title: 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.
  
  
  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.affiliation: Toronto General Research Institute, Toronto, Canada.
authors.forename: Mohammad Hossein
authors.initials: MH
authors.lastname: Noyan-Ashraf
authors.forename: Eric Akihiko
authors.initials: EA
authors.lastname: Shikatani
authors.forename: Irmgard
authors.initials: I
authors.lastname: Schuiki
authors.forename: Ilya
authors.initials: I
authors.lastname: Mukovozov
authors.forename: Jun
authors.initials: J
authors.lastname: Wu
authors.forename: Ren-Ke
authors.initials: RK
authors.lastname: Li
authors.forename: Allen
authors.initials: A
authors.lastname: Volchuk
authors.forename: Lisa Annette
authors.initials: LA
authors.lastname: Robinson
authors.forename: Filio
authors.initials: F
authors.lastname: Billia
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Drucker
authors.forename: Mansoor
authors.initials: M
authors.lastname: Husain
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D002316:Cardiotonic Agents / Q000494:pharmacology*; D002460:Cell Line; D018031:Connexin 43 / Q000235:genetics; D003331:Coronary Vessels / Q000166:cytology; D004195:Disease Models, Animal; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects; D052216:Glucagon-Like Peptide 1 / Q000031:analogs & derivatives* / Q000494:pharmacology; D006331:Heart Diseases / Q000453:epidemiology / Q000517:prevention & control*; D006801:Humans; D006937:Hypercholesterolemia / Q000188:drug therapy / Q000453:epidemiology; D007333:Insulin Resistance; D000069450:Liraglutide; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000166:cytology / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects; D052250:Nitric Oxide Synthase Type III / Q000235:genetics; D009765:Obesity / Q000188:drug therapy* / Q000453:epidemiology; D012307:Risk Factors; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D002316:Cardiotonic Agents; D018031:Connexin 43; D014409:Tumor Necrosis Factor-alpha; D000069450:Liraglutide; D052216:Glucagon-Like Peptide 1; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse