状态下，如肥胖时，胰腺β细胞会适应性增殖并分泌更多胰岛素以防止血糖升高。我们之前报道过在肥胖发展过程中肝脏ERK激活会刺激一个神经中继系统，该系统由来自肝脏的内脏传入神经和通向胰腺的迷走传出神经组成，从而触发β细胞的适应性增殖。然而，将肥胖与源自肝脏ERK激活的器官间系统联系起来的机制仍不清楚。在此，我们阐明结肠炎症通过从肝脏到胰腺的这个器官间系统促进β细胞增殖。首先，葡聚糖硫酸钠（DSS）处理诱导了结肠炎症、肝脏ERK激活以及β细胞增殖，而通过几种方法阻断神经中继系统均能抑制所有这些现象。此外，用抗淋巴细胞派伊尔结黏附分子-1（抗-LPAM1）抗体处理可抑制DSS处理诱导的β细胞增殖。重要的是，高脂饮食（HFD）喂养也引发了结肠炎症，而给予抗-LPAM1抗体抑制HFD诱导的肝脏ERK激活和β细胞增殖。因此，结肠炎症通过源自肝脏ERK激活的器官间机制触发适应性β细胞增殖。本研究揭示了胃肠道在维持β细胞调节方面一个潜在的新作用。
