title: 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.affiliation: Department of Physiology and Metabolism, Brain/Liver Interface Medicine Research Center, Kanazawa University, Kanazawa, Ishikawa 920-8641, Japan.
authors.forename: Kumi
authors.initials: K
authors.lastname: Kimura
authors.affiliation: Department of Physiology II, Kanazawa Medical University, Uchinada, Ishikawa 920-0293, Japan.
authors.forename: Mamoru
authors.initials: M
authors.lastname: Tanida
authors.affiliation: Department of Cell Metabolism and Nutrition, Brain/Liver Interface Medicine Research Center, Kanazawa University, Kanazawa, Ishikawa 920-8641, Japan.
authors.forename: Naoto
authors.initials: N
authors.lastname: Nagata
authors.affiliation: Department of Physiology and Metabolism, Brain/Liver Interface Medicine Research Center, Kanazawa University, Kanazawa, Ishikawa 920-8641, Japan; Metabolism and Nutrition Research Unit, Institute for Frontier Science Initiative, Kanazawa University, Kanazawa, Ishikawa 920-8641, Japan.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Inaba
authors.affiliation: Department of Physiology and Metabolism, Brain/Liver Interface Medicine Research Center, Kanazawa University, Kanazawa, Ishikawa 920-8641, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Watanabe
authors.affiliation: Department of Cell Metabolism and Nutrition, Brain/Liver Interface Medicine Research Center, Kanazawa University, Kanazawa, Ishikawa 920-8641, Japan.
authors.forename: Mayumi
authors.initials: M
authors.lastname: Nagashimada
authors.affiliation: Department of Cell Metabolism and Nutrition, Brain/Liver Interface Medicine Research Center, Kanazawa University, Kanazawa, Ishikawa 920-8641, Japan.
authors.forename: Tsuguhito
authors.initials: T
authors.lastname: Ota
authors.affiliation: Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Hyogo 650-0017, Japan.
authors.forename: Shun-ichiro
authors.initials: S
authors.lastname: Asahara
authors.affiliation: Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Hyogo 650-0017, Japan; Division of Medical Chemistry, Department of Biophysics, Kobe University Graduate School of Health Sciences, Kobe, Hyogo 654-0142, Japan.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Kido
authors.affiliation: Department of Molecular Metabolic Regulation, Diabetes Research Center, Research Institute, National Center for Global Health and Medicine, Tokyo 162-8655, Japan.
authors.forename: Michihiro
authors.initials: M
authors.lastname: Matsumoto
authors.affiliation: Department of Neurology, Respirology, Endocrinology, and Metabolism, Faculty of Internal Medicine, University of Miyazaki, Miyazaki, Miyazaki 889-1692, Japan; Department of Sports and Fitness, Faculty of Wellness, Shigakkan University, Obu, Aichi 474-8651, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Toshinai
authors.affiliation: Department of Neurology, Respirology, Endocrinology, and Metabolism, Faculty of Internal Medicine, University of Miyazaki, Miyazaki, Miyazaki 889-1692, Japan.
authors.forename: Masamitsu
authors.initials: M
authors.lastname: Nakazato
authors.affiliation: Department of Physiology II, Kanazawa Medical University, Uchinada, Ishikawa 920-0293, Japan.
authors.forename: Toshishige
authors.initials: T
authors.lastname: Shibamoto
authors.affiliation: Department of Disease Control and Homeostasis, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Ishikawa 920-8641, Japan.
authors.forename: Shuichi
authors.initials: S
authors.lastname: Kaneko
authors.affiliation: National Center for Global Health and Medicine, Tokyo 162-8655, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Kasuga
authors.affiliation: Department of Physiology and Metabolism, Brain/Liver Interface Medicine Research Center, Kanazawa University, Kanazawa, Ishikawa 920-8641, Japan; Metabolism and Nutrition Research Unit, Institute for Frontier Science Initiative, Kanazawa University, Kanazawa, Ishikawa 920-8641, Japan. Electronic address: inoue-h@staff.kanazawa-u.ac.jp.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Inoue
mesh_terms: D000109:Acetylcholine / Q000378:metabolism; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D002135:Calcium-Binding Proteins; D002478:Cells, Cultured; D002714:Chlorisondamine / Q000494:pharmacology; D059305:Diet, High-Fat; D007328:Insulin / Q000494:pharmacology*; D015850:Interleukin-6 / Q000097:blood / Q000235:genetics / Q000378:metabolism; D007728:Kupffer Cells / Q000166:cytology / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009538:Nicotine / Q000494:pharmacology; D009765:Obesity / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014630:Vagus Nerve / Q000187:drug effects* / Q000502:physiology; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: C000634132:Adgre1 protein, mouse; D001786:Blood Glucose; D002135:Calcium-Binding Proteins; D007328:Insulin; D015850:Interleukin-6; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D050796:STAT3 Transcription Factor; D064569:alpha7 Nicotinic Acetylcholine Receptor; D009538:Nicotine; D002714:Chlorisondamine; D000109:Acetylcholine