FADD is a key regulator of lipid metabolism

• Published in: EMBO molecular medicine 2016-08, Vol.8 (8), p.895-918
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Signal Transducing - metabolism; Adipocytes; Adipose tissue; Animal models; Animals; Apoptosis; Cell cycle; Dehydrogenases; Diabetes; EMBO21; Energy; Energy expenditure; Experiments; FADD; FADD protein; Fas-Associated Death Domain Protein - metabolism; Fat metabolism; Fatty acids; Gene Deletion; Gene expression; Gene Expression Regulation; Gene silencing; Glucose - metabolism; Homeostasis; Insulin; Insulin resistance; Lipid Metabolism; Lipids; Metabolic syndrome; Mice, Knockout; Mice, Obese; Mutation; Nuclear Proteins - metabolism; Nuclear Receptor Interacting Protein 1; Obesity; Oxidation; Oxygen consumption; Peroxisome proliferator-activated receptors; Phenotypes; Phosphorylation; PPAR alpha - metabolism; PPAR‐α; Protein Binding; Proteins; Research Article; Software; Transcription, Genetic; Variance analysis
• ISSN: 1757-4676; 1757-4684
• DOI: 10.15252/emmm.201505924

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. Synopsis FADD is a classical adaptor protein in death receptor signaling. For the first time, FADD is shown to have a major role in modulating adipose tissue lipid metabolism by regulating PPAR‐α activation. FADD‐D mutation or FADD deficiency promotes PPAR‐α's activation via RIP140 derepression in vitro and in vivo . FADD‐D mutation or adipose‐specific FADD disruption in mice prevented obesity induced by feeding on a HFD or by leptin deficiency. FADD‐D mutation or adipose‐specific FADD disruption in mice prevented HFD‐induced insulin resistance and decreased adipose tissue inflammation. Graphical Abstract FADD is a classical adaptor protein in death receptor signaling. For the first time, FADD is shown to have a major role in modulating adipose tissue lipid metabolism by regulating PPAR‐α activation.