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Intermittent Fasting Exerts Antidepressant-Like Effects by Restoring HPA Axis Homeostasis Through Coordinated GR-MR
Miaomiao Tang1, Qihan Sun1, Jinfang Song1
1Jilin Provincial Key Laboratory on Molecular and Chemical Genetic, The Second Hospital of Jilin University, Changchun, People's Republic of China.
Summary
Intermittent fasting (IF) reverses depression-like behaviors in mice by restoring hypothalamic glucocorticoid and mineralocorticoid receptor (GR/MR) signaling. This fasting-induced mechanism rebalances neural activity, offering a potential non-pharmacological approach for depression.
Area of Science:
- Neuroscience
- Endocrinology
- Metabolic Research
Background:
- Fasting is a non-pharmacological intervention with known antidepressant-like effects.
- The precise neural and molecular mechanisms underlying fasting's antidepressant effects are not fully understood.
- Corticosterone (CORT) administration induces depressive-like behaviors in mice, providing a model to study these mechanisms.
Purpose of the Study:
- To investigate if intermittent fasting (IF) can alleviate CORT-induced depressive-like behaviors in mice.
- To explore the underlying neural and molecular mechanisms of IF's antidepressant effects.
- To determine the role of glucocorticoid and mineralocorticoid receptor (GR/MR) signaling in IF's therapeutic actions.
Main Methods:
- Mice were subjected to IF and CORT administration to model depression.
- Hypothalamic GR/MR expression, arcuate nucleus (ARC) neuronal activity (AgRP/NPY and POMC neurons), and paraventricular nucleus (PVN) activity were assessed.
- Changes in neuropeptide Y (NPY) output and c-fos expression were quantified.
- The effects of GR and MR antagonists (RU486 and spironolactone) on IF's benefits were evaluated.
Main Results:
- IF reversed CORT-induced decreases in hypothalamic GR/MR expression.
- IF normalized CORT-induced decreases in ARC AgRP/NPY neuronal activity and NPY output, while suppressing POMC neuron activity.
- This rebalancing of ARC output attenuated PVN hyperactivity, indicated by reduced c-fos and increased NPY.
- GR and MR antagonist co-administration abolished the behavioral and neural effects of IF.
Conclusions:
- Intermittent fasting alleviates CORT-induced depressive-like behaviors by restoring hypothalamic GR/MR signaling.
- IF rescues the functional output of AgRP/NPYARC neurons, addressing activity-output dissociation.
- These findings reveal a mechanism through which IF restores HPA axis homeostasis and exerts antidepressant-like effects.
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