HFD refeeding in mice after fasting impairs learning by activating caspase-1 in the brain

Area of Science:

• Neuroscience
• Metabolic research
• Dietary science

Background:

• Fasting diets are increasingly popular and known to reduce brain inflammasome activity.
• Fasting has been shown to improve cognitive functions, such as learning and memory.
• The impact of refeeding specific diets after fasting on brain function requires further investigation.

Purpose of the Study:

• To investigate the effects of refeeding a low-fat diet (LFD) or high-fat diet (HFD) on learning and memory after fasting.
• To explore the underlying mechanisms, including inflammasome activity, involving caspase-1 and IL-1R1.
• To assess the role of oxidative stress and FFAR1 in diet-induced cognitive impairment post-fasting.

Main Methods:

• Male wildtype (WT), caspase-1 knockout (KO), and IL-1R1 KO mice were subjected to a 24-hour fast or ad libitum feeding.
• Following fasting, mice were refed with LFD, HFD, or chow for 2 hours.
• Learning was assessed using novel object recognition (NOR) and novel location recognition (NLR) tests. Brain caspase-1 activity was quantified using histochemistry.

Main Results:

• Refeeding with HFD, but not LFD or chow, significantly impaired both NOR and NLR performance.
• HFD refeeding markedly increased caspase-1 activity in the amygdala, particularly in the posterior basolateral nuclei (BLp).
• Impairment of learning and memory after HFD refeeding was abolished in caspase-1 KO and IL-1R1 KO mice. N-acetylcysteine and an FFAR1 antagonist prevented these effects.

Conclusions:

• Consumption of a HFD after fasting impairs learning and memory through a mechanism dependent on caspase-1 and the IL-1R1 receptor.
• The observed cognitive deficits are associated with increased caspase-1 activity in the amygdala's BLp.
• These effects appear to be linked to oxidative stress and the free-fatty acid receptor 1 (FFAR1).