Role of DPP4-ADA interaction in obesity-induced inflammation

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Principal Investigator: Jixin  Zhong
Organization: CASE WESTERN RESERVE UNIVERSITY
Fiscal Year: 2020
Award: $77,000
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases

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.

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