Jamie I. van der Vaart1, Robin van Eenige1, Patrick C.N. Rensen1, Sander Kooijman1
(1) Dept. of Medicine, Div. of Endocrinology, and Einthoven Laboratory for Experimental Vascular Medicine, LUMC, Leiden, Leiden University Medical Centre (LUMC), Leiden, The Netherlands.
Introduction
Glucagon is well studied for its effects on glucose metabolism but its actions on lipid metabolism are less defined. Interestingly, emerging evidence suggests glucagon promotes hepatic fatty acid oxidation and potentially influences lipid fluxes. This study evaluated the effects of a long-acting glucagon receptor agonist on lipid fluxes in the context of obesity.
Methods
Diet-induced obese male C57BL/6N mice were fed a Western diet (40% fat, 40% sucrose) and treated daily with a glucagon receptor agonist (GFA-015; 10 nmol/kg) or vehicle for 2 weeks. During which, body weight, body composition, and energy expenditure were monitored. Subsequently, mice were treated every three days for 2 weeks, after which 4 h-fasted plasma triglyceride (TG) levels VLDL production and VLDL catabolism were assessed.
Results
Compared to vehicle, daily treatment with glucagon receptor agonist reduced fat mass (-31%), lean mass (-16%) and food intake (-15%), while increasing energy expenditure (+7,5%). Interestingly, while reducing hepatic TG levels (-47%) the agonist increased plasma TG levels (+64%) upon treatment every three days. Mechanistically, the glucagon receptor agonist did not impact clearance VLDL-like particles, but enhanced VLDL-ApoB production (+51%) while decreasing VLDL-TG (-18%) production.
Conclusions
Long-acting glucagon receptor agonism increases plasma TG levels, accompanied by hepatic overproduction of lipid-poor VLDL particles. We anticipate that smaller VLDL particles are lipolyzed less efficiently by lipoprotein lipase on peripheral tissues, thereby increasing circulating TG levels. An increase in circulating TG levels should be considered in the development of glucagon receptor agonists for the treatment of obesity.