A Glucagon-Like Peptide-1 Analogue Reverses the Molecular Pathology and Cardiac Dysfunction of a Mouse Model of Obesity
Background—Cardiac consequences of obesity include inflammation, hypertrophy, and compromised energy metabolism. Glucagon-like peptide-1 (GLP-1) is an incretin hormone capable of cytoprotective actions that reduces inflammation and endoplasmic reticulum (ER) stress in other tissues. Here we examine the cardiac effects of the GLP-1 analogue liraglutide in a model of obesity, independent of changes in body weight.
Methods and Results—C57Bl6 mice were placed on 45% high fat (HFD) or regular chow diet (RD). Mice on HFD developed 46±2% and 60±2% greater body weight relative to RD-fed mice at 16 and 32 weeks respectively (both p<0.0001), manifesting impaired glucose tolerance, insulin resistance and cardiac ceramide accumulation by 16 weeks. One week treatment with liraglutide (30 μg/kg twice daily) did not reduce body weight, but reversed insulin resistance, cardiac TNF-α expression, NFκB translocation, obesity-induced perturbations in cardiac eNOS, connexin-43 and markers of hypertrophy and fibrosis, as compared to placebo-treated HFD controls. Liraglutide improved the cardiac ER-stress response, and also improved cardiac function in animals on HFD by an AMPK (AMP-activated protein kinase)-dependent mechanism. Supporting a direct mechanism of action, liraglutide (100 nM) prevented palmitate-induced lipotoxicity in isolated mouse cardiomyocytes and primary human coronary smooth muscle cells, and prevented adhesion of human monocytes to TNF-α-activated human endothelial cells in vitro.
Conclusions—Weight-neutral treatment with a GLP-1 analogue activates several cardioprotective pathways, prevents HFD-induced insulin-resistance and inflammation, reduces monocyte vascular adhesion and improves cardiac function in vivo by activating AMPK. These data support a role for GLP-1 analogues in limiting the cardiovascular risks of obesity.
- AMP-activated protein kinase signal transduction
- glucagon-like peptide
- Received January 5, 2012.
- Accepted November 16, 2012.
- 05 1 2012 16 11 2012
- Copyright © 2012, American Heart Association, Inc. All rights reserved. Unauthorized use prohibited