| Summary: | Abstract Park2 is an E3 ubiquitin ligase known for its role in mitochondrial quality control via the mitophagy pathway. Park2 KO mice are protected from diet‐induced obesity and hepatic insulin sensitivity is improved in high‐fat diet (HFD)‐fed Park2 KO mice even under body weight‐matched conditions. In order to better understand the cellular mechanism by which Park2 KO mice are protected from diet‐induced hepatic insulin resistance, we determined changes in multiple pathways commonly associated with the pathogenesis of insulin resistance, namely levels of bioactive lipid species, activation of the endoplasmic reticulum (ER) stress response and changes in cytokine levels and signaling. We report for the first time that whole‐body insulin sensitivity is unchanged in regular chow (RC)‐fed Park2 KO mice, and that liver diacylglycerol levels are reduced and very‐long‐chain ceramides are increased in Park2 KO mice fed HFD for 1 week. Hepatic transcriptional markers of the ER stress response were reduced and plasma tumor necrosis factor‐α (TNFα), interleukin‐6 and −10 (IL6, IL10) were significantly increased in HFD‐fed Park2 KO mice; however, there were no detectable differences in hepatic inflammatory signaling pathways between groups. Interestingly, hepatic adenylate charge was reduced in HFD‐fed Park2 KO liver and was associated increased activation of AMPK. These data suggest that negative energy balance that contributed to protection from obesity during chronic HFD manifested at the level of the hepatocyte during short‐term HFD feeding and contributed to the improved hepatic insulin sensitivity.
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