Glucagon receptor antagonism impairs and glucagon receptor agonism enhances triglycerides metabolism in mice
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Objective: Treatment with glucagon receptor antagonists (GRAs) reduces blood glucose but causes dyslipidemia and accumulation of fat in the liver. We investigated the acute and chronic effects of glucagon on lipid metabolism in mice. Methods: Chronic effects of glucagon receptor signaling on lipid metabolism were studied using oral lipid tolerance tests (OLTTs) in overnight fasted glucagon receptor knockout (Gcgr−/−) mice, and in C57Bl/6JRj mice treated with a glucagon receptor antibody (GCGR Ab) or a long-acting glucagon analogue (GCGA) for eight weeks. Following treatment, liver tissue was harvested for RNA-sequencing and triglyceride measurements. Acute effects were studied in C57Bl/6JRj mice treated with a GRA or GCGA 1 h or immediately before OLTTs, respectively. Direct effects of glucagon on hepatic lipolysis were studied using isolated perfused mouse liver preparations. To investigate potential effects of GCGA and GRA on gastric emptying, paracetamol was, in separate experiments, administered immediately before OLTTs. Results: Plasma triglyceride concentrations increased 2-fold in Gcgr−/− mice compared to their wild-type littermates during the OLTT (P = 0.001). Chronic treatment with GCGR Ab increased, whereas GCGA treatment decreased, plasma triglyceride concentrations during OLTTs (P < 0.05). Genes involved in lipid metabolism were upregulated upon GCGR Ab treatment while GCGA treatment had opposite effects. Acute GRA and GCGA treatment, respectively, increased (P = 0.02) and decreased (P = 0.003) plasma triglyceride concentrations during OLTTs. Glucagon stimulated hepatic lipolysis, evident by an increase in free fatty acid concentrations in the effluent from perfused mouse livers. In line with this, GCGR Ab treatment increased, while GCGA treatment decreased, liver triglyceride concentrations. The effects of glucagon appeared independent of changes in gastric emptying of paracetamol. Conclusions: Glucagon receptor signaling regulates triglyceride metabolism, both chronically and acutely, in mice. These data expand glucagon´s biological role and implicate that intact glucagon signaling is important for lipid metabolism. Glucagon agonism may have beneficial effects on hepatic and peripheral triglyceride metabolism.
|Status||Udgivet - 2022|
We thank Maureen J. Charron, Departments of Biochemistry, Obstetrics and Gynecology and Women's Health, and Medicine, Albert Einstein College of Medicine, New York, for providing glucagon receptor knockout mice. We thank Jesper Lau, Novo Nordisk A/S, Måløv, Denmark, for providing the glucagon receptor antagonist 26-2548. We thank Regeneron for providing the antibodies REGN1193 and REGN1945. We thank laboratory technician Heidi Marie Paulsen for preparation and staining of liver slices and Associate Professor Jens Brings Jacobsen for access to his microscope. We thank laboratory technician Christine Rasmussen for assistance at the Department of Clinical Biochemistry, Rigshospitalet. The graphical abstract is created with BioRender.com.
The project is supported by grants from the The A.P. Møller Foundation; NNF Tandem Programme (NNF Application Number: 31526); NNF Project Support in Endocrinology and Metabolism–Nordic Region (NNF Application Number: 34250). Associate Prof. Nicolai J. Wewer Albrechtsen is supported by NNF Excellence Emerging Investigator Grant – Endocrinology and Metabolism (Application No. NNF19OC0055001), EFSD Future Leader Award (NNF21SA0072746) and DFF Sapere Aude (1052-00003B). NNF Center for Protein Research is supported financially by the NNF (grant agreement NNF14CC0001). Prof. Jens Juul Holst is supported by the Novo Nordisk Foundation (NNF) Center for Basic Metabolic Research University of Copenhagen (NNF Application Number: 13563). Emilie Elmelund is supported by the Novo Scholarship Program (2022). Some of the data were presented at American Diabetes Association’s 82nd Scientific Session, June 3rd–7th, New Orleans, LA, USA.
© 2022 The Author(s)