title: Time course of cardiometabolic alterations in a high fat high sucrose diet mice model and improvement after GLP-1 analog treatment using multimodal cardiovascular magnetic resonance.
abstract: BACKGROUND
  Cardiovascular complications of obesity and diabetes are major health problems. Assessing their development, their link with ectopic fat deposition and their flexibility with therapeutic intervention is essential. The aim of this study was to longitudinally investigate cardiac alterations and ectopic fat accumulation associated with diet-induced obesity using multimodal cardiovascular magnetic resonance (CMR) in mice. The second objective was to monitor cardiac response to exendin-4 (GLP-1 receptor agonist).
  
  
  METHODS
  Male C57BL6R mice subjected to a high fat (35 %) high sucrose (34 %) (HFHSD) or a standard diet (SD) during 4 months were explored every month with multimodal CMR to determine hepatic and myocardial triglyceride content (HTGC, MTGC) using proton MR spectroscopy, cardiac function with cine cardiac MR (CMR) and myocardial perfusion with arterial spin labeling CMR. Furthermore, mice treated with exendin-4 (30 μg/kg SC BID) after 4 months of diet were explored before and 14 days post-treatment with multimodal CMR.
  
  
  RESULTS
  HFHSD mice became significantly heavier (+33 %) and displayed glucose homeostasis impairment (1-month) as compared to SD mice, and developed early increase in HTGC (1 month, +59 %) and MTGC (2-month, +63 %). After 3 months, HFHSD mice developed cardiac dysfunction with significantly higher diastolic septum wall thickness (sWtnD) (1.28 ± 0.03 mm vs. 1.12 ± 0.03 mm) and lower cardiac index (0.45 ± 0.06 mL/min/g vs. 0.68 ± 0.07 mL/min/g, p = 0.02) compared to SD mice. A significantly lower cardiac perfusion was also observed (4 months:7.5 ± 0.8 mL/g/min vs. 10.0 ± 0.7 mL/g/min, p = 0.03). Cardiac function at 4 months was negatively correlated to both HTGC and MTGC (p < 0.05). 14-day treatment with Exendin-4 (Ex-4) dramatically reversed all these alterations in comparison with placebo-treated HFHSD. Ex-4 diminished myocardial triglyceride content (-57.8 ± 4.1 %), improved cardiac index (+38.9 ± 10.9 %) and restored myocardial perfusion (+52.8 ± 16.4 %) under isoflurane anesthesia. Interestingly, increased wall thickness and hepatic steatosis reductions were independent of weight loss and glycemia decrease in multivariate analysis (p < 0.05).
  
  
  CONCLUSIONS
  CMR longitudinal follow-up of cardiac consequences of obesity and diabetes showed early accumulation of ectopic fat in mice before the occurrence of microvascular and contractile dysfunction. This study also supports a cardioprotective effect of glucagon-like peptide-1 receptor agonist.
authors.affiliation: Aix-Marseille Université, CNRS, CRMBM, UMR7339, 27, Bd Jean Moulin, 13385, Marseille, France.|Aix-Marseille Université, NORT, Inserm U1062/Inra1260, 13385, Marseille, France.
authors.forename: Inès
authors.initials: I
authors.lastname: Abdesselam
authors.affiliation: Aix-Marseille Université, CNRS, CRMBM, UMR7339, 27, Bd Jean Moulin, 13385, Marseille, France.
authors.forename: Pauline
authors.initials: P
authors.lastname: Pepino
authors.affiliation: Aix-Marseille Université, CNRS, CRMBM, UMR7339, 27, Bd Jean Moulin, 13385, Marseille, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Troalen
authors.affiliation: Aix-Marseille Université, CNRS, CRMBM, UMR7339, 27, Bd Jean Moulin, 13385, Marseille, France.
authors.forename: Michael
authors.initials: M
authors.lastname: Macia
authors.affiliation: Aix-Marseille Université, NORT, Inserm U1062/Inra1260, 13385, Marseille, France.
authors.forename: Patricia
authors.initials: P
authors.lastname: Ancel
authors.affiliation: Aix-Marseille Université, CNRS, CRMBM, UMR7339, 27, Bd Jean Moulin, 13385, Marseille, France.
authors.forename: Brice
authors.initials: B
authors.lastname: Masi
authors.affiliation: Aix-Marseille Université, CNRS, CRMBM, UMR7339, 27, Bd Jean Moulin, 13385, Marseille, France.
authors.forename: Natacha
authors.initials: N
authors.lastname: Fourny
authors.affiliation: Aix-Marseille Université, NORT, Inserm U1062/Inra1260, 13385, Marseille, France.|Endocrinology, Metabolic diseases and nutrition, CHU Nord, Marseille, France.
authors.forename: Bénédicte
authors.initials: B
authors.lastname: Gaborit
authors.affiliation: Aix-Marseille Université, CNRS, CRMBM, UMR7339, 27, Bd Jean Moulin, 13385, Marseille, France.
authors.forename: Benoît
authors.initials: B
authors.lastname: Giannesini
authors.affiliation: Aix-Marseille Université, CNRS, CRMBM, UMR7339, 27, Bd Jean Moulin, 13385, Marseille, France.
authors.forename: Frank
authors.initials: F
authors.lastname: Kober
authors.affiliation: Aix-Marseille Université, NORT, Inserm U1062/Inra1260, 13385, Marseille, France.|Endocrinology, Metabolic diseases and nutrition, CHU Nord, Marseille, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Dutour
authors.affiliation: Aix-Marseille Université, CNRS, CRMBM, UMR7339, 27, Bd Jean Moulin, 13385, Marseille, France. monique.bernard@univ-amu.fr.
authors.forename: Monique
authors.initials: M
authors.lastname: Bernard
mesh_terms: D050154:Adiposity / Q000187:drug effects; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D003326:Coronary Circulation / Q000187:drug effects; D003920:Diabetes Mellitus / Q000097:blood / Q000188:drug therapy* / Q000209:etiology; D059305:Diet, High-Fat; D019422:Dietary Sucrose; D004195:Disease Models, Animal; D000077270:Exenatide; D005234:Fatty Liver / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D052216:Glucagon-Like Peptide 1 / Q000031:analogs & derivatives / Q000494:pharmacology*; D006331:Heart Diseases / Q000097:blood / Q000209:etiology / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D019028:Magnetic Resonance Imaging, Cine; D008297:Male; D008810:Mice, Inbred C57BL; D064847:Multimodal Imaging / Q000379:methods*; D015999:Multivariate Analysis; D009200:Myocardial Contraction / Q000187:drug effects; D055414:Myocardial Perfusion Imaging / Q000379:methods*; D009206:Myocardium / Q000378:metabolism*; D009765:Obesity / Q000097:blood / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D010455:Peptides / Q000494:pharmacology*; D011237:Predictive Value of Tests; D066244:Proton Magnetic Resonance Spectroscopy; D020127:Recovery of Function; D013997:Time Factors; D014280:Triglycerides / Q000378:metabolism; D014688:Venoms / Q000494:pharmacology*; D016276:Ventricular Function / Q000187:drug effects; D015430:Weight Gain / Q000187:drug effects
chemical_list: D001786:Blood Glucose; D019422:Dietary Sucrose; D010455:Peptides; D014280:Triglycerides; D014688:Venoms; D052216:Glucagon-Like Peptide 1; D000077270:Exenatide