暴露于慢性社会心理压力是代谢紊乱的危险因素。由于二肽基肽酶-4(DPP4)和半胱氨酰组织蛋白酶K(CTSK)在人类病理生物学中起重要作用,我们研究了DPP4在应激相关脂肪细胞分化中的作用,重点关注体内和体外胰高血糖素样肽-1(GLP-1)/脂联素-CTSK轴。来自非应激野生型(DPP4+/+)的血浆和腹股沟脂肪组织,DPP4敲除(DPP4-/-)和CTSK敲除(CTSK-/-)小鼠,并强调DPP4+/+,DPP4-/-,CTSK-/-,和DPP4+/+小鼠接受应激暴露加GLP-1受体激动剂艾塞那肽负荷2周,然后分析应激相关的生物学和/或形态学改变.在慢性压力下的第14天,压力降低脂肪组织的重量,并导致血浆中DPP4,GLP-1,CTSK,脂联素,和肿瘤坏死因子-α蛋白和CTSK的脂肪组织水平,前脂肪细胞因子-1,脂肪酸结合蛋白-4,CCAAT/增强子结合蛋白-α,GLP-1受体,过氧化物酶体增殖物激活受体-γ,perilipin2,分泌卷曲相关蛋白4,Wnt5α,Wnt11和β-catenin蛋白和/或mRNA以及脂肪组织中的巨噬细胞浸润;这些变化通过DPP4缺失得到纠正。GLP-1受体激活和CTSK缺失模拟DPP4缺乏的脂肪益处。体外,CTSK沉默和过表达分别阻止和促进应激血清和氧化应激诱导的脂肪细胞分化,伴随着pref-1,C/EBP-α水平的变化,和PPAR-γ在3T3-L1细胞中的表达。因此,这些结果表明,增加的DPP4在应激相关的脂肪细胞分化中起着至关重要的作用,可能是通过对慢性应激条件下小鼠GLP-1/脂联素-CTSK轴激活的负调控。
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-α proteins and the adipose tissue levels of CTSK, preadipocyte factor-1, fatty acid binding protein-4, CCAAT/enhancer binding protein-α, GLP-1 receptor, peroxisome proliferator-activated receptor-γ, perilipin2, secreted frizzled-related protein-4, Wnt5α, Wnt11 and β-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-α, and PPAR-γ 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.