Gasdermin D Deficiency Does Not Protect Mice from High-Fat Diet-Induced Glucose Intolerance and Adipose Tissue Inflammation

Abstract

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-1β levels. Interestingly, GSDMD deficiency caused accumulation of fat mass when challenged with HFD, partly by suppressing the expression of peroxisome proliferator-activated receptor gamma (PPARγ). The expression of GSDMD mRNA and protein was dramatically suppressed during adipocyte differentiation and was inversely correlated with PPARγ 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 PPARγ.

Inhibition of autophagy with chloroquine dysregulates mitochondrial quality control and energetics in adipocytes

“…Our results showed that chloroquine inhibited MnSOD but increased the total GSH levels and GPX expression. Glutathione is an intracellular antioxidant (Kwon et al 2019), and its increase has been suggested as a compensatory response against oxidative stress in obese adipose tissues (Kobayashi et al 2009;Ma et al 2022). We also observed an increase in GPX3 and GPX4 expression by chloroquine treatment; this finding was consistent with our previous study, which demonstrated that GPX4 gene expression increases in response to inflammation and oxidative stress in the adipose tissue of high-fat diet mice (Ma et al 2022).…”

“…Glutathione is an intracellular antioxidant (Kwon et al 2019), and its increase has been suggested as a compensatory response against oxidative stress in obese adipose tissues (Kobayashi et al 2009;Ma et al 2022). We also observed an increase in GPX3 and GPX4 expression by chloroquine treatment; this finding was consistent with our previous study, which demonstrated that GPX4 gene expression increases in response to inflammation and oxidative stress in the adipose tissue of high-fat diet mice (Ma et al 2022). Since GPX3 and GPX4 exert protective effects on adipocytes (Lee et al 2008;Schwarzler et al 2022), our results implied a compensatory increase in the glutathione system to counteract mitochondrial oxidative stress by chloroquine treatment.…”

Gasdermin‐E‐Dependent Non‐Canonical Pyroptosis Promotes Drug‐Induced Liver Failure by Promoting CPS1 deISGylation and Degradation

“…For instance, GSDMD deficiency failed to protect mice from high-fat diet-induced fatty liver, and GSDMDdependent pyroptosis even alleviated APAP-related DILI. [18,19] This study aimed to investigate the role of GSDME-mediated pyroptosis in APAP-related DILI and explore its underlying mechanisms. Our findings suggest that GSDME-mediated pyroptosis in hepatocytes, rather than in myeloid cells, drives APAP-related DILI by mechanisms involving the promotion of deISGylation and K48-linked ubiquitination degradation of carbamoyl phosphate synthetase-1 (CPS-1), a mitochondrial matrix enzyme that catalyzes the reaction of hepatic urea cycle for ammonia detoxification.…”

“…For instance, GSDMD deficiency failed to protect mice from high‐fat diet‐induced fatty liver, and GSDMD‐dependent pyroptosis even alleviated APAP‐related DILI. [ 18 , 19 ]…”

Physiological functions of glucose transporter-2: From cell physiology to links with diabetes mellitus

“…When transported, monosaccharides such as glucose must successfully cross the barrier of a dense layer of epithelial cells [ 1 ]. These cells contain tiny intercellular spaces produced by the tight junctions, creating a barrier that hinders glucose from entering the membrane pores [ 2 ]. Therefore, glucose entry relies on diffusion-promoting transporters (GLUTs) located in the luminal brush boundary membrane (BBM) and basolateral membrane (BLM) of small intestinal epithelial cells.…”