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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 sug...
Autores principales: | , , , , , , , , , , , |
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Formato: | Texto |
Lenguaje: | English |
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American Diabetes Association
2009
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2780871/ https://www.ncbi.nlm.nih.gov/pubmed/19752163 http://dx.doi.org/10.2337/db09-0522 |
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author | Li, Jian H. Gautam, Dinesh Han, Sung-Jun Guettier, Jean-Marc Cui, Yinghong Lu, Huiyan Deng, Chuxia O'Hare, James Jou, William Gavrilova, Oksana Buettner, Christoph Wess, Jürgen |
author_facet | Li, Jian H. Gautam, Dinesh Han, Sung-Jun Guettier, Jean-Marc Cui, Yinghong Lu, Huiyan Deng, Chuxia O'Hare, James Jou, William Gavrilova, Oksana Buettner, Christoph Wess, Jürgen |
author_sort | Li, Jian H. |
collection | PubMed |
description | 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 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. |
format | Text |
id | pubmed-2780871 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2009 |
publisher | American Diabetes Association |
record_format | MEDLINE/PubMed |
spelling | pubmed-27808712010-12-01 Hepatic Muscarinic Acetylcholine Receptors Are Not Critically Involved in Maintaining Glucose Homeostasis in Mice Li, Jian H. Gautam, Dinesh Han, Sung-Jun Guettier, Jean-Marc Cui, Yinghong Lu, Huiyan Deng, Chuxia O'Hare, James Jou, William Gavrilova, Oksana Buettner, Christoph Wess, Jürgen Diabetes Original Article 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 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. American Diabetes Association 2009-12 2009-09-14 /pmc/articles/PMC2780871/ /pubmed/19752163 http://dx.doi.org/10.2337/db09-0522 Text en © 2009 American Diabetes Association Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details. |
spellingShingle | Original Article Li, Jian H. Gautam, Dinesh Han, Sung-Jun Guettier, Jean-Marc Cui, Yinghong Lu, Huiyan Deng, Chuxia O'Hare, James Jou, William Gavrilova, Oksana Buettner, Christoph Wess, Jürgen Hepatic Muscarinic Acetylcholine Receptors Are Not Critically Involved in Maintaining Glucose Homeostasis in Mice |
title | Hepatic Muscarinic Acetylcholine Receptors Are Not Critically Involved in Maintaining Glucose Homeostasis in Mice |
title_full | Hepatic Muscarinic Acetylcholine Receptors Are Not Critically Involved in Maintaining Glucose Homeostasis in Mice |
title_fullStr | Hepatic Muscarinic Acetylcholine Receptors Are Not Critically Involved in Maintaining Glucose Homeostasis in Mice |
title_full_unstemmed | Hepatic Muscarinic Acetylcholine Receptors Are Not Critically Involved in Maintaining Glucose Homeostasis in Mice |
title_short | Hepatic Muscarinic Acetylcholine Receptors Are Not Critically Involved in Maintaining Glucose Homeostasis in Mice |
title_sort | hepatic muscarinic acetylcholine receptors are not critically involved in maintaining glucose homeostasis in mice |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2780871/ https://www.ncbi.nlm.nih.gov/pubmed/19752163 http://dx.doi.org/10.2337/db09-0522 |
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