Chronic low-grade inflammation is involved in TLR4 knockout-induced spontaneous obesity in aged mice

Chronic inflammation plays an important role in obesity-related complications, including insulin resistance, type 2 diabetes, and cardiovascular disease. The imbalances between T helper (Th)1/Th2 cells and Th17/regulatory T (Treg) cells participate in the pathogenesis of inflammation. Previously it was demonstrated that Toll-like receptor (TLR) 4 knockout (KO) prevents high-fat diet (HFD)-induced obesity of young mice (6 months of age), however the effect of TLR4 KO on spontaneous obesity in aged mice (18 month of age) is still unknown. To further study this, TLR4 KO and WT mice were fed with a standard chow diet from weaning to the endpoint of the experiment. We found that TLR4^-/- mice were thinner compared with WT mice at 6 months (M) old. However, TLR4^-/- mice spontaneously developed obesity with increased weight and adiposity in both subcutaneous and visceral fat depots by 18 M old. Our results also indicated that TLR4 KO activated TRIF/IRF3 signalling, induced inflammation, and repolarised alternatively-activated (M2) macrophages to classically-activated (M1) macrophages. In addition, TLR4 KO resulted in an increased spleen index and induced imbalances of Th1/Th2 and Th17/Treg cells which indicated the occurrence of chronic low-grade inflammation. In conclusion, chronic low-grade inflammation induced by TLR4 KO was involved in spontaneous obesity in aged mice. An emerging link was established among the TRIF/IRF3 pathway, chronic low-grade inflammation, and obesity. We hope that these novel findings will provide a potential preventive strategy for obesity and build a spontaneous obesity mouse model.