Glucagon receptor antagonism impairs and glucagon receptor agonism enhances triglycerides metabolism in mice

Katrine D Galsgaard; Emilie Elmelund; Christian D Johansen; Anna B Bomholt; Hüsün S Kizilkaya; Frederik Ceutz; Jenna E Hunt; Hannelouise Kissow; Marie Winther-Sørensen; Charlotte M Sørensen; Thomas Kruse; Jesper F Lau; Mette M Rosenkilde; Cathrine Ørskov; Christina Christoffersen; Jens J Holst; Nicolai J Wewer Albrechtsen

doi:10.1016/j.molmet.2022.101639

Glucagon receptor antagonism impairs and glucagon receptor agonism enhances triglycerides metabolism in mice

Mol Metab. 2022 Dec:66:101639. doi: 10.1016/j.molmet.2022.101639. Epub 2022 Nov 15.

Authors

Katrine D Galsgaard¹, Emilie Elmelund², Christian D Johansen³, Anna B Bomholt², Hüsün S Kizilkaya², Frederik Ceutz², Jenna E Hunt¹, Hannelouise Kissow², Marie Winther-Sørensen³, Charlotte M Sørensen², Thomas Kruse⁴, Jesper F Lau⁴, Mette M Rosenkilde², Cathrine Ørskov², Christina Christoffersen⁵, Jens J Holst¹, Nicolai J Wewer Albrechtsen⁶

Affiliations

¹ Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
² Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
³ Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Novo Nordisk Foundation Center for Protein Research, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.
⁴ Novo Nordisk A/S, Research Chemistry, Novo Nordisk Park, DK-2760 Måløv, Denmark.
⁵ Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Department of Clinical Biochemistry, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
⁶ Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Novo Nordisk Foundation Center for Protein Research, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark; Department of Clinical Biochemistry, Bispebjerg & Frederiksberg Hospitals, University of Copenhagen, 2400 Bispebjerg, Denmark. Electronic address: nicolai.albrechtsen@sund.ku.dk.

Abstract

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.

Keywords: Cholesterol; Glucagon; Non-esterified/ free fatty acids; Steatosis; Triglycerides.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acetaminophen / pharmacology
Animals
Glucagon* / metabolism
Lipid Metabolism / physiology
Mice
Mice, Inbred C57BL
Receptors, Glucagon* / metabolism
Triglycerides* / blood
Triglycerides* / metabolism

Substances

Acetaminophen
Glucagon
Receptors, Glucagon
Triglycerides