Regulatory impact of intermittent fasting on autophagy in high fat diet induced structural and cognitive brain deteriorations in rats ABSTRACT Obesity-induced cognitive decline has been linked to alterations in brain autophagy. However, research concerning the high-fat diet (HFD) impacts on the brain still lacks evidence, and results are controversial. Intermittent fasting (IF) may lead to increased neurogenesis levels in the hippocampus in neurodegenerative diseases; however, the involved molecular mechanisms are not well understood. The current work aimed to evaluate the neuroprotective effect of IF against obese rat model-related cognitive disorders that disrupted brain autophagy. 24 male rats were allocated to control, fasting lean group, obese (HFD-fed), and obese fasting groups; behavioral tests, biochemical assays, and molecular analyses (inflammatory markers, BDNF, and autophagy-related genes) were conducted to assess cognitive function and underlying mechanisms. Our findings suggest that IF intervention significantly attenuated HFD-induced cognitive impairment and neuroinflammation, increased BDNF levels, improved histological alterations, decreased Beclin-1 and p62 immunohistochemical expression, and upregulated LC3 and ATG5 mRNA expression. IF can prevent HFD-induced cognitive disorders that could be mediated by the cerebral cortex and hippocampal autophagy dysfunction, emphasizing the importance of the autophagy pathway to normal neuronal functions. These results suggested that IF protected the neural system from HFD-induced inflammation and oxidative stress in obese rats and is essential for neuronal survival via modulation of autophagy function in rats