College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea.
Laboratory of Developmental Biology and Genomics, BK21 Plus Program for Advanced Veterinary Science, Research Institute for Veterinary Science, College of Veterinary Medicine, and Korea Mouse Phenotyping Center, Seoul National University, Seoul, Republic of Korea
Diabetes. 2021 Sep;70(9):2000-2013. doi: 10.2337/db21-0145. Epub 2021 Jun 29.
Transmembrane 4 L six family member 5 (TM4SF5) functions as a sensor for lysosomal arginine levels and activates the mammalian target of rapamycin complex 1 (mTORC1). While the mTORC1 signaling pathway plays a key role in adipose tissue metabolism, the regulatory function of TM4SF5 in adipocytes remains unclear. In this study we aimed to establish a TM4SF5 knockout (KO) mouse model and investigated the effects of TM4SF5 KO on mTORC1 signaling-mediated autophagy and mitochondrial metabolism in adipose tissue. TM4SF5 expression was higher in inguinal white adipose tissue (iWAT) than in brown adipose tissue and significantly upregulated by a high-fat diet (HFD). TM4SF5 KO reduced mTORC1 activation and enhanced autophagy and lipolysis in adipocytes. RNA sequencing analysis of TM4SF5 KO mouse iWAT showed that the expression of genes involved in peroxisome proliferator-activated receptor α signaling pathways and mitochondrial oxidative metabolism was upregulated. Consequently, TM4SF5 KO reduced adiposity and increased energy expenditure and mitochondrial oxidative metabolism. TM4SF5 KO prevented HFD-induced glucose intolerance and inflammation in adipose tissue. Collectively, the results of our study demonstrate that TM4SF5 regulates autophagy and lipid catabolism in adipose tissue and suggest that TM4SF5 could be therapeutically targeted for the treatment of obesity-related metabolic diseases.
跨膜 4 L 六家族成员 5（TM4SF5）作为溶酶体精氨酸水平的传感器，激活哺乳动物雷帕霉素靶蛋白复合物 1（mTORC1）。虽然 mTORC1 信号通路在脂肪组织代谢中发挥着关键作用，但 TM4SF5 在脂肪细胞中的调节功能尚不清楚。在这项研究中，我们旨在建立 TM4SF5 敲除（KO）小鼠模型，并研究 TM4SF5 KO 对脂肪组织中 mTORC1 信号介导的自噬和线粒体代谢的影响。TM4SF5 在腹股沟白色脂肪组织（iWAT）中的表达高于棕色脂肪组织，并且高脂肪饮食（HFD）显著上调。TM4SF5 KO 降低了 mTORC1 的激活，并增强了脂肪细胞中的自噬和脂肪分解。TM4SF5 KO 小鼠 iWAT 的 RNA 测序分析表明，参与过氧化物酶体增殖物激活受体 α 信号通路和线粒体氧化代谢的基因表达上调。因此，TM4SF5 KO 减少了肥胖症和增加了能量消耗和线粒体氧化代谢。TM4SF5 KO 预防了 HFD 诱导的脂肪组织葡萄糖不耐受和炎症。总之，我们的研究结果表明，TM4SF5 调节脂肪组织中的自噬和脂质分解代谢，并表明 TM4SF5 可能成为治疗肥胖相关代谢疾病的治疗靶点。
