Hematopoietic Cell-Specific Deletion of Toll-like Receptor 4 Ameliorates Hepatic and Adipose Tissue Insulin Resistance in High-Fat-Fed Mice

Chronic low-grade inflammation, particularly in adipose tissue, is an important modulator of obesity-induced insulin resistance. The Toll-like receptor 4 (TIr4) is a key initiator of inflammatory responses in macrophages. We performed bone marrow transplantation (BMT) of TIr4lps-del or control C57BI/10J donor cells into irradiated wild-type C57BI6 recipient mice to generate hematopoietic cell-specific TIr4 deletion mutant (BMT-TIr4(-/-)) and control (BMT-WT) mice. After 16 weeks of a high-fat diet (HFD), BMT-WT mice developed obesity, hyperinsulinemia, glucose intolerance, and insulin resistance. In contrast, BMT-TIr4(-/-) mice became obese but did not develop fasting hyperinsulinemia and had improved hepatic and adipose insulin sensitivity during euglycemic clamp studies, compared to HFD BMT-WT controls. HFD BMT-TIr4(-/-) mice also showed markedly reduced adipose tissue inflammatory markers and macrophage content. In summary, our results indicate that TIr4 signaling in hematopoietic-derived cells is important for the development of hepatic and adipose tissue insulin resistance in obese mice.