High-fat diet and chronic restraint stress exacerbate anxiety-depressive behaviors via astrocytic A1 phenotype transformation

Obesity and depression are likely to co-occur. However, there are few reports on the relationship between obesity and depression. We aimed to investigate the effect of high-fat diet combined with chronic restraint stress on depressive-like behaviors, focusing on the phenotypic transformation of astrocytes. Male C57BL/6 mice were randomly divided into four equal groups: control, high-fat diet (HFD), chronic restraint stress (CRS) and HFD + CRS groups. They were subjected to an 8-week high-fat diet and 3-week restraint stress stimulation. In vitro, palmitic acid (PA) and corticosterone (Cort) were used to mimic HFD and CRS respectively on C8-D1A astrocytes. Our results showed that HFD aggravates anxiety and depression-like behaviors and learning and memory deficits induced by CRS, as reflected by sucrose preference, forced swimming test, tail suspension tests, open field test and the Morris water maze. The expression level of C3 protein in the hippocampus of the mice in the HFD + CRS group was three times that of the CON group. HFD combined with CRS significantly inhibited the protein expression of the Wnt/β-catenin signaling pathway. Consistent with the results of animal experiments, the results of the in vitro experiments showed that the protein expressions of A1 astrocytes marker in C8-D1A astrocytes were much higher in the PA + Cort group. And the protein expressions the Wnt/β-catenin signaling pathway-associated proteins were obviously lower in the PA + Cort group. Furthermore, Wnt/β-catenin pathway agonist SKL2001 treatment decreased the A1 astrocytes marker expressions in C8-D1A astrocytes, and improves the anxiety and depression-like behaviors and learning and memory deficits in HFD mice combined with CRS. This study suggested that HFD combined with CRS could promote the transformation of astrocytes into A1 type and the Wnt/β-catenin signaling pathway may be involved in this process.