Related Experiment Video
Updated: Aug 5, 2026
Fat Preference: A Novel Model of Eating Behavior in Rats
Published on: June 27, 2014
Early-Life High-Fat Diet Impairs Autophagy and Reduces GABAA Receptor Expression in Hypothalamic Neurons, Promoting
Muzi Qian1, Ogula Doubra1, Yadi Su1
1School of Public Health, Jinzhou Medical University, Jinzhou 121001, China.
Insights
Early-life high-fat diet exposure in mice disrupts hypothalamic autophagy and GABA receptor function, leading to depressive-like behaviors. Targeting the autophagy-GABARAP pathway may offer therapeutic potential for offspring affected by nutritional excess.
Area of Science:
- Neuroscience
- Metabolic Disorders
- Cellular Biology
Background:
- Early-life nutritional excess is linked to increased risk of depressive-like phenotypes in offspring.
- The precise mechanisms underlying this association remain largely unknown.
- This study focuses on the role of the autophagy-GABARAP pathway in hypothalamic neurons.
Purpose of the Study:
- To investigate the impact of perinatal and adolescent high-fat diet (HFD) exposure on depressive-like behaviors in mice.
- To determine if HFD-induced depressive-like behaviors are mediated by disruptions in the autophagy-GABARAP pathway within hypothalamic neurons.
- To explore the molecular mechanisms, including transcriptomic changes and protein interactions, involved in this process.
Main Methods:
- Establishment of a mouse model with HFD exposure during perinatal and adolescent periods.
- Assessment of depressive-like behaviors, hypothalamic autophagic flux, and GABARAP-GABAAR co-localization.
- Utilizing primary hypothalamic neuronal cultures treated with rapamycin, RNA sequencing, and co-immunoprecipitation.
Main Results:
- HFD exposure induced metabolic disturbances and depressive-like behaviors, suppressed autophagic flux, and increased GABARAP-GABAAR co-localization.
- Reduced GABAAR protein abundance and elevated hypothalamic neuronal activity were observed in HFD mice.
- Rapamycin treatment reversed these HFD-induced alterations in primary neurons; RNA sequencing identified specific gene expression changes linked to cellular stress pathways.
Conclusions:
- Impaired autophagic flux is correlated with reduced GABAAR protein levels and increased hypothalamic neuronal activity.
- Dysregulation of the autophagy-GABARAP axis, alongside transcriptomic reprogramming, links early-life nutritional excess to offspring depressive-like phenotypes.
- The autophagy-GABARAP pathway presents a potential therapeutic target for mitigating the effects of early-life nutritional excess on offspring mental health.
Backgrounds:
Early-life nutritional excess increases the risk of depressive-like phenotypes in offspring, yet the underlying mechanisms remain unclear. This study investigated whether perinatal and adolescent high-fat diet (HFD) exposure is associated with depressive-like behaviors through disruption of the autophagy-GABARAP pathway in hypothalamic neurons.
Methods:
A mouse model of HFD exposure during both periods was established. Depressive-like behaviors, hypothalamic autophagic flux, and GABARAP-GABAAR co-localization were assessed. Primary hypothalamic neuronal cultures were treated with rapamycin. RNA sequencing and co-immunoprecipitation were performed to identify transcriptional changes and protein-protein interactions.
Results:
HFD exposure induced metabolic disturbances and depressive-like behaviors, suppressed autophagic flux (p62 and LC3-II accumulation), increased GABARAP-GABAAR co-localization, and reduced GABAAR protein abundance with elevated hypothalamic neuronal activity. Rapamycin reversed these alterations in primary neurons. RNA sequencing identified 87 differentially expressed genes (e.g., upregulated Plin4, Txnip; downregulated Npas4, Avp), while GABA receptor subunits and core autophagy genes remained unchanged at the transcriptional level. Enrichment analyses linked differentially expressed genes to mitophagy, oxidative phosphorylation, and the ubiquitin-proteasome system, with downregulated neuronal pathways. Co-immunoprecipitation confirmed direct GABARAP-GABAAR interaction.
Conclusions:
Impaired autophagic flux correlates with reduced GABAAR protein levels and increased hypothalamic neuronal activity, suggesting a link between autophagy-GABARAP dysregulation and depressive-like behaviors. The autophagy-GABARAP axis, together with transcriptomic reprogramming, may represent a key link between early-life nutritional excess and offspring depressive-like phenotypes, warranting further investigation as an intervention target.
