PPARγ-mediated Microglial Activation Phenotype Is Involved In Depressive-like Behaviors And Neuroinflammation In Stressed Mice

Background:There is an increased risk for obese patients with chronic low-grade inflammation to develop depression,and depression and obesity are usually comorbid.Obesity-related biological dysregulation could influence the response to antidepressants in depressive disorders.Stress induces microglial activation and neuroinflammation that play crucial roles in the pathogenesis of depression.Peroxisome proliferator-activated receptor gamma(PPARγ),a nuclear transcription factor,regulates microglial polarization and neuroinflammation.Pioglitazone,a PPARγagonist,has been shown to have antidepressant effects.Objective:Our study aimed to investigate the effect of chronic stress on depressive-like behaviors,neuroinflammation,and PPARγ expression in normal weight and obese mice,and explore the role of PPARy in depressive-like behaviors and neuroinflammation.Methods:CUMS was used to build a depression model with wild-type/C57BL/6J(wt)and leptin-deficient(ob/ob)mice.After 7 days of adaptation,wt mice and ob/ob mice were randomly divided into 4 groups according to body weight:wt control group(wt,n=10),wt CUMS group(wt+ CUMS,n=20),ob/ob control group(ob/ob,n=10),and ob/ob CUMS group(ob/ob+CUMS,n=20).Two CUMS groups were subjected to the CUMS program for 4 consecutive weeks.Depressive-like behaviors were evaluated by sucrose preference test,open field test,and tail suspension test after 4 weeks,and then,the two groups of CUMS-treated mice were randomly assigned to vehicle groups and drug-treatment groups.Therefore,all mice were regrouped into 6 groups(10 mice per group):wt control+vehicle group(wt),wt CUMS+vehicle group(wt+CUMS),wt CUMS+pioglitazone group(wt+CUMS+Pio),ob/ob control+vehicle group(ob/ob),ob/ob CUMS+vehicle group(ob/ob+CUMS),and ob/ob CUMS+pioglitazone group(ob/ob+CUMS+Pio).The CUMS groups received an additional 2 weeks of the CUMS procedure.The CUMS+Pio groups received 2 weeks of CUMS procedure and a daily intragastric administration of pioglitazone(30 mg/kg body weight)30 min prior to stress exposure.At the same time,the control and CUMS groups received a daily intragastric administration of 1%DMSO diluted with 0.9%saline(vehicle).After 2 weeks,depressive-like behaviors were evaluated by sucrose preference test,open field test,tail suspension test,and Morris water maze test.Cytokines(TNF-α,IL-1β,IL-6,IL-4,and IL-10),the activated microglial state(M1/M2),and nuclear factor-κB(NF-κB)and PPARγ expression in the prefrontal cortex(PFC)and hippocampus(HIP)were examined by enzyme-linked immunosorbent assay(ELISA),immunofluorescence,and western blotting.Results:(1)ob/ob mice developed more severe depressive-like behaviors than wt mice following 4 weeks of CUMS.(2)ob/ob mice exhibited severe depressive-like behaviors and spatial memory impairment,higher levels of pro-inflammatory cytokines,lower levels of anti-inflammatory cytokines,higher M1/M2 ratios of microglia,increased NF-κB and NF-κBp65 expression,and decreased PPARγ expression in the PFC and HIP compared to wt mice following 6 weeks of CUMS.(3)Administration of pioglitazone improved most of the behavioral disorders,suppressed the increases of pro-inflammatory cytokine levels,M1/M2 ratio,NF-κB and NF-κBp65 expression,and ameliorated the decreases of anti-inflammatory cytokine levels and PPARγ expression.Conclusions:CUMS was able to induce severe depressive-like behaviors,neuroinflammation,and reduced expression of PPARy in ob/ob mice as compared to wt mice.This suggests that PPARy mediates the microglial activation phenotype,which might be related to the susceptibility of stressed ob/ob mice to develop depressive disorder.