Intermittent Fasting Exerts Antidepressant‐Like Effects by Restoring HPA Axis Homeostasis Through Coordinated GR – MR Signaling

Fasting, as a non‐pharmacological intervention, elicits antidepressant‐like effects. However, its neural and molecular mechanisms remain unclear. This study investigated whether intermittent fasting (IF) alleviates corticosterone (CORT)‐induced depressive‐like behaviors in mice and explored the underlying mechanisms. This study demonstrated that IF reversed the CORT‐induced reduction in hypothalamic glucocorticoid and mineralocorticoid receptor (GR/MR) expression in mice. In addition, IF reversed a CORT‐induced decrease in arcuate nucleus (ARC) AgRP/NPY neuronal activity and NPY output from these neurons while concurrently suppressing the activity of neighboring POMC neurons. This rebalanced ARC output attenuated paraventricular nucleus (PVN) hyperactivity, as evidenced by reduced c‐fos and increased NPY immunoreactivity. Remarkably, co‐administration of GR and MR antagonists (RU486 and spironolactone) abolished both the behavioral benefits and hypothalamic neuropeptidergic and activity changes induced by IF. Together, these findings identify a mechanism involving GR/MR signaling through which IF alleviates depressive‐like states by rescuing the functional output of AgRP/NPY ARC neurons from a state of activity‐output dissociation, thereby restoring HPA axis homeostasis.