To study the role of innate immunity and dendritic cells (DCs) in obesity and metabolic syndrome, we generated transgenic mice expressing MyD88, a master molecule for innate immunity, only in DCs (CD11c+), designated as CD11cMyD88+/+MyD88-/- mice. We used a standard high fat diet induced obesity (HFDIO) model. Young male experimental CD11cMyD88+/+MyD88-/- mice (n=18) ,control MyD88-/- mice (n=18) and wild type (WT) B6 mice (n=24) were fed with HF diet for 16 weeks. A further 3 groups of age and gender matched mice were fed with conventional diet (CD, n=13-17/group). We found that the body weight (BW) of MyD88-/- mice was significantly lower than B6 mice after HFD for 6 weeks (P<0.05), whereas there was no obvious difference in BW between B6 and MyD88-/- mice on CD. CD11cMyD88+/+MyD88-/- mice and B6 mice gained a similar amount of weight on HFD and they were significantly heavier than MyD88-/- mice (P<0.05) after 6 wks on HFD. We further investigated metabolic function after HFDIO. Glucose (IPGTT) and insulin tolerance tests (ITT) showed that MyD88-/- mice were sensitive to insulin regulation, whereas WT B6 and CD11cMyD88+/+MyD88-/- mice showed more insulin resistance and there was no difference between WT B6 and CD11cMyD88+/+MyD88-/- mice. Similarly, serum levels of triglyceride, total cholesterol, HDL-ch, LDL-ch, adiponectin, leptin, frbrinogen and insulin, were significantly different in MyD88-/- mice compared to WT B6 or CD11cMyD88+/+MyD88-/- mice but there was no difference between WT B6 and CD11cMyD88+/+MyD88-/- mice. Furthermore, we found that primary epididymal adipose stromal cells from B6 and CD11cMyD88 +/+MyD88-/- differentiated into more mature adipoctyes than cells from MyD88-/- mice. Our study suggests that expression of MyD88 only in DCs affects the phenotype of obesity and metabolic syndrome that develops on HFDIO treatment. Further functional experiments will determine the mechanism by which this occurs.