PPARγ-mediated microglial activation phenotype is involved in depressive-like behaviors and neuroinflammation in stressed C57BL/6J and ob/ob mice

Abstract

Background: There is an increased risk for obese patients with chronic low-grade inflammation to develop depression. 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. Our study aimed to investigate the role of PPARγ in the development of depressive symptoms and neuroinflammation induced by chronic unpredictable mild stress (CUMS) in wild-type/C57BL/6J (wt) and leptin-deficient (ob/ob) mice.

Methods: CUMS was used to build a depression model with wt and ob/ob mice. Depressive-like behaviors were evaluated by sucrose preference test, open field test, tail suspension test, and Morris water maze test. Cytokines, the activated microglial state, 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. Additionally, pioglitazone, an agonist of PPARγ, was used as a treatment intervention.

Results: After CUMS, ob/ob mice exhibited severe behavioral disorders and spatial memory impairment, and higher levels of pro-inflammatory cytokines, M1/M2 ratios, and NF-κB activation, as well as lower levels of anti-inflammatory cytokines and PPARγ expression in the PFC and HIP compared to wt mice. Administration of pioglitazone relieved these alterations in wt and ob/ob mice.

Conclusions: CUMS was able to induce severe depressive-like behaviors, neuroinflammation, and reduced expression of PPARγ in ob/ob mice as compared to wt mice. This suggests that PPARγ mediates the microglial activation phenotype, which might be related to the susceptibility of stressed ob/ob mice to develop depressive disorder.

Keywords: Cytokine; Depression; Microglia; Neuroinflammation; Obesity; PPARγ.