Age-dependent effects of high fat-diet on murine left ventricles: role of palmitate

Obesity-associated heart disease results in myocardial lipid accumulation leading to lipotoxicity. However, recent studies are suggestive of protective effects of high-fat diets (HFD). To determine whether age results in differential changes in diet-induced obesity, we fed young and old (3 and 18 months) male C57Bl/6 mice control diet, low-fat diet (both 10 kcal% fat) or HFD (45 kcal% fat) for 16 weeks, after which we analyzed LV function, mitochondrial changes, and potential modifiers of myocardial structure. HFD or age did not change LV systolic function, although a mildly increased BNP was observed in all old mice. This was associated with increased myocardial collagen, triglyceride, diacylglycerol, and ceramide content as well as higher caspase 3 activation in old mice with highest levels in old HFD mice. Pyruvatedependent respiration and mitochondrial biogenesis were reduced in all old mice and in young HFD mice. Activation of AMPK, a strong inducer of mitochondrial biogenesis, was reduced in both HFD groups and in old control or LFD mice. Cardiomyocytes from old rats demonstrated significantly reduced AMPK activation, impaired mitochondrial biogenesis, higher ceramide content, and reduced viability after palmitate (C16:0) in vitro, while no major deleterious effects were observed in young cardiomyocytes. Aged but not young cardiomyocytes were unable to respond to higher palmitate with increased fatty acid oxidation. Thus, HFD results in cardiac structural alterations and accumulation of lipid intermediates predominantly in old mice, possibly due to the inability of old cardiomyocytes to adapt to high-fatty acid load.