title: Hepatic muscarinic acetylcholine receptors are not critically involved in maintaining glucose homeostasis in mice.
abstract: OBJECTIVE
  An increase in the rate of hepatic glucose production is the major determinant of fasting hyperglycemia in type 2 diabetes. A better understanding of the signaling pathways and molecules that regulate hepatic glucose metabolism is therefore of great clinical importance. Recent studies suggest that an increase in vagal outflow to the liver leads to decreased hepatic glucose production and reduced blood glucose levels. Since acetylcholine (ACh) is the major neurotransmitter of the vagus nerve and exerts its parasympathetic actions via activation of muscarinic ACh receptors (mAChRs), we examined the potential metabolic relevance of hepatocyte mAChRs.
  
  
  METHODS
  We initially demonstrated that the M(3) mAChR is the only mAChR subtype expressed by mouse liver/hepatocytes. To assess the physiological role of this receptor subtype in regulating hepatic glucose fluxes and glucose homeostasis in vivo, we used gene targeting and transgenic techniques to generate mutant mice lacking or overexpressing M(3) receptors in hepatocytes only.
  
  
  RESULTS
  Strikingly, detailed in vivo phenotyping studies failed to reveal any significant metabolic differences between the M(3) receptor mutant mice and their control littermates, independent of whether the mice were fed regular or a high-fat diet. Moreover, the expression levels of genes for various key transcription factors, signaling molecules, and enzymes regulating hepatic glucose fluxes were not significantly altered in the M(3) receptor mutant mice.
  
  
  CONCLUSIONS
  This rather surprising finding suggests that the pronounced metabolic effects mediated by activation of hepatic vagal nerves are mediated by noncholinergic signaling pathways.
authors.affiliation: Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Jian H
authors.initials: JH
authors.lastname: Li
authors.forename: Dinesh
authors.initials: D
authors.lastname: Gautam
authors.forename: Sung-Jun
authors.initials: SJ
authors.lastname: Han
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Guettier
authors.forename: Yinghong
authors.initials: Y
authors.lastname: Cui
authors.forename: Huiyan
authors.initials: H
authors.lastname: Lu
authors.forename: Chuxia
authors.initials: C
authors.lastname: Deng
authors.forename: James
authors.initials: J
authors.lastname: O'Hare
authors.forename: William
authors.initials: W
authors.lastname: Jou
authors.forename: Oksana
authors.initials: O
authors.lastname: Gavrilova
authors.forename: Christoph
authors.initials: C
authors.lastname: Buettner
authors.forename: Jürgen
authors.initials: J
authors.lastname: Wess
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D015153:Blotting, Western; D005947:Glucose / Q000378:metabolism*; D022781:Hepatocytes / Q000378:metabolism*; D007728:Kupffer Cells / Q000378:metabolism*; D008099:Liver / Q000166:cytology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010641:Phenotype; D043587:Receptor, Muscarinic M3 / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D015854:Up-Regulation
chemical_list: D001786:Blood Glucose; D043587:Receptor, Muscarinic M3; D005947:Glucose