Central Insulin Action Activates Kupffer Cells by Suppressing Hepatic Vagal Activation via the Nicotinic Alpha 7 Acetylcholine Receptor

• DOI: 10.1016/j.celrep.2016.02.032
• Publication Date: 2016-03-05T07:17:42Z
• Authors: Kumi Kimura; Mamoru Tanida; Naoto Nagata; Yuka Inaba; Hitoshi Watanabe; Mayumi Nagashimada; Tsuguhito Ota; Shun-ichiro Asahara; Yoshiaki Kido; Michihiro Matsumoto; Koji Toshinai; Masamitsu Nakazato; Toshishige Shibamoto; Shuichi Kaneko; Masato Kasuga; Hiroshi Inoue
• Keywords: Blood Glucose; Male; 0301 basic medicine; Nicotine; QH301-705.5; Interleukin-6; Kupffer Cells; Calcium-Binding Proteins; Receptors, Cell Surface; Diet, High-Fat; Chlorisondamine; Acetylcholine; Receptors, G-Protein-Coupled; Mice, Inbred C57BL; Mice; 03 medical and health sciences; Liver; Animals; Insulin; Obesity; Biology (General); Phosphorylation; Cells, Cultured; Protein Binding

Central insulin action activates hepatic IL-6/STAT3 signaling, which suppresses the gene expression of hepatic gluconeogenic enzymes. The vagus nerve plays an important role in this centrally mediated hepatic response; however, the precise mechanism underlying this brain-liver interaction is unclear. Here, we present our findings that the vagus nerve suppresses hepatic IL-6/STAT3 signaling via α7-nicotinic acetylcholine receptors (α7-nAchR) on Kupffer cells, and that central insulin action activates hepatic IL-6/STAT3 signaling by suppressing vagal activity. Indeed, central insulin-mediated hepatic IL-6/STAT3 activation and gluconeogenic gene suppression were impeded in mice with hepatic vagotomy, pharmacological cholinergic blockade, or α7-nAchR deficiency. In high-fat diet-induced obese and insulin-resistant mice, control of the vagus nerve by central insulin action was disturbed, inducing a persistent increase of inflammatory cytokines. These findings suggest that dysregulation of the α7-nAchR-mediated control of Kupffer cells by central insulin action may affect the pathogenesis of chronic hepatic inflammation in obesity.