Accute effect of a dual-acting GLP-1R/GCGR agonist in inducing WAT lipolysis and BAT activation in obese mice

Trabajo presentado en EMBO MEETING: Organ Cross-talk in Energy Balance and Metabolic Disease, celebrado en Chiclana, Cádiz (España), del 8 al 11 de abril de 2019.The increasing incidence of obesity and type 2 diabeles worldwide has prompted the need for new therapies. We have recently reported the beneficial role of G49, an oxymomodulin-like dual­acting GLP-1 R/GCGR agonist, in rodent models of non-alcoholic steatohepatitis. In this study, we have investigated the acute effcts of G49 in preventing diet-induced obesity in mice. Eight 8-week ­ old male C5781/6j mice were fed a chow or HFD for 12 weeks followed by injection of G49 (4,4 mg/kg s.c.) every 2 days. Parameters that assess obesity, BAT activation, and lipolysis were analyzed from one hour to 7 days after injection . G49 injected mice showed a 14.5±2.8% reduction of the initial body weight and decreased adiposity at day 7 concurrent with an early and transien elevation in plasma free fatty acids at 6 h after the first injection. The analysis of e\VAT revealed an increase in Adipoq and UCPl mR.t>\JA levels peaking at 48-72 h post-injection. Moreover, an increase in Ucpl mRNA levels and UCP I protein immunostaining was detected in BAT at 48 h. These data were confirmed by elevation of iBAT temperature reflecting a rapid BAT activation that was al o assessed by Seahorse analysis and fatty acid oxidation in brown adipocytes. lnterestingly, G49 injection induced a transient increase in liver triglyceride levels with a peak at 6 h (42.2± 1 .7 mg/mg liver lissue) that was reduced to leve\s of control mice fod a cbow diet ( 13±1.9 mglmg/ liver ti ssue) at 24 h which paralleled with a transiem elevation in plasma triglyceride levels from 12 to 24 h post-injection. Moreover, in G49-injceted mice we found an increase in Fgf21 and Hmgcs2 mRNA levels in the liver aud elevated plasma ketone bodies (0.8 Hm101Jl) at 48 h