Treatment with spexin mitigates diet-induced hepatic steatosis in vivo and in vitro through activation of galanin receptor 2. (15th July 2022)

• Record Type: Journal Article
• Authors: Wang, Mengyuan; Zhu, Ziyue; Kan, Yue; Yu, Mei; Guo, Wancheng; Ju, Mengxian; Wang, Junjun; Yi, Shuxin; Han, Shiyu; Shang, Wenbin; Zhang, Zhenwen; Zhang, Li; Fang, Penghua
• Is Part Of: Molecular and cellular endocrinology. Volume 552(2022)
• Publication Date: 2022-07-15
• Subjects: Spexin -- GALR2 -- NAFLD -- Insulin resistance; ACC1 acetyl-CoA carboxylase 1 -- AMPK adenosine 5'-monophosphate-activated protein kinase -- AUC areas under the curve -- CPT1A carnitine palmitoyl transferase 1A -- DMSO dimethyl sulfoxide -- DMEM Dulbecco's modified eagle medium -- FAS fas death receptor -- FAT/CD36 fatty acid translocase -- FBS fetal bovine serum -- FOXO1 fork head box O1 -- GALR2 galanin receptor 2 -- GALR3 galanin receptor 3 -- H&E hematoxylin and eosin -- HFD high-fat diet -- i.p. intraperitoneal -- IL-1β interleukin-1beta -- IL-10 interleukin-10 -- IL-6 interleukin-6 -- KLF9 kruppel-like factor 9 -- NAFLD Nonalcoholic fatty liver disease -- NASH Nonalcoholic steatohepatitis -- PA sodium palmitic acid -- PEPCK phosphoenolpyruvate carboxykinase -- PGC-1ɑ peroxisome proliferator-activated receptor gamma coactivator-1alpha -- PPARα peroxisome proliferator-activated receptor alpha -- PPARɣ peroxisome proliferator-activated receptor gama -- PVDF polyvinylidene difluoride filter membrane -- qRT-PCR quantificational real-time polymerase chain reaction -- SIRT1 sirtuin 1 -- SREBP-1c sterol regulatory element-binding protein-1c -- TG triglyceride -- TNF-α tumor necrosis factor-alpha; Endocrinology -- Periodicals; Molecular biology -- Periodicals; Cytology -- Periodicals; Endocrinology -- Periodicals; Hormones -- Periodicals; Endocrinologie -- Périodiques; Cytology; Endocrinology; Molecular biology; Periodicals; 573.4
• DOI: 10.1016/j.mce.2022.111688
• Languages: English
• ISSNs: 0303-7207

Abstract

Abstract: It was reported that spexin as an adipocyte-secreted protein could regulate obesity and insulin resistance. However, the specific metabolic contribution of spexin to fatty liver remains incompletely understood. Herein, we investigated the effects of spexin on hepatosteatosis and explored the underlying molecular mechanisms. HFD-fed mice were injected with spexin and/or GALR2 antagonist M871, while PA-induced HepG2 cells were treated with spexin in the absence or presence of M871 for 12 h, respectively. Gene expression in liver tissues and hepatocytes was assessed by qRT-PCR and western blotting, respectively. The results showed that body weight, visceral fat content, liver lipid droplet formation, hepatic intracellular triglyceride, and serum triglyceride were reduced in spexin-treated mice. Furthermore, spexin increased the expression of hepatic CPT1A, PPARα, SIRT1, KLF9, PGC-1α and PEPCK in vivo and in vitro. Additionally, spexin treatment improved glucose tolerance and insulin sensitivity in mice fed the HFD. Interestingly, these spexin-mediated beneficial effects were abolished by the GALR2 antagonist M871 in mice fed HFD and PA-induced HepG2 cells, suggesting that spexin mitigated HFD-induced hepatic steatosis by activating the GALR2, thereby increasing CPT1A, PPARα, SIRT1, KLF9, PGC-1α and PEPCK expression. Taken together, these data suggest that spexin ameliorates NAFLD by improving lipolysis and fatty acid oxidation via activation of GALR2 signaling. Highlights: Spexin augmented lipolysis and fatty acid oxidation of liver in vivo and in vitro. Spexin reversed high fat diet-induced insulin resistance via activation of GALR2. Spexin protected against lipid droplet formation and hepatic TG accumulation through activation of GALR2. Spexin mitigated HFD-induced hepatic steatosis via activation of GALR2.