title: FADD is a key regulator of lipid metabolism.
abstract: 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.
authors.affiliation: The State Key Laboratory of Pharmaceutical Biotechnology, College of Life Science and School of Stomatology, Affiliated Stomatological Hospital, Nanjing University, Nanjing, China.
authors.forename: Hongqin
authors.initials: H
authors.lastname: Zhuang
authors.affiliation: The State Key Laboratory of Pharmaceutical Biotechnology, College of Life Science and School of Stomatology, Affiliated Stomatological Hospital, Nanjing University, Nanjing, China.
authors.forename: Xueshi
authors.initials: X
authors.lastname: Wang
authors.affiliation: The State Key Laboratory of Pharmaceutical Biotechnology, College of Life Science and School of Stomatology, Affiliated Stomatological Hospital, Nanjing University, Nanjing, China.
authors.forename: Daolong
authors.initials: D
authors.lastname: Zha
authors.affiliation: The State Key Laboratory of Pharmaceutical Biotechnology, College of Life Science and School of Stomatology, Affiliated Stomatological Hospital, Nanjing University, Nanjing, China.
authors.forename: Ziyi
authors.initials: Z
authors.lastname: Gan
authors.affiliation: The State Key Laboratory of Pharmaceutical Biotechnology, College of Life Science and School of Stomatology, Affiliated Stomatological Hospital, Nanjing University, Nanjing, China.
authors.forename: Fangfang
authors.initials: F
authors.lastname: Cai
authors.affiliation: The State Key Laboratory of Pharmaceutical Biotechnology, College of Life Science and School of Stomatology, Affiliated Stomatological Hospital, Nanjing University, Nanjing, China.
authors.forename: Pan
authors.initials: P
authors.lastname: Du
authors.affiliation: The State Key Laboratory of Pharmaceutical Biotechnology, College of Life Science and School of Stomatology, Affiliated Stomatological Hospital, Nanjing University, Nanjing, China.
authors.forename: Yunwen
authors.initials: Y
authors.lastname: Yang
authors.affiliation: The State Key Laboratory of Pharmaceutical Biotechnology, College of Life Science and School of Stomatology, Affiliated Stomatological Hospital, Nanjing University, Nanjing, China.
authors.forename: Bingya
authors.initials: B
authors.lastname: Yang
authors.affiliation: The State Key Laboratory of Pharmaceutical Biotechnology, College of Life Science and School of Stomatology, Affiliated Stomatological Hospital, Nanjing University, Nanjing, China.
authors.forename: Xiangyu
authors.initials: X
authors.lastname: Zhang
authors.affiliation: The State Key Laboratory of Pharmaceutical Biotechnology, College of Life Science and School of Stomatology, Affiliated Stomatological Hospital, Nanjing University, Nanjing, China.
authors.forename: Chun
authors.initials: C
authors.lastname: Yao
authors.affiliation: The State Key Laboratory of Pharmaceutical Biotechnology, College of Life Science and School of Stomatology, Affiliated Stomatological Hospital, Nanjing University, Nanjing, China.
authors.forename: Yuqiang
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: The State Key Laboratory of Pharmaceutical Biotechnology, College of Life Science and School of Stomatology, Affiliated Stomatological Hospital, Nanjing University, Nanjing, China.
authors.forename: Chizhou
authors.initials: C
authors.lastname: Jiang
authors.affiliation: Changzhou High-Tech Research Institute of Nanjing University and Jiangsu TargetPharma Laboratories Inc., Changzhou, China.
authors.forename: Shengwen
authors.initials: S
authors.lastname: Guan
authors.affiliation: The State Key Laboratory of Pharmaceutical Biotechnology, College of Life Science and School of Stomatology, Affiliated Stomatological Hospital, Nanjing University, Nanjing, China.
authors.forename: Xuerui
authors.initials: X
authors.lastname: Zhang
authors.affiliation: The State Key Laboratory of Pharmaceutical Biotechnology, College of Life Science and School of Stomatology, Affiliated Stomatological Hospital, Nanjing University, Nanjing, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.affiliation: The State Key Laboratory of Pharmaceutical Biotechnology, College of Life Science and School of Stomatology, Affiliated Stomatological Hospital, Nanjing University, Nanjing, China.
authors.forename: Wenhui
authors.initials: W
authors.lastname: Jiang
authors.affiliation: The State Key Laboratory of Pharmaceutical Biotechnology, College of Life Science and School of Stomatology, Affiliated Stomatological Hospital, Nanjing University, Nanjing, China.
authors.forename: Qingang
authors.initials: Q
authors.lastname: Hu
authors.affiliation: 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 hzc1117@nju.edu.cn.
authors.forename: Zi-Chun
authors.identifier: 0000-0002-3740-1639
authors.initials: ZC
authors.lastname: Hua
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D053200:Fas-Associated Death Domain Protein / Q000378:metabolism*; D017353:Gene Deletion; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism; D050356:Lipid Metabolism; D018345:Mice, Knockout; D008820:Mice, Obese; D009154:Mutation; D009687:Nuclear Proteins / Q000378:metabolism; D000078723:Nuclear Receptor Interacting Protein 1; D047493:PPAR alpha / Q000378:metabolism; D011485:Protein Binding; D014158:Transcription, Genetic
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C505534:Fadd protein, mouse; D053200:Fas-Associated Death Domain Protein; D009687:Nuclear Proteins; D000078723:Nuclear Receptor Interacting Protein 1; D047493:PPAR alpha; D005947:Glucose
keywords: FADD; PPAR‐α; lipid metabolism; obesity