The innate immune receptors, toll-like receptor-2 (Tlr2) and toll-like receptor-4 (Tlr4), are implicated in the development of inflammation and insulin resistance in various cell populations. However, little is known about the relationship of these receptors in dietinduced obesity (DIO). We have shown that Tlr4 deficient C57BL/10ScN mice were protected against DIO, specifically when mice were fed a high saturated fatty acid (SFA) diet. Moreover, these mice exhibited a specific reduction in adipose tissue (AT) inflammation as evidenced by the reduction in nuclear factor kappa B (NFkB) activation, proinflammatory gene expression, and macrophage accumulation. There was also a marked increase in Tlr2 expression in mice fed a high fat diet. 3T3-L1 adipocytes treated with the Tlr2 agonist, zymosan A (ZymA), exhibited increased NFkB and activator protein-1 (AP-1) activation, proinflammatory gene expression, reactive oxygen species (ROS) accumulation, and insulin resistance, similarly to palmitate or Tlr4 agonist lipopolysaccharide (LPS). These effects were attenuated in adipocytes treated with a specific c-jun N-terminal kinase (JNK) inhibitor (SP600125) indicating involvement of this intracellular kinase in SFA and Tlr agonistmediated signaling. Finally, we demonstrated that Tlr2-/- mice were also protected from DIO. However, unlike Tlr4 deficient 10ScN mice there were no significant changes in body weight, energy intake, or lipid profile. Inflammatory and oxidative stress markers in serum

(C-reactive protein (CRP), endotoxin, and monocyte chemoattractant protein-1(MCP-1)) and AT (Tumor necrosis factor; (TNF), interleukin-6 (IL-6), MCP-1, F4/80, and nitric oxide synthase-2 (NOS2) transcript abundance) were attenuated in Tlr2-/- and 10ScN mice, which was more apparent in mice fed high SFA diet. Insulin sensitivity was improved in 10ScN, but not Tlr2-/- mice. However, stromal vascular (SV) cells isolated from AT of Tlr2-/- mice had a marked increase in insulin sensitivity, demonstrating the potential involvement of Tlr2 in obesity-induced insulin resistance in AT. Based on these studies, Tlr2 and Tlr4 may represent ideal targets for pharmaceutical, as well as dietary, interventions designed to attenuate obesity and related co-morbidities, including Type 2 diabetes mellitus (DM) and cardiovascular disease (CVD).