Alternate-day fasting prevents non-alcoholic fatty liver disease and working memory impairment in diet-induced obese mice

Alternate-day fasting (ADF) regimen has been reported to alleviate obesity and insulin resistance. However, the effects of ADF on preventing diet-induced non-alcoholic fatty liver disease (NAFLD) and related cognitive deficits are still elusive. In the present study, a high-fat diet (HFD)-induced obese (DIO) C57BL/6 mouse model was established. Mice were treated with a 4-week long ADF regimen and/or switching the diet to a standard diet. ADF reduced lipid accumulation, activated AMPK/ULK1 signaling, and suppressed the phosphorylation of mTOR. Also, ADF inhibited lipid accumulation and inflammatory responses in the white adipose tissue and down-regulated expressions of PPAR-γ and cytokines. Moreover, ADF improved the working memory and synaptic structure in the DIO mice and upregulated PSD-95 and BDNF in the hippocampus. ADF reduced oxidative stress and microglial over-activation in the CNS. These results suggest that ADF attenuates NAFLD development in the liver of DIO mice, which is related to the mediating effects of ADF on autophagy and energy metabolism. ADF also enhanced cognitive function, which could be partly explained by the down-regulated peripheral inflammatory responses. This study indicates that ADF could be a promising intervention for alleviating NAFLD development and cognitive decline.