Serpina3c attenuates adipose tissue and heart damage during obesity by inhibiting oxidative stress and endoplasmic reticulum stress

Abstract

Abstract Background Adipose tissue (AT) dysfunction is closely associated with obesity-related heart damage. Serpina3c which is highly expressed in mature adipocytes, is a secreted serine protease inhibitor that can regulate AT function. The present study aimed to investigate the effect of Serpina3c on AT and heart during obesity. Methods Wild type (WT) and Serpina3c knockout (3cKO) mice were fed with high-fat diet (HFD) for 20 weeks. AAV-mediated overexpression of Serpina3c was injected locally in epididymal white adipose tissue (eWAT) to examine the effect of Serpina3c. Palmitic acid was established to interfere with the differentiated mature 3T3L1 cells of Serpina3c knockdown (3cKD) or overexpression (3cOV) and corresponding control groups. RNA-seq of mature 3T3L1 cells was performed to assess the effect of Serpina3c on the transcriptome. Results Decrease of Serpina3c protein in AT of obese mice induced by HFD. The body weight and serum cholesterol, triglycerides, free fatty acid and pro-inflammatory cytokines were increased significantly in 3cKO mice. Increased inflammation, fibrosis and apoptosis of AT as well as cardiac fat deposition, inflammation and apoptosis were detected, and the impairment of cardiac diastolic function was aggravated in KO mice. Overexpression of Serpina3c in eWAT alleviated these adverse phenotypes. Through RNA-seq, we found endoplasmic reticulum stress (ERS)-related genes were significantly increased in 3cKD group, but significantly down-regulated in 3cOV group. Oxidative stress was generally considered to be the upstream of ERS, and we detected a significant increase in ROS levels in 3cKO group. Serpina3c alleviated ERS and production of pro-inflammatory cytokines in adipocytes by inhibiting NOX4 and iNOS mediated oxidative stress. Conclusion Our results highlight a protective role for Serpina3c as a novel adipocytokine in the obesity-related heart damage, with Serpina3c conferring protection through inhibiting NOX4 and iNOS mediated oxidative stress to negatively regulate ERS and inflammation in adipocytes.Schematic illustration