Zhang_2024_Faseb.j_38_e23684

Exposure to chronic psychosocial stress is a risk factor for metabolic disorders. Because dipeptidyl peptidase-4 (DPP4) and cysteinyl cathepsin K (CTSK) play important roles in human pathobiology, we investigated the role(s) of DPP4 in stress-related adipocyte differentiation, with a focus on the glucagon-like peptide-1 (GLP-1)/adiponectin-CTSK axis in vivo and in vitro. Plasma and inguinal adipose tissue from non-stress wild-type (DPP4(+/+)), DPP4-knockout (DPP4(-/-)) and CTSK-knockout (CTSK(-/-)) mice, and stressed DPP4(+/+), DPP4(-/-), CTSK(-/-), and DPP4(+/+) mice underwent stress exposure plus GLP-1 receptor agonist exenatide loading for 2 weeks and then were analyzed for stress-related biological and/or morphological alterations. On day 14 under chronic stress, stress decreased the weights of adipose tissue and resulted in harmful changes in the plasma levels of DPP4, GLP-1, CTSK, adiponectin, and tumor necrosis factor-alpha proteins and the adipose tissue levels of CTSK, preadipocyte factor-1, fatty acid binding protein-4, CCAAT/enhancer binding protein-alpha, GLP-1 receptor, peroxisome proliferator-activated receptor-gamma, perilipin2, secreted frizzled-related protein-4, Wnt5alpha, Wnt11 and beta-catenin proteins and/or mRNAs as well as macrophage infiltration in adipose tissue; these changes were rectified by DPP4 deletion. GLP-1 receptor activation and CTSK deletion mimic the adipose benefits of DPP4 deficiency. In vitro, CTSK silencing and overexpression respectively prevented and facilitated stress serum and oxidative stress-induced adipocyte differentiation accompanied with changes in the levels of pref-1, C/EBP-alpha, and PPAR-gamma in 3T3-L1 cells. Thus, these findings indicated that increased DPP4 plays an essential role in stress-related adipocyte differentiation, possibly through a negative regulation of GLP-1/adiponectin-CTSK axis activation in mice under chronic stress conditions.