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Cell Rep. 2016 Mar 15;14(10):2362-74. doi: 10.1016/j.celrep.2016.02.032. Epub 2016 Mar 3.

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

Author information

1
Department of Physiology and Metabolism, Brain/Liver Interface Medicine Research Center, Kanazawa University, Kanazawa, Ishikawa 920-8641, Japan.
2
Department of Physiology II, Kanazawa Medical University, Uchinada, Ishikawa 920-0293, Japan.
3
Department of Cell Metabolism and Nutrition, Brain/Liver Interface Medicine Research Center, Kanazawa University, Kanazawa, Ishikawa 920-8641, Japan.
4
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.
5
Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Hyogo 650-0017, Japan.
6
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.
7
Department of Molecular Metabolic Regulation, Diabetes Research Center, Research Institute, National Center for Global Health and Medicine, Tokyo 162-8655, Japan.
8
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.
9
Department of Neurology, Respirology, Endocrinology, and Metabolism, Faculty of Internal Medicine, University of Miyazaki, Miyazaki, Miyazaki 889-1692, Japan.
10
Department of Disease Control and Homeostasis, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Ishikawa 920-8641, Japan.
11
National Center for Global Health and Medicine, Tokyo 162-8655, Japan.
12
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.

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.

PMID:
26947072
DOI:
10.1016/j.celrep.2016.02.032
[Indexed for MEDLINE]
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