Authors & affiliations:
Jamie I. van der Vaart1,2, Mariëtte R. Boon1,2, Tamer Coskun3, Patrick C.N. Rensen1,2, Sander Kooijman1,2, Robin van Eenige1,2
1Dept. of Medicine, Div. of Endocrinology; 2Einthoven Laboratory for Experimental Vascular Medicine; 3Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN, United States
Background and aim:
Glucagon is well-studied for its role in glucose homeostasis, including processes such as glycogenolysis and gluconeogenesis, but its involvement in lipid metabolism remains less explored. Current evidence indicates that glucagon stimulates fatty acid oxidation in the liver, leading to lower circulating triglyceride (TG) levels. This study isaimed at evaluating the effects of a long-acting glucagon receptor agonist on lipid fluxes.
Methods:
Diet-induced obese male C57BL/6N mice were fed a Western diet (40% fat, 40% sucrose) and were treated every three days with a glucagon receptor agonist (GFA-015; 10 nmol/kg) or vehicle for 2 weeks. Body weight, body composition, and 4h-fasted plasma triglyceride levels were monitored throughout the study. At the end of the treatment period,VLDL production and VLDL catabolism were assessed.
Results:
Compared with vehicle treatment, GFA-015 treatment reduced fat mass (-16%), without affecting food intake. Interestingly, GFA-015 increased plasma triglyceride levels (+64%). Mechanistically, GFA-015 did not impact plasma clearance of intravenous injectedVLDL-like particles, but enhanced VLDL-ApoB production (+51%) while decreasing VLDL-TG (-18%) production.
Conclusion:
Our preliminary results show that long-acting glucagon receptor agonism increases plasma TG levels, accompanied by hepatic overproduction of lipid-poor VLDL particles. We anticipate that smaller VLDL are lipolyzed less efficiently by lipoprotein lipase (LPL) on peripheral tissues, thereby increasing circulating TG levels.