Given that a higher level of blood lipid is one of the DAMPs that could initiate TLR4 and inhibition of the TLR4-NF-κB signaling pathway, which might be a potential strategy in depression treatment, the aim of the study was to compare the depressive-like behaviors and the levels of cytokines (IL-1β, IL-6, and TNF-α) and NF-κB in the brain between C57BL/6 mice and ob/ob mice after CUMS and whether the TLR4 antagonist Tak242 could reverse the depressive-like behaviors and overexpressions of cytokines and NF-κB in stressed mice. This evidence concerns the gene TLR4 and major depressive disorder.