title: Role of Fas-associated death domain-containing protein (FADD) phosphorylation in regulating glucose homeostasis: from proteomic discovery to physiological validation.
abstract: Fas-associated death domain-containing protein (FADD), a classical apoptotic signaling adaptor, participates in different nonapoptotic processes regulated by its phosphorylation. However, the influence of FADD on metabolism, especially glucose homeostasis, has not been evaluated to date. Here, using both two-dimensional electrophoresis and liquid chromatography linked to tandem mass spectrometry (LC/MS/MS), we found that glycogen synthesis, glycolysis, and gluconeogenesis were dysregulated because of FADD phosphorylation, both in MEFs and liver tissue of the mice bearing phosphorylation-mimicking mutation form of FADD (FADD-D). Further physiological studies showed that FADD-D mice exhibited lower blood glucose, enhanced glucose tolerance, and increased liver glycogen content without alterations in insulin sensitivity. Moreover, investigations on the molecular mechanisms revealed that, under basal conditions, FADD-D mice had elevated phosphorylation of Akt with alterations in its downstream signaling, leading to increased glycogen synthesis and decreased gluconeogenesis. Thus, we uncover a novel role of FADD in the regulation of glucose homeostasis by proteomic discovery and physiological validation.
authors.affiliation: The State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, 210093, China;
authors.forename: Chun
authors.initials: C
authors.lastname: Yao
authors.forename: Hongqin
authors.initials: H
authors.lastname: Zhuang
authors.forename: Pan
authors.initials: P
authors.lastname: Du
authors.forename: Wei
authors.initials: W
authors.lastname: Cheng
authors.forename: Bingya
authors.initials: B
authors.lastname: Yang
authors.forename: Shengwen
authors.initials: S
authors.lastname: Guan
authors.forename: Yun
authors.initials: Y
authors.lastname: Hu
authors.forename: Dalong
authors.initials: D
authors.lastname: Zhu
authors.forename: Miller
authors.initials: M
authors.lastname: Christine
authors.forename: Lv
authors.initials: L
authors.lastname: Shi
authors.forename: Zi-Chun
authors.initials: ZC
authors.lastname: Hua
mesh_terms: D000818:Animals; D002460:Cell Line; D053200:Fas-Associated Death Domain Protein / Q000235:genetics / Q000378:metabolism*; D005347:Fibroblasts; D015870:Gene Expression; D005947:Glucose / Q000378:metabolism*; D006003:Glycogen / Q000378:metabolism; D006706:Homeostasis; D008099:Liver / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D010766:Phosphorylation; D040901:Proteomics; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism
chemical_list: D053200:Fas-Associated Death Domain Protein; D006003:Glycogen; D051057:Proto-Oncogene Proteins c-akt; D005947:Glucose