Zhuang Hongqin, Wang Xueshi, Zha Daolong, Gan Ziyi, Cai Fangfang, Du Pan, Yang Yunwen, Yang Bingya, Zhang Xiangyu, Yao Chun, Zhou Yuqiang, Jiang Chizhou, Guan Shengwen, Zhang Xuerui, Zhang Jing, Jiang Wenhui, Hu Qingang, Hua Zi-Chun
The State Key Laboratory of Pharmaceutical Biotechnology, College of Life Science and School of Stomatology, Affiliated Stomatological Hospital, Nanjing University, Nanjing, China.
Changzhou High-Tech Research Institute of Nanjing University and Jiangsu TargetPharma Laboratories Inc., Changzhou, China.
EMBO Mol Med. 2016 Aug 1;8(8):895-918. doi: 10.15252/emmm.201505924. Print 2016 Aug.
FADD, a classical apoptotic signaling adaptor, was recently reported to have non-apoptotic functions. Here, we report the discovery that FADD regulates lipid metabolism. PPAR-α is a dietary lipid sensor, whose activation results in hypolipidemic effects. We show that FADD interacts with RIP140, which is a corepressor for PPAR-α, and FADD phosphorylation-mimic mutation (FADD-D) or FADD deficiency abolishes RIP140-mediated transcriptional repression, leading to the activation of PPAR-α. FADD-D-mutant mice exhibit significantly decreased adipose tissue mass and triglyceride accumulation. Also, they exhibit increased energy expenditure with enhanced fatty acid oxidation in adipocytes due to the activation of PPAR-α. Similar metabolic phenotypes, such as reduced fat formation, insulin resistance, and resistance to HFD-induced obesity, are shown in adipose-specific FADD knockout mice. Additionally, FADD-D mutation can reverse the severe genetic obesity phenotype of ob/ob mice, with elevated fatty acid oxidation and oxygen consumption in adipose tissue, improved insulin resistance, and decreased triglyceride storage. We conclude that FADD is a master regulator of glucose and fat metabolism with potential applications for treatment of insulin resistance and obesity.
FADD是一种经典的凋亡信号转导衔接蛋白，最近有报道称其具有非凋亡功能。在此，我们报告发现FADD可调节脂质代谢。PPAR-α是一种膳食脂质传感器，其激活会产生降血脂作用。我们发现FADD与RIP140相互作用，RIP140是PPAR-α的共抑制因子，FADD磷酸化模拟突变（FADD-D）或FADD缺陷会消除RIP140介导的转录抑制，从而导致PPAR-α的激活。FADD-D突变小鼠的脂肪组织质量和甘油三酯积累显著减少。此外，由于PPAR-α的激活，它们在脂肪细胞中表现出能量消耗增加以及脂肪酸氧化增强。脂肪特异性FADD基因敲除小鼠也表现出类似的代谢表型，如脂肪形成减少、胰岛素抵抗以及对高脂饮食诱导的肥胖具有抗性。此外，FADD-D突变可逆转ob/ob小鼠的严重遗传性肥胖表型，使脂肪组织中的脂肪酸氧化和氧消耗增加，胰岛素抵抗改善，甘油三酯储存减少。我们得出结论，FADD是葡萄糖和脂肪代谢的主要调节因子，在治疗胰岛素抵抗和肥胖方面具有潜在应用价值。
