Abstract 24077: Differential, Sex Related, Response To High-fat Diet In Mice Impairs Cardiac Autophagy And Mitophagy

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Introduction: Premenopausal women, as well as females in animal studies, have a reduced risk of cardiovascular diseases and a reduced myocardial susceptibility to ischemia/reperfusion (I/R) injury. However, with constantly increasing prevalence of obesity, the impact of diet-induced obesity on females remains unclear. Mechanisms of autophagy and mitophagy, differentially regulated between males and females, have been shown to be cardioprotective and impacted under nutritional overload.

Hypothesis: Autophagy and mitophagy pathways can be involved in both female cardio protection and deleterious effect of obesity.

Methods: Male and female C57Bl/6J mice (n =20 per group) of 8 weeks old were fed a low-fat (LFD, 10% fat) or high-fat (HFD, 60% fat) diet for 12 weeks. At 12 weeks, hearts from mice were studied under basal conditions and after global no-flow ischemia and reperfusion on a Langendorff perfusion system.

Results: In both males and females, HFD significantly increases body weight (31.4g vs 48.3g and 22.1g vs 39.9g respectively), fat mass (+200% in males and +300% in females) and blood glucose (+79mg/dl and + 54mg/dl, respectively) (all p<0.01). HFD tends to decrease flow reperfusion after global no-flow ischemia and to increase infarct size (p=0.08 in female and p=0.1 in male, n=5) in both sexes. In males and females, HFD increases pSer757-Ulk1 and decreases Parkin levels under basal conditions (all p<0.006). Moreover, HFD tends to decrease pThr172-AMPK only in females. After I/R, Parkin levels remain lower in HFD groups without sex-difference (p<0.004) but a drastic increase of LC3-II occurs only in females under HFD (p=0.047).

Conclusion: All together, these results suggest an impairment of autophagy and mitophagy pathways under HFD. A more drastic change occurs in female mice and may imply a more important response of female mice to HFD, although further studies are needed. However, this result suggests that cardiovascular disease may be more deleterious in women despite their lower cardiovascular risk; additional studies examining sex differences in the response to metabolic syndrome and ischemic heart disease are warranted.

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