TLR4 Deficiency Fails to Protect Against Diet-Induced Behavioral Impairments Under High-Sucrose Feeding

Obesity and type 2 diabetes (T2D) are accompanied by systemic and neural inflammation that contribute to cognitive and behavioral impairments. Toll-like receptor 4 (TLR4) links nutrient excess to inflammatory signaling and has been implicated in both metabolic dysfunction and neurocognitive decline. While TLR4 deficiency offers protection against high-fat diet (HFD) induced obesity and insulin resistance, the role of dietary sucrose in shaping TLR4 mediated behavioral outcomes remains unclear. We compared wild-type (WT) and TLR4 knockout (KO) mice fed chow, a normal sucrose HFD (NS-HFD), or a high sucrose HFD (HS-HFD) for 13 weeks. TLR4 KO mice on NS-HFD exhibited reduced weight gain, improved insulin sensitivity, and enhanced exploratory behavior with reduced anxiety-like activity in an open field test. However, these protective metabolic and behavioral effects were abolished under HS-HFD, where TLR4 KO and WT mice performed similarly. These findings reveal that high dietary sucrose overrides TLR4 dependent protection, underscoring critical gene and diet interactions in obesity and cognitive dysfunction.