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The Glucagon Receptor Is Required for the Adaptive Metabolic Response to Fasting
Open accessAbstract
Glucagon receptor (Gcgr) signaling maintains hepatic glucose production during the fasting state; however, the importance of the Gcgr for lipid metabolism is unclear. We show here that fasted Gcgr-/- mice exhibit a significant increase in hepatic triglyceride secretion and fasting increases fatty acid oxidation (FAO) in wild-type (WT) but not in Gcgr-/- mice. Moreover fasting upregulated the expression of FAO-related hepatic mRNA transcripts in Gcgr+/+ but not in Gcgr-/- mice. Exogenous glucagon administration reduced plasma triglycerides in WT mice, inhibited TG synthesis and secretion, and stimulated FA beta oxidation in Gcgr+/+ hepatocytes. The actions of glucagon on TG synthesis and FAO were abolished in PPARalpha-/- hepatocytes. These findings demonstrate that the Gcgr receptor is required for control of lipid metabolism during the adaptive metabolic response to fasting.
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“Based on these findings, activation of the glucagon receptor may have a favorable effect on the development and treatment of MAFLD, commonly seen in T2DM.”
From New Developments in Pharmacological Treatment of Obesity and Type 2 Diabetes—Beyond and within GLP-1 Receptor Agonists (2024) · cites this paper as [66]
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“In addition to its blood glucose-increasing effect, glucagon activates fat breakdown and inhibits lipogenesis in the liver, reducing concentrations of non-esterified fatty acids and triacylglycerol, and moderating triglyceride content in liver cells in animal experiments [66].”
From New Developments in Pharmacological Treatment of Obesity and Type 2 Diabetes—Beyond and within GLP-1 Receptor Agonists (2024) · cites this paper as [66]
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Metadata
- Authors
- Longuet, C., Sinclair, E. M., Maida, A., Baggio, L. L., Maziarz, M., Charron, M. J., & Drucker, D. J.
- Affiliations
- Mount Sinai Hospital (CA)
- Albert Einstein College of Medicine (US)
- Corresponding author
- Drucker, Daniel J.
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2008-11
- Volume
- 8
- Issue
- 5
- Pages
- 359-371
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC2593715
- OpenAlex
- W2085330452
- Cited by
- 272
- References
- 47
- Citations by year
- 2026: 14 · 2025: 16 · 2024: 23 · 2023: 17 · 2022: 17 · 2021: 16 · 2020: 17 · 2019: 14 · 2018: 10 · 2017: 20 · 2016: 10 · 2015: 19 · 2014: 18 · 2013: 12 · 2012: 20
- FWCI
- 3.98
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Lund University Publications (Lund University) (submittedVersion)
- Funders
- Canadian Institutes of Health Research (10903)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK047425, R01DK47425)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
- Keywords
- glucagon receptor, fasting, hepatic lipid metabolism, fatty acid oxidation, hepatic triglyceride secretion, triglyceride synthesis, PPARα, glucagon, hepatic glucose production
- MeSH terms
- Adaptation, Biological, Animals, Cells, Cultured, Fasting, Fatty Acids, Female, Glucagon, Male, Oxidation-Reduction, RNA, Messenger, Triglycerides, Receptors, Glucagon, Mice, Knockout, Hepatocytes, PPAR alpha, p38 Mitogen-Activated Protein Kinases, Lipid Metabolism, Mice, AMP-Activated Protein Kinases
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