The radioprotective 105 (RP105)/MD-1 complex is a member of the Toll-like receptor (TLR) family of proteins. We have previously reported that this complex cooperates with the essential lipopolysaccharide (LPS) receptor TLR4/MD-2 complex and plays a crucial role in LPS responses by B cells. Recent evidences suggest that TLRs can also recognize endogenous ligands and promote non-infectious chronic inflammation. For instance, TLR4/MD-2 can be ligated by adipose tissue-derived saturated free fatty acids (FAs) and induce adipose tissue inflammation and insulin resistance. Recently, we reported that RP105 knockout (KO) or MD-1 KO mice have less high-fat diet (HFD)-induced obesity, adipose tissue inflammation and insulin resistance than wild-type (WT) or TLR4 KO mice. As RP105/MD-1 is not involved in recognition of palmitic and stearic acids, which are endogenous ligands for TLR4/MD-2, we conclude that RP105/MD-1 is itself a key regulator of diet-induced chronic inflammation in adipose tissue, obesity and insulin resistance that appears to be independent of the TLR4-dependent pathway. In this mini-review, we will highlight the significance of the RP105/MD-1 complex in adipose tissue inflammation and discuss implications for human diseases.