Abstract 19477: The Glucagon-Like Peptide-1 Receptor Agonist Liraglutide Reduces Inflammation and Improves Cardiac Function in a Mouse Model of Obesity
Background: Obesity contributes to diabetes, hypertension and cardiovascular disease. Glucagon-like peptide-1 receptor (GLP-1R) activation has been shown to prevent injury in several tissues. Here we test if the GLP-1R agonist liraglutide alters cardiac pathophysiology in a high-fat diet (HFD) model of obesity.
Methods: Male 8 wk old C57bl/6 mice were fed a HFD (45% calories) or regular chow for 16 (16HFD) or 32 (32HFD) wks prior to a 1 wk treatment with a weight-neutral dose of liraglutide (30 μg/kg bid sc) or placebo (PBS bid sc). Hearts from control and 16HFD mice (N=10/group) underwent Western blot and immunohistochemistry for analysis of signalling pathways, eNOS, ER-stress and inflammation. Control and 32HFD mice (N=6/group) underwent echocardiography before and after treatment. Effects of liraglutide (100 μM) on inflammatory cell-adhesion were examined using calcein AM-labelled THP-1 human monocytic cells and TNFα-activated human umbilical vein endothelial cells (HUVEC).
Results: 16HFD and 32HFD mice were 38% and 28% heavier than controls (both P=0.0001). Liraglutide reduced blood glucose levels in obese mice (-2.1 mM; P=0.001), having no effect in lean controls. Liraglutide for 1 wk had no effect on levels of phospho-Akt/PkB, GLP-1R, PGC-1α or mitochondrial enzymes, cytochrome C and COX-IV in obese mice, but corrected HFD-induced hypophosphorylation of GSK-3β and ERK, down-regulation of eNOS, and the unfolded protein response (UPR). Liraglutide also reduced markers of cardiac inflammation, such as TNF-α and macrophage-associated F4/80. In 32HFD mice, liraglutide improved indices of cardiac function (%FS, EF, CO) in both obese and lean controls (Obese: FS% +13%; EF: +16%; CO: +3.4 ml/min. Lean: %FS: +13%; EF: +18%; CO: +2.0 ml/min. P<0.05 for all comparisons). Liraglutide decreased the adhesion of THP-1 cells to HUVEC (2721±204 vs. 4685±315; P<0.05), an effect blocked by the GLP-1R antagonist GLP-1(9-39) (4126±284; P=NS).
Conclusions: In a HFD-induced model of obesity, a weight-neutral dose of the GLP-1R agonist liraglutide ameliorated disturbed signalling pathways, ER-stress, and markers of tissue inflammation, improving cardiac function in vivo. GLP-1R activation also prevented adhesion of THP-1 cells to activated HUVEC in vitro.
- © 2010 by American Heart Association, Inc.