ABSTRACT DPP4 inhibitors (DPP4i) are a novel class of oral anti-diabetic drugs that modulate blood glucose by suppressing DPP4-mediated enzymatic degradation of insulinotropic incretin hormones. However, the non- enzymatic function of DPP4 in diabetes is not well understood. Recent data by us and others suggest a far more complex role for DPP4, independent of its enzymatic function. We found DPP4 is up-regulated in obesity and non-enzymatic function of DPP4 might be involved in adipose tissue inflammation in type 2 diabetes (T2DM) via interaction with adenosine deaminase (ADA). In additional preliminary studies, we found: (1) DPP4 was up-regulated in obese patients; (2) Deficiency of hematopoietic DPP4 reduced T cell inflammation in the adipose tissue; (3) DPP4 deficiency showed reduced migratory activity towards multiple chemokines. Our overall hypothesis is that DPP4 on T cells promotes T cell recruitment and activation in obesity. In this proposal, we will use a humanized animal model (hDpp4KI, a mouse model expressing human DPP4) to dissect how DPP4, especially its non-enzymatic function, is implicated in obesity/T2DM and use a novel decoy (Middle Eastern Respiratory Syndrome coronavirus spike protein receptor binding domain, MERS S-RBD) to interrupt DPP4/ADA signaling and modulate obesity-induced inflammation in T2DM. Successful execution of this proposal will provide solid pilot data for my future R01 application and may provide experimental support for developing a novel therapeutic approach.