Abstract 219: Cardiac Autophagy in Response to Fasting is Impaired in Mice with Metabolic Syndrome

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Introduction: Macroautophagy (autophagy) is highly responsive to nutrient/energy status and cellular stress. It plays an adaptive role in limiting ischemia/reperfusion (I/R) injury in the heart. Nutrient depletion is a potent inducer of autophagy and is mediated by reciprocal regulation of AMPK and mTOR pathways which in turn regulate autophagy initiation via ULK1/Atg1. Autophagy is reduced in the setting of obesity, dyslipidemia, and insulin resistance associated with metabolic syndrome (MetS). The purpose of this study was determine whether impaired autophagy in MetS is due to altered upstream signaling or a disruption in the autophagic pathway.

Methods: Mice were ad-lib fed a chow (Lean) or a high fat diet (HFD) (D12492, 60% fat) for 18 weeks. In both groups, half of the mice were freely fed with the other half fasted for 24 hours prior to cardiac harvest. Protein levels were determined with Western blotting and gene expression with quantitative PCR.

Results: Consistent with previous data, HFD animals exhibited obesity and insulin resistance as reflected by increased body weight, and elevated serum insulin/HOMA compared to Lean animals. Fasting resulted in a marked reduction in serum insulin in both Lean (p=0.013) and HFD (p =0.002) animals. This was accompanied by marked increases in cardiac AMPK activation as reflected by increased phosphorylation in both Lean (p =0.002) and HFD (p=0.002) groups with parallel reciprocal suppression of mTOR activity as reflected by decreased pS6K and pS6. As expected, the Lean group exhibited a fasting-induced increase in LC3-II (p=0.020) indicating an increase in autophagy. This did not occur in the HFD group despite a similar induction in LC3B and p62 gene expression. This lack of autophagy stimulation with fasting in HFD animals was not explained by differences in autophagy initiation as the phosphorylation status of ULK1 decreased similarly with fasting in both groups.

Conclusions: These data indicate that the impairment of cardiac autophagy in the presence of MetS is not attributable to abnormal upstream nutrient sensing pathways. The findings suggest a MetS-associated defect in the autophagy/lysosomal fusion pathway. This could explain the increased vulnerability of the heart to I/R injury in the setting of MetS.

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