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

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Abstract

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.

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Data Availability

All datasets generated and analyzed during this study are included in this published article and its supplementary information files. Materials are available upon request.

Abbreviations

PPARγ:

Peroxisome proliferator-activated receptor gamma

CNS:

Central nervous system

FST:

Forced swim test

TST:

Tail suspension test

HFD:

High-fat diet

mPFC:

Medial prefrontal cortex

CaMKIIα:

Calcium/calmodulin-dependent protein kinase II alpha

GTT:

Glucose tolerance test

CSDS:

Chronic social defeat stress

SPT:

Sucrose preference test

CDK5:

Cyclin-dependent kinase 5

FGF2:

Fibroblast growth factor 2

VAMP2:

Vesicle-associated membrane protein 2

STXBP5:

Syntaxin-binding protein 5

POMC:

Proopiomelanocortin

ATCH:

Adrenocorticotrophic hormone

GR:

Glucocorticoid receptor

HPA:

Hypothalamus–pituitary–adrenal

BDNF:

Brain-derived neurotrophic factor

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Funding

This work was supported by the National Natural Science Foundation of China (81971234), the Program for Changjiang Scholars and Innovative Research Team in University (IRT_16R37), the Key Area Research and Development Program of Guangdong Province (2018B030334001 and 2018B030340001), and the Science and Technology Program of Guangzhou (202007030013).

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Authors and Affiliations

  1. Key Laboratory of Mental Health of the Ministry of Education, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Guangdong Province Key Laboratory of Psychiatric Disorders, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China

    Cong-Cong Fu, Xin-Yi Zhang, Liu Xu, Hui-Xian Huang, Shuang Xu, Qiao-Qi Wu, Zhen Wang, Xi Gu, Li-Fang Lin, Song Lin, Ying-Ying Fang, Xiong Cao & Xuemin Wang

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  1. Cong-Cong Fu
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Contributions

C.C. Fu: contributed to the conception of the study, performed the experiment, collected the data, and wrote the manuscript; X.Y. Zhang: performed the data analyses;

L. Xu and S. Xu helped to produce the HFD-induced obese mice and conducted the behaviors test; Q.Q. Wu, Z. Wang, L.F. Lin, and H.X. Huang contributed to produce and validate the PPARγfl/fl mice and neuronal-specific PPARγ knockout mice; X. Gu, S. Lin, and Y.Y. Fang helped with the data collection and experiments preparation; X. Cao helped designed the study; X.M. Wang designed the study, revised the manuscript, and oversaw the entire project.

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Correspondence to Xuemin Wang.

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All experiments animals were performed with the approval of the Southern Medical University Animal Ethics Committee.

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Fu, CC., Zhang, XY., Xu, L. et al. PPARγ Dysfunction in the Medial Prefrontal Cortex Mediates High-Fat Diet-Induced Depression. Mol Neurobiol 59, 4030–4043 (2022). https://doi.org/10.1007/s12035-022-02806-6

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