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

Abstract

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.

• 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
• Journal: Cell reports (Cell Rep) Vol. 14 Issue 10 Pg. 2362-74 (Mar 15 2016) ISSN: 2211-1247 [Electronic] United States
• PMID: 26947072 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• Adgre1 protein, mouse
• Blood Glucose
• Calcium-Binding Proteins
• Insulin
• Interleukin-6
• Receptors, Cell Surface
• Receptors, G-Protein-Coupled
• STAT3 Transcription Factor
• alpha7 Nicotinic Acetylcholine Receptor
• Nicotine
• Chlorisondamine
• Acetylcholine

Topics

• Acetylcholine (metabolism)
• Animals
• Blood Glucose (analysis)
• Calcium-Binding Proteins
• Cells, Cultured
• Chlorisondamine (pharmacology)
• Diet, High-Fat
• Insulin (pharmacology)
• Interleukin-6 (blood, genetics, metabolism)
• Kupffer Cells (cytology, metabolism)
• Liver (metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Nicotine (pharmacology)
• Obesity (metabolism, pathology)
• Phosphorylation (drug effects)
• Protein Binding (drug effects)
• Receptors, Cell Surface (genetics, metabolism)
• Receptors, G-Protein-Coupled
• STAT3 Transcription Factor (metabolism)
• Signal Transduction (drug effects)
• Vagus Nerve (drug effects, physiology)
• alpha7 Nicotinic Acetylcholine Receptor (deficiency, genetics, metabolism)