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

Epidemiological studies suggest a bidirectional association between depression and obesity; however, the biological mechanisms that link the development of depression to a metabolic disorder remain unclear. Even though nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ) agonists show anti-depressive effect, and high-fat diet-(HFD)-induced PPARγ dysfunction is involved in the pathogenesis of metabolic disorders, the neuronal PPARγ has never been studied in HFD-induced depression. Thus, we aimed to investigate the effect of neuronal PPARγ on depressive-like behaviors in HFD-induced obese mice. We fed male C57BL/6 J mice with HFD to generate obese mice and conducted a series of behavioral tests to assess the effects of HFD feeding on depression. We generated neuron-specific PPARγ knockout mice (NKO) to determine whether neuronal PPARγ deficiency was correlated with depressive-like behaviors. To further prove whether PPARγ in the medial prefrontal cortex (mPFC) neurons is involved in depressive-like behaviors, we applied AAV- CaMKIIα-Cre approach to specifically knockout PPARγ in the mPFC neurons of LoxP mice and used AAV-syn-PPARγ vectors to overexpress PPARγ in the mPFC neurons of NKO mice. We observed a low mPFC PPARγ level and an increase in depressive-like behaviors in the HFD-fed mice. Moreover, neuronal-specific PPARγ deficiency in mice induced depressive-like behaviors, which could be abolished by imipramine. Furthermore, overexpressing PPARγ in the mPFC reversed the depressive-like behaviors in HFD-fed mice as well as in neuronal-specific PPARγ knockout mice. These results implicate that dysregulation of neuronal PPARγ in the mPFC may contribute to an increased risk for depression in obese populations.