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

BackgroundCardiovascular 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).MethodsMale 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.ResultsHFHSD 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).ConclusionCMR 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12968-015-0198-x) contains supplementary material, which is available to authorized users.

Cardiovascular magnetic resonance detects the progression of impaired myocardial perfusion reserve and increased left-ventricular mass in mice fed a high-fat diet

“…Several factors such as myocardial lipid accumulation and lipotoxicity may contribute to the increased cardiac fibrosis observed in the mice fed a high-fat diet. A recent study by Abdesselam et al [50] showed increased myocardial lipid accumulation along with increased cardiac fibrosis in mice fed a high-fat and high-sucrose diet. Furthermore, Glenn et al [44] showed increased cardiac fibrosis in a mouse model of cardiac steatosis.…”

Exenatide decreases liver fat content and epicardial adipose tissue in patients with obesity and type 2 diabetes: a prospective randomized clinical trial using magnetic resonance imaging and spectroscopy

“…Multiple animal studies have shown beneficial effects of GLP‐1 RAs on ectopic fat development. In mice, they have been shown to decrease myocardial steatosis and fibrosis, to improve myocardial function and perfusion, and to decrease hepatic steatosis . These effects were shown to be both indirect, through benefit on weight loss and glycaemic improvement, and direct, through the activation of the GLP‐1 receptor, modulating key elements of the insulin signalling pathway, lipid peroxidation (oxidative stress) and hepatic de novo lipogenesis .…”

Glucagon-like peptide-1, glucagon-like peptide-2, and lipid metabolism

“…Exendin-4 or liraglutide has been shown to reduce the occurrence and degree of hepatic steatosis independent of their action on body weight [47]. These effects were observed in experimental animals but also in the clinical setting.…”