Time-dependent cellular response in the liver and heart in a dietary-induced obese mouse model: the potential role of ER stress and autophagy

Purpose: Both endoplasmic reticulum stress (ER stress) and autophagy are essential for the response of the protein quality control system to cellular stresses. This study investigated the influence of the duration of a high-fat diet (HFD) in mice on tissue-specific cellular responses, specifically with regard to the role of autophagy and ER stress. Methods: Male mice aged 6–7 weeks were fed ad libitum with a standard chow diet or with a HFD for 2, 4, 8, or 16 weeks. Results: The HFD progressively increased mean body weight and induced tissue hypertrophy. The expression of PERK was suppressed in the liver after 16 weeks of the HFD and in the heart after 8 weeks of the HFD. Procaspase 12 and its activated form were induced in the liver with the HFD after 2 weeks, but not in the heart over the 16-week period. The activation of hepatic AMPK was elevated following 4 weeks of the HFD, but was inhibited after 16 weeks of the HFD. The ratio of LC3II to LC3I in the liver did not increase except in those mice fed the HFD for 16 weeks. The expression of AMPK and LC3 in the heart did not change over the entire 16 weeks of feeding the HFD. Cleaved PARP was increased in the liver and heart of mice receiving the HFD for 8 weeks. Conclusions: This study provides evidence that a HFD affects the cellular protein quality control processes responsible for metabolic disorder in a tissue- and duration-dependent manner.