Inhibition of Hyperglycemia and Hyperlipidemia by Blocking Toll-like Receptor 4: Comparison of Wild-Type and Toll-like Receptor 4 Gene Knockout Mice on Obesity and Diabetes Modeling

Simple Summary Toll-like receptor 4 (TLR4) is a transmembrane protein with important immune activity. However, emerging evidence has shown that TLR4 also regulates glucose and lipid metabolism by an as-yet-unknown mechanism. A study of TLR4's role in glycolipid metabolism could contribute to the prevention of metabolic syndrome, which seriously affects human health. This study investigated the change in body weight, blood glucose, and blood lipids in both male and female wild-type (WT) and TLR4 gene knockout (TLR4-/-) mice during the development of obesity or diabetes models. The knockout of the TLR4 gene significantly alleviated the overweight and hyperlipidemia/hypoglycemic syndromes in mice, which confirmed that TLR4 plays an important role in glycolipid metabolism. Male mice changed more than female mice, reflecting the distinct differences in the responses between sexes. The findings of this study indicate that TLR4 has potential as a novel target to prevent and treat metabolic diseases. The established models in this study would help to screen suitable TLR4 inhibitors for application in curing obesity and diabetes.Abstract Innate immune receptor TLR4 plays an important role in glycolipid metabolism. The objective of this study is to investigate the inhibitory effects of blocking TLR4 on hyperglycemia and hyperlipidemia by comparing WT and TLR4-/- mice in obesity and diabetes modeling. The knockout of the TLR4 gene could prevent weight gain induced by a high-fat diet (HFD)/high-sugar and high-fat diet (HSHFD), and the differences in the responses existed between the sexes. It extends the time required to reach the obesity criteria. However, when mice were injected with intraperitoneal streptozotocin (STZ) after being fed by HSHFD for two months, TLR4-/- mice exhibited less weight loss than WT. Blocking TLR4 alleviated the changes in body weight and blood glucose, consequently reducing the efficiency of diabetes modeling, especially for male mice. Additionally, male TLR4-/- obese mice exhibit lower total cholesterol (TC) and low-density lipoprotein (LDL) levels in serum and less formation of fat droplets in the liver compared to WT. On the other hand, the knockout of TLR4 significantly increased the high-density lipoprotein (HDL) of male mice. This study should provide new insights into the role of TLR4, as well as opportunities to target novel approaches to the prevention and treatment of metabolic diseases like obesity and diabetes.