Takuya Funayama: Division of Hematology, Department of Medicine, Asahikawa Medical University, Japan.
Tsukasa Nozu: Department of Regional Medicine and Education, Asahikawa Medical University, Japan; Department of General Medicine, Asahikawa Medical University, Japan.
Masatomo Ishioh: Department of General Medicine, Asahikawa Medical University, Japan.
Chihiro Sumi: Division of Hematology, Department of Medicine, Asahikawa Medical University, Japan.
Takeshi Saito: Division of Hematology, Department of Medicine, Asahikawa Medical University, Japan.
Mayumi Hatayama: Division of Hematology, Department of Medicine, Asahikawa Medical University, Japan.
Masayo Yamamoto: Division of Hematology, Department of Medicine, Asahikawa Medical University, Japan.
Motohiro Shindo: Division of Hematology, Department of Medicine, Asahikawa Medical University, Japan.
Shuichiro Takahashi: Division of Hematology, Department of Medicine, Asahikawa Medical University, Japan.
Toshikatsu Okumura: Division of Hematology, Department of Medicine, Asahikawa Medical University, Japan; Division of Gastroenterology, Department of Medicine, Asahikawa Medical University, Japan. Electronic address: okumurat@asahikawa-med.ac.jp.
Leaky gut, an increased intestinal permeability, has been described in many diseases. We have recently demonstrated that neuropeptides such as orexin in the brain improved leaky gut, suggesting that the brain is involved in maintaining intestinal barrier function. It has been suggested that AMPK in the hypothalamus play a role in food intake. Because the hypothalamus is involved in the regulation of not only feeding behavior but also gut function, the present study was performed to clarify a hypothesis that AMPK in the brain regulate gut barrier function. Colonic permeability was determined by quantifying the absorbed Evans blue within the colonic tissue in rats. Intracisternal AICAR, an AMPK activator, could reduce LPS-induced colonic hyperpermeability while peripherally administered AICAR failed to change it. The improvement of colonic hyperpermeability by intracisternal AICAR was blocked by intracisternal but not subcutaneous compound C, AMPK inhibitor, atropine or vagotomy. The improvement of colonic hyperpermeability by intracisternal AICAR was blocked by intracisternal orexin receptor antagonist but not oxytocin or GLP-1 receptor antagonist. Intracisternal compound C prevented brain oxytocin or GLP-1 but not orexin-induced improvement of colonic hyperpermeability. These results suggest that activation of brain AMPK is capable of reducing colonic hyperpermeability through brain orexin signaling and the vagus nerve. In addition, endogenous AMPK in the brain may mediate the oxytocin or GLP-induced improvement of colonic hyperpermeability. We would suggest that improvement of leaky gut by activation of brain AMPK may play a role in leaky gut-related diseases.
