Colonic inflammation triggers β cell proliferation during obesity development via a liver-to-pancreas interorgan mechanism

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Abstract

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.

Authors

Haremaru Kubo, Junta Imai, Tomohito Izumi, Masato Kohata, Yohei Kawana, Akira Endo, Hiroto Sugawara, Junro Seike, Takahiro Horiuchi, Hiroshi Komamura, Toshihiro Sato, Shinichiro Hosaka, Yoichiro Asai, Shinjiro Kodama, Kei Takahashi, Keizo Kaneko, Hideki Katagiri