Proceedings of The Physiological Society

Europhysiology 2018 (London, UK) (2018) Proc Physiol Soc 41, PCB031

Poster Communications

High fat-load induces cardioprotection in hearts from obese mice

N. Boardman1, T. M. Pedersen1, A. Hafstad1, L. Rossvoll1, E. Aasum1

1. Department of Medical Biology, Univ. of Tromsø - The Arctic University of Norway, Tromsø, Norway.

An ischemic insult is associated with increase circulating fatty acids (FA) due to an adrenergic activation of adipose tissue lipolysis. Therefore, hearts will not only be challenged by hypoxia, but also by an acute FA-load, which have been shown to induce adverse cardiac effects such as mitochondrial dysfunction, oxidative stress, oxygen wasting and inefficiency. Although obesity is a contributing factor to the development of type 2 diabetes and heart failure it remains unclear if and how the obesity-associated chronic hyperlipidemia affects the cardiac response to an acute FA-load. Thus, we have examined the effect of high FA on hearts from a murine model of obesity. Diet-induced obesity (DIO) was obtained by feeding 5-wk old male C57BL/6J mice obesogenic diet for 20 wks. Age-matched chow-fed mice were included as controls (CON). Ex vivo left ventricular (LV) function (working heart perfusions, n=8-11) and ischemic susceptibility (LV post-ischemic functional recovery and infarct size, Langendorff perfusions, n=12-15) were examined in hearts exposed to normal (0.35 mM) or high (1.8 mM) palmitate levels. We also assessed myocardial O2 consumption (MVO2), FA oxidation and mechanical efficiency (n=12-15), as well as myocardial ROS content (DHE tissue staining) and mitochondrial respiration (high-resolution respirometry, n=6-8). DIO mice were obese with elevated plasma FA levels (0.37±0.03 vs 0.58±0.04 mM, p<0.01) and insulin resistance (4.4 fold higher HOMA-IR). They also developed diastolic dysfunction with only a mild systolic dysfunction. High FA perfusion did not alter LV function in neither CON nor DIO hearts. However, elevated FA decreased mechanical efficiency (due to increased MVO2, 28±2 vs 37±2 µmol/min/g, p<0.01), induced oxidative stress and reduced mitochondrial OXPHOS rate and coupling (RCR) in CON hearts. These FA-mediated changes were not found in DIO hearts. Furthermore, in contrast to CON hearts (where ischemic tolerance was not altered by the FA-load), DIO hearts exposed to high FA levels showed increased functional recovery (53±5 vs 36±5 % Rate-Pressure-Product, p<0.01) and decreased infarct size (47±2 vs 62±5%, p<0.02). This cardioprotective effect was corroborated in hearts from db/db mice which is a model of obesity and type 2 diabetes (54±6 vs 36±5 % recovery of RPP, p<0.05, and 55±5 vs72±2 % infarction, p<0.01, respectively). This study show that obese/diabetic hearts are resistant to the adverse effects a high FA-load. We therefore suggest that, although chronic dyslipidemia may play a role in the development of diabetic/obesity-mediated heart failure, these hearts undergo adaptive changes that counteract adverse effects of high FA and where elevated FA levels exert cardioprotection.

Where applicable, experiments conform with Society ethical requirements