Hepatic muscarinic acetylcholine receptors are not critically involved in maintaining glucose homeostasis in mice.
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.
Li
Jian H
JH
Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA.
Gautam
Dinesh
D
Han
Sung-Jun
SJ
Guettier
Jean-Marc
JM
Cui
Yinghong
Y
Lu
Huiyan
H
Deng
Chuxia
C
O'Hare
James
J
Jou
William
W
Gavrilova
Oksana
O
Buettner
Christoph
C
Wess
Jürgen
J
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
D001786:Blood Glucose; D043587:Receptor, Muscarinic M3; D005947:Glucose