期刊
CIRCULATION
卷 127, 期 1, 页码 74-+出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCULATIONAHA.112.091215
关键词
obesity; heart; glucagon-like peptide-1; inflammation; connexin-43; AMP-activated protein kinase
资金
- Heart and Stroke Foundation of Ontario (HSFO) [T6757, NA6997, CI6824]
- Novo Nordisk Inc.
- Canada Research Chair in Regulatory Peptides
- Banting and Best Diabetes Center-Novo Nordisk Chair in Incretin Biology
- Canadian Institutes of Health Research (CIHR) [MOP-114922]
- Canada Research Chair in Diabetes Research
- NovoNordisk
- Merck Co.
Background-Cardiac consequences of obesity include inflammation, hypertrophy, and compromised energy metabolism. Glucagon-like peptide-1 is an incretin hormone capable of cytoprotective actions that reduces inflammation and endoplasmic reticulum stress in other tissues. Here we examine the cardiac effects of the glucagon-like peptide-1 analog liraglutide in a model of obesity, independent of changes in body weight. Methods and Results-C57Bl6 mice were placed on a 45% high-fat diet (HFD) or a regular chow diet. Mice on HFD developed 46 +/- 2% and 60 +/- 2% greater body weight relative to regular chow diet-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 mu g/kg twice daily) did not reduce body weight, but reversed insulin resistance, cardiac tumor necrosis factor-alpha expression, nuclear factor kappa B translocation, obesity-induced perturbations in cardiac endothelial nitric oxide synthase, connexin-43, and markers of hypertrophy and fibrosis, in comparison with placebo-treated HFD controls. Liraglutide improved the cardiac endoplasmic reticulum stress response and also improved cardiac function in animals on HFD by an AMP-activated protein kinase-dependent mechanism. Supporting a direct mechanism of action, liraglutide (100 nmol/L) prevented palmitate-induced lipotoxicity in isolated mouse cardiomyocytes and primary human coronary smooth muscle cells and prevented adhesion of human monocytes to tumor necrosis factor-alpha-activated human endothelial cells in vitro. Conclusions-Weight-neutral treatment with a glucagon-like peptide-1 analog activates several cardioprotective pathways, prevents HFD-induced insulin resistance and inflammation, reduces monocyte vascular adhesion, and improves cardiac function in vivo by activating AMP-activated protein kinase. These data support a role for glucagon-like peptide-1 analogs in limiting the cardiovascular risks of obesity. (Circulation. 2013;127:74-85.)
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