Increased Dipeptidyl Peptidase-4 Promotes Adipose Inflammation and Dysfunction in Mice Under Chronic Stress.

Exposure to chronic psychological stress is an intractable risk factor for inflammatory and metabolic disorders. Given that dipeptidyl peptidase-4 (DPP4) is upregulated in stressed adipose and vascular tissues and modulates intracellular signaling pathways related to glucagon-like peptide-1 (GLP-1) metabolism, we investigated the role of the DPP4/GLP-1 axis by examining adipose inflammation and dysfunction in mice subjected to chronic stress. Eight-week-old male wild-type mice (DPP4(+/+)) and DPP4-knockout (DPP4(-/-)) mice were randomly assigned to non-stress or 2-week immobilization stress groups for morphological and biochemical analyses. On Day 14 post-stress, the stressed mice had reduced subcutaneous adipose tissue (SWAT) weights and detrimental changes in the protein and/or mRNA levels of phospho-phosphatidylinositol 3-kinase, phospho-protein kinase B, oxidative stress (gp91(phox))-, apoptosis (cytochrome c, caspase-8, B-cell lymphoma 2 and Bcl2-associated X protein)-, monocyte chemoattractant protein-1, interleukin-6, tumor-necrosis factor-α, and inducible nitric oxide synthase-related molecules, plus increased F4/80(+) macrophage infiltration; these changes were reversed by DPP4 deficiency. The GLP-1 receptor agonist exenatide mimicked the adipose benefits of DPP4 deletion. In vitro, exenatide reduced the production of reactive oxygen species and the apoptosis induced by stressed serum, and it altered the levels of p-AKT protein. DPP4 deletion also reduced these changes. These findings suggest that DPP4 functions as an important mediator of chronic stress-stimulated adipose inflammation and dysfunction via the modulation of adipocyte oxidative stress production and apoptosis that is mediated by the GLP-1/PI3K-AKT axis, indicating that DPP4 inhibition and/or GLP-1R stimulation may have applications for treating metabolic disorders of patients under chronic stress conditions.