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Hepatic muscarinic acetylcholine receptors are not critically involved in maintaining glucose homeostasis in mice.

Diabetes | Dec 26, 2009

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.

Pubmed ID: 19752163 RIS Download

Mesh terms: Animals | Blood Glucose | Blotting, Western | Glucose | Hepatocytes | Kupffer Cells | Liver | Male | Mice | Mice, Inbred C57BL | Mice, Knockout | Mice, Transgenic | Phenotype | Receptor, Muscarinic M3 | Reverse Transcriptase Polymerase Chain Reaction | Signal Transduction | Up-Regulation

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Associated grants

  • Agency: NIDDK NIH HHS, Id: DK074873
  • Agency: NIDDK NIH HHS, Id: R03 DK082724
  • Agency: Intramural NIH HHS, Id: DK082724
  • Agency: NIDDK NIH HHS, Id: K08 DK074873
  • Agency: NIDDK NIH HHS, Id: R01 DK083658
  • Agency: NIDDK NIH HHS, Id:

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Intramural Research Program

A research program of the NIA which focuses on neuroscience, aging biology, and translational gerontology. The central focus of the program's research is understanding age-related changes in physiology and the ability to adapt to environmental stress, and using that understanding to develop insight about the pathophysiology of age-related diseases. The IRP webpage provides access to other NIH resources such as the Biological Biochemical Image Database, the Bioinformatics Portal, and the Baltimore Longitudinal Study of Aging.

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