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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

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