Hepatic Muscarinic Acetylcholine Receptors Are Not Critically Involved in Maintaining Glucose Homeostasis in Mice
Hepatic Muscarinic Acetylcholine Receptors Are Not Critically Involved in Maintaining Glucose Homeostasis in Mice Jian H. Li 1 , Dinesh Gautam 1 , Sung-Jun Han 1 , Jean-Marc Guettier 1 , Yinghong Cui 1 , Huiyan Lu 2 , Chuxia Deng 3 , James O'Hare 4 , William Jou 5 , Oksana Gavrilova 5 , Christo...
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Veröffentlicht in: | Diabetes (New York, N.Y.) N.Y.), 2009-12, Vol.58 (12), p.2776-2787 |
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Zusammenfassung: | Hepatic Muscarinic Acetylcholine Receptors Are Not Critically Involved in Maintaining Glucose Homeostasis in Mice
Jian H. Li 1 ,
Dinesh Gautam 1 ,
Sung-Jun Han 1 ,
Jean-Marc Guettier 1 ,
Yinghong Cui 1 ,
Huiyan Lu 2 ,
Chuxia Deng 3 ,
James O'Hare 4 ,
William Jou 5 ,
Oksana Gavrilova 5 ,
Christoph Buettner 4 and
Jürgen Wess 1
1 Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases,
National Institutes of Health, Bethesda, Maryland;
2 Mouse Transgenic Core Facility, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health,
Bethesda, Maryland;
3 Mammalian Genetics Section, Genetics of Development and Diseases Branch, National Institute of Diabetes and Digestive and
Kidney Diseases, National Institutes of Health, Bethesda, Maryland;
4 Departments of Medicine and Neuroscience, Mount Sinai School of Medicine, New York, New York;
5 Mouse Metabolic Core Facility, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health,
Bethesda, Maryland.
Corresponding author: Jürgen Wess, jwess{at}helix.nih.gov .
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.
RESEARCH DESIGN AND 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 exp |
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ISSN: | 0012-1797 1939-327X |
DOI: | 10.2337/db09-0522 |