A glucagon-like peptide-1 analog reverses the molecular pathology and cardiac dysfunction of a mouse model of obesity.

Abstract

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 µg/kg twice daily) did not reduce body weight, but reversed insulin resistance, cardiac tumor necrosis factor-α 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-α-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.

• Authors: Mohammad Hossein Noyan-Ashraf, Eric Akihiko Shikatani, Irmgard Schuiki, Ilya Mukovozov, Jun Wu, Ren-Ke Li, Allen Volchuk, Lisa Annette Robinson, Filio Billia, Daniel J Drucker, Mansoor Husain
• Journal: Circulation (Circulation) Vol. 127 Issue 1 Pg. 74-85 (Jan 01 2013) ISSN: 1524-4539 [Electronic] United States
• PMID: 23186644 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Blood Glucose
• Cardiotonic Agents
• Connexin 43
• Tumor Necrosis Factor-alpha
• Liraglutide
• Glucagon-Like Peptide 1
• Nitric Oxide Synthase Type III
• Nos3 protein, mouse

Topics

• Animals
• Blood Glucose (drug effects)
• Cardiotonic Agents (pharmacology)
• Cell Line
• Connexin 43 (genetics)
• Coronary Vessels (cytology)
• Disease Models, Animal
• Endoplasmic Reticulum Stress (drug effects)
• Endothelial Cells (cytology, drug effects)
• Gene Expression (drug effects)
• Glucagon-Like Peptide 1 (analogs & derivatives, pharmacology)
• Heart Diseases (epidemiology, prevention & control)
• Humans
• Hypercholesterolemia (drug therapy, epidemiology)
• Insulin Resistance
• Liraglutide
• Mice
• Mice, Inbred C57BL
• Monocytes (cytology, drug effects)
• Muscle, Smooth, Vascular (cytology, drug effects)
• Myocytes, Cardiac (cytology, drug effects)
• Nitric Oxide Synthase Type III (genetics)
• Obesity (drug therapy, epidemiology)
• Risk Factors
• Signal Transduction (drug effects)
• Tumor Necrosis Factor-alpha (metabolism)