GSDME Deficiency Sensitizes Mice to Diet-Induced Obesity by suppressing Lipolysis

Yuanyuan Wei; Yue Wu; Zuyi Yuan; Jian; De Ling Yin

doi:10.1530/endoabs.99.OC4.6

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Endocrine Abstracts (2024) 99 OC4.6 | DOI: 10.1530/endoabs.99.OC4.6

ECE2024 Oral Communications Oral Communications 4: Diabetes, Obesity, Metabolism and Nutrition | Part I (6 abstracts)

GSDME Deficiency Sensitizes Mice to Diet-Induced Obesity by suppressing Lipolysis

Yuanyuan Wei ^1,2 , Yue Wu ² , Zuyi Yuan ² , Jian’an Wang ¹ & De Ling Yin ¹

Err

Author affiliations

¹Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Department of Cardiology, Hangzhou, China; ²The First Affiliated Hospital of Xi’an Jiaotong University, Department of Cardiology, Xi’An, China

Background: Obesity, as a worldwide healthcare problem, has been attracting more and more attention. Chronic low-grade inflammation is regarded as an inducer of adipocyte cell death. Pyroptosis,a kind of inflammatory cell death,is involved in various inflammatory diseases.Gasdermin E(GSDME) is a mediator of pyroptosis via the cleavage of caspase-3. However, whether GSDME is involved in the regulation of adipose tissue function remains unknown. In the present study, we aim to investigate the role of GSDME in the development of obesity.

Methods and results: To investigate the role of adipose GSDME, we generate GSDME knockout (GSDME^-/-) mice. As compared with control mice, GSDME-/- mice show obesity when induced with a high-fat diet(HFD), along with hepatic steatosis, insulin resistance, glucose intolerance, and hypercholesterolemia. The effect of GSDME ablation on basic metabolic activity was also evaluated. Under the HFD condition, GSDME^-/- mice showed significantly increased respiratory exchange rate (RER) and reduced oxygen consumption as compared with the controls. Gene array assay of control and GSDME-deficient adipose tissue revealed that lipolysis-associated genes including ATGL were significantly decreased with GSDME ablation in adipose tissues. Furthermore,the epiWAT from HFD-fed control and GSDME^-/- mice was isolated and treated with isoproterenol (ISO). ISO-stimulated glycerol and FFA release were decreased in GSDME^-/- explants.In vivo,the serum FFA and glycerol levels were measured after stimulated lipolysis by CL316243. Serum FFA as well as glycerol levels were significantly lower in GSDME^-/- than control mice 15 min after CL316243 stimulation.

Conclusions: This study reveals that GSDME functions as a positive regulator of lipolysis by the ATGL expression regulation. Deletion of GSDME promoted HFD-induced obesity, impaired adipose function and deteriorated glucose intolerance and insulin resistance. GSDME may be a potential therapeutic target for ameliorating obesity and obesity related metabolic disorders.