PPARγ Dysfunction in the Medial Prefrontal Cortex Mediates High-Fat Diet-Induced Depression

Area of Science:

• Neuroscience
• Metabolic Disorders
• Psychiatry

Background:

• Bidirectional links between depression and obesity are known, but underlying biological mechanisms are unclear.
• Nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ) agonists have shown antidepressant effects.
• High-fat diet (HFD)-induced PPARγ dysfunction is implicated in metabolic disorders, but its role in neuronal function and depression is unexplored.

Purpose of the Study:

• To investigate the role of neuronal PPARγ in the development of depressive-like behaviors in mice fed a high-fat diet (HFD).
• To determine if PPARγ deficiency in neurons, particularly in the medial prefrontal cortex (mPFC), influences depressive behaviors.

Main Methods:

• Male C57BL/6J mice were fed HFD to induce obesity and assessed for depressive behaviors.
• Neuron-specific PPARγ knockout (NKO) mice were generated to evaluate the impact of neuronal PPARγ deficiency.
• PPARγ was specifically knocked out in the mPFC using AAV-CaMKIIα-Cre and overexpressed using AAV-syn-PPARγ vectors.

Main Results:

• HFD-fed mice exhibited increased depressive-like behaviors and reduced mPFC PPARγ levels.
• Neuron-specific PPARγ deficiency induced depressive-like behaviors, which were reversed by imipramine treatment.
• Overexpression of PPARγ in the mPFC ameliorated depressive-like behaviors in both HFD-fed and NKO mice.

Conclusions:

• Dysregulation of neuronal PPARγ in the mPFC is implicated in the increased risk of depression associated with obesity.
• Targeting neuronal PPARγ may offer a therapeutic strategy for depression in obese individuals.