College of Pharmacy, Chonnam National University, Gwangju, Republic of Korea.
Laboratory Animal Medicine, College of Veterinary Medicine, Chonnam National University, Gwangju, Republic of Korea.
Mediators Inflamm. 2022 Aug 26;2022:7853482. doi: 10.1155/2022/7853482. eCollection 2022.
The adipose tissue NLRP3 inflammasome has recently emerged as a contributor to obesity-related metabolic inflammation. Recent studies have demonstrated that the activation of the NLRP3 inflammasome cleaves gasdermin D (GSDMD) and induces pyroptosis, a proinflammatory programmed cell death. However, whether GSDMD is involved in the regulation of adipose tissue function and the development of obesity-induced metabolic disease remains unknown. The aim of the present study was to investigate the role of GSDMD in adipose tissue inflammation as well as whole-body metabolism using GSDMD-deficient mice fed a high-fat diet (HFD) for 30 weeks. The effects of GSDMD deficiency on adipose tissue, liver, and isolated macrophages from wild-type (WT) and GSDMD knockout (KO) mice were examined. In addition, 3T3-L1 cells were used to examine the expression of GSDMD during adipogenesis. The results demonstrate that although HFD-induced inflammation was partly ameliorated in isolated macrophages and liver, adipose tissue remained unaffected by GSDMD deficiency. Compared with the WT HFD mice, GSDMD KO HFD mice exhibited a mild increase in HFD-induced glucose intolerance with increased systemic and adipose tissue IL-1 levels. Interestingly, GSDMD deficiency caused accumulation of fat mass when challenged with HFD, partly by suppressing the expression of peroxisome proliferator-activated receptor gamma (PPAR). The expression of GSDMD mRNA and protein was dramatically suppressed during adipocyte differentiation and was inversely correlated with PPAR expression. Together, these findings indicate that GSDMD is not a prerequisite for HFD-induced adipose tissue inflammation and suggest a noncanonical function of GSDMD in regulation of fat mass through PPAR.
脂肪组织 NLRP3 炎性小体最近被认为是肥胖相关代谢炎症的一个贡献者。最近的研究表明，NLRP3 炎性小体的激活可切割 Gasdermin D (GSDMD) 并诱导细胞焦亡，这是一种促炎程序性细胞死亡。然而，GSDMD 是否参与调节脂肪组织功能和肥胖诱导的代谢性疾病的发展尚不清楚。本研究旨在使用高脂肪饮食（HFD）喂养 30 周的 GSDMD 缺陷小鼠来研究 GSDMD 在脂肪组织炎症以及全身代谢中的作用。研究了 GSDMD 缺陷对野生型（WT）和 GSDMD 敲除（KO）小鼠的脂肪组织、肝脏和分离的巨噬细胞的影响。此外，还使用 3T3-L1 细胞来检查 GSDMD 在脂肪生成过程中的表达。结果表明，尽管 HFD 诱导的炎症在分离的巨噬细胞和肝脏中部分得到改善，但脂肪组织对 GSDMD 缺陷没有影响。与 WT HFD 小鼠相比，GSDMD KO HFD 小鼠在 HFD 诱导的葡萄糖耐量方面表现出轻度增加，全身和脂肪组织中的 IL-1 水平升高。有趣的是，GSDMD 缺陷导致 HFD 时脂肪量增加，部分原因是抑制过氧化物酶体增殖物激活受体 γ (PPAR) 的表达。在脂肪细胞分化过程中，GSDMD mRNA 和蛋白的表达被显著抑制，与 PPAR 表达呈负相关。总之，这些发现表明 GSDMD 不是 HFD 诱导的脂肪组织炎症的必要条件，并表明 GSDMD 通过 PPAR 调节脂肪量的非经典功能。
