title: Mutation of mouse Samd4 causes leanness, myopathy, uncoupled mitochondrial respiration, and dysregulated mTORC1 signaling.
abstract: Sterile alpha motif domain containing protein 4 (Samd4) is an RNA binding protein that mediates translational repression. We identified a Samd4 missense mutation, designated supermodel, that caused leanness and kyphosis associated with myopathy and adipocyte defects in C57BL/6J mice. The supermodel mutation protected homozygous mice from high fat diet-induced obesity, likely by promoting enhanced energy expenditure through uncoupled mitochondrial respiration. Glucose tolerance was impaired due to diminished insulin release in homozygous mutant mice. The defects of metabolism in supermodel mice may be explained by dysregulated mechanistic target of rapamycin complex 1 (mTORC1) signaling, evidenced by hypophosphorylation of 4E-BP1 and S6 in muscle and adipose tissues of homozygous mice. Samd4 may interface with mTORC1 signaling through an interaction with 14-3-3 proteins and with Akt, which phosphorylates Samd4 in vitro.
authors.affiliation: Center for Genetics of Host Defense.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Department of Internal Medicine, Touchstone Diabetes Center.
authors.forename: William
authors.initials: W
authors.lastname: Holland
authors.affiliation: Department of Internal Medicine, Division of Cardiology.
authors.forename: John M
authors.initials: JM
authors.lastname: Shelton
authors.affiliation: Department of Internal Medicine, and.
authors.forename: Aktar
authors.initials: A
authors.lastname: Ali
authors.affiliation: Center for Genetics of Host Defense.
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Zhan
authors.affiliation: Center for Genetics of Host Defense.
authors.forename: Sungyong
authors.initials: S
authors.lastname: Won
authors.affiliation: Center for Genetics of Host Defense.
authors.forename: Wataru
authors.initials: W
authors.lastname: Tomisato
authors.affiliation: Department of Internal Medicine, Division of Hypothalamic Research, University of Texas Southwestern Medical Center, Dallas, TX 75390.
authors.forename: Chen
authors.initials: C
authors.lastname: Liu
authors.affiliation: Center for Genetics of Host Defense.
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Li
authors.affiliation: Center for Genetics of Host Defense.
authors.forename: Eva Marie Y
authors.initials: EM
authors.lastname: Moresco
authors.affiliation: Center for Genetics of Host Defense, bruce.beutler@utsouthwestern.edu.
authors.forename: Bruce
authors.initials: B
authors.lastname: Beutler
mesh_terms: D048948:14-3-3 Proteins / Q000378:metabolism; D017667:Adipocytes / Q000166:cytology; D020816:Amino Acid Motifs; D000818:Animals; D001823:Body Composition; D005260:Female; D005947:Glucose / Q000378:metabolism; D005951:Glucose Tolerance Test; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008810:Mice, Inbred C57BL; D046912:Multiprotein Complexes / Q000378:metabolism*; D016296:Mutagenesis; D009154:Mutation; D010641:Phenotype; D010766:Phosphorylation; D016601:RNA-Binding Proteins / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics* / Q000502:physiology; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D048948:14-3-3 Proteins; D046912:Multiprotein Complexes; D016601:RNA-Binding Proteins; D012097:Repressor Proteins; C507994:Smaug1 protein, mouse; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D005947:Glucose
keywords: Akt/PKB; N-ethyl-N-nitrosourea