Dipeptidyl Peptidase-4 at the Interface Between Inflammation and Metabolism

Dipeptidyl peptidase-4 (DPP4) is a serine protease that rapidly inactivates the incretin peptides, glucagon-like peptide-1, and glucose-dependent insulinotropic polypeptide to modulate postprandial islet hormone secretion and glycemia. Dipeptidyl peptidase-4 also has nonglycemic effects by controlling the progression of inflammation, which may be mediated more through direct protein-protein interactions than catalytic activity in the context of nonalcoholic fatty liver disease (NAFLD), obesity, and type 2 diabetes (T2D). Failure to resolve inflammation resulting in chronic subclinical activation of the immune system may influence the development of metabolic dysregulation. Thus, through both its cleavage and regulation of the bioactivity of peptide hormones and its influence on inflammation, DPP4 exhibits a diverse array of effects that can influence the progression of metabolic disease. Here, we highlight our current understanding of the complex biology of DPP4 at the intersection of inflammation, obesity, T2D, and NAFLD. We compare and review new mechanisms identified in basic laboratory and clinical studies, which may have therapeutic application and relevance to the pathogenesis of obesity and T2D.