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

Albert E. Towers, Maci L. Oelschlager, Michal B. Juda, Sparsh Jain, Stephen J. Gainey, Gregory G. Freund

Research output: Contribution to journalArticlepeer-review


Background: Diets that include some aspect of fasting have dramatically increased in popularity. In addition, fasting reduces inflammasome activity in the brain while improving learning. Here, we examine the impact of refeeding a low-fat diet (LFD) or high-fat diet (HFD) after fasting. Methods: Male wildtype (WT), caspase-1 knockout (KO) and/or IL-1 receptor 1 (IL-1R1) KO mice were fasted for 24 h or allowed ad libitum access to food (chow). Immediately after fasting, mice were allowed to refeed for 2 h in the presence of LFD, HFD or chow. Mouse learning was examined using novel object recognition (NOR) and novel location recognition (NLR). Caspase-1 activity was quantified in the brain using histochemistry (HC) and image analysis. Results: Refeeding with a HFD but not a LFD or chow fully impaired both NOR and NLR. Likewise, HFD when compared to LFD refeeding increased caspase-1 activity in the whole amygdala and, particularly, in the posterior basolateral nuclei (BLp) by 2.5-fold and 4.6-fold, respectively. When caspase-1 KO or IL-1R1 KO mice were examined, learning impairment secondary to HFD refeeding did not occur. Equally, administration of n-acetylcysteine to fasted WT mice prevented HFD-dependent learning impairment and caspase-1 activation in the BLp. Finally, the free-fatty acid receptor 1 (FFAR1) antagonist, DC260126, mitigated learning impairment associated with HFD refeeding while blocking caspase-1 activation in the BLp. Conclusions: Consumption of a HFD after fasting impairs learning by a mechanism that is dependent on caspase-1 and the IL-1R1 receptor. These consequences of a HFD refeeding on the BLP of the amygdala appear linked to oxidative stress and FFAR1.

Original languageEnglish (US)
Article number153989
JournalMetabolism: Clinical and Experimental
StatePublished - Jan 2020


  • Amygdala
  • Calorie restriction
  • Caspase-1
  • Fasting
  • High-fat diet
  • Learning
  • Low-fat diet
  • Memory
  • Neuroimmunity
  • Oxidative stress
  • Refeeding

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Endocrinology


Dive into the research topics of 'HFD refeeding in mice after fasting impairs learning by activating caspase-1 in the brain'. Together they form a unique fingerprint.

Cite this