title: Elevated Fra-1 expression causes severe lipodystrophy.
abstract: A shift from osteoblastogenesis to adipogenesis is one of the underlying mechanisms of decreased bone mass and increased fat during aging. We now uncover a new role for the transcription factor Fra-1 in suppressing adipogenesis. Indeed, Fra1 (Fosl1) transgenic (Fra1tg) mice, which developed progressive osteosclerosis as a result of accelerated osteoblast differentiation, also developed a severe general lipodystrophy. The residual fat of these mice appeared immature and expressed lower levels of adipogenic markers, including the fatty acid transporter Cd36 and the CCAAT/enhancer binding protein Cebpa. Consequently accumulation of triglycerides and free fatty acids were detected in the serum of fasting Fra1tg mice. Fra-1 acts cell autonomously because the adipogenic differentiation of Fra1 transgenic primary osteoblasts was drastically reduced, and overexpression of Fra-1 in an adipogenic cell line blocked their differentiation into adipocytes. Strikingly, Cebpa was downregulated in the Fra-1-overexpressing cells and Fra-1 could bind to the Cebpa promoter and directly suppress its activity. Thus, our data add to the known common systemic control of fat and bone mass, a new cell-autonomous level of control of cell fate decision by which the osteogenic transcription factor Fra-1 opposes adipocyte differentiation by inhibiting C/EBPα.
authors.affiliation: Department of Internal Medicine 3, University of Erlangen-Nuremberg, D91054 Erlangen, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Luther
authors.forename: Frank
authors.initials: F
authors.lastname: Driessler
authors.forename: Matthias
authors.initials: M
authors.lastname: Megges
authors.forename: Andreas
authors.initials: A
authors.lastname: Hess
authors.forename: Bettina
authors.initials: B
authors.lastname: Herbort
authors.forename: Vice
authors.initials: V
authors.lastname: Mandic
authors.forename: Mario M
authors.initials: MM
authors.lastname: Zaiss
authors.forename: Anne
authors.initials: A
authors.lastname: Reichardt
authors.forename: Christine
authors.initials: C
authors.lastname: Zech
authors.forename: Jan P
authors.initials: JP
authors.lastname: Tuckermann
authors.forename: Cornelis F
authors.initials: CF
authors.lastname: Calkhoven
authors.forename: Erwin F
authors.initials: EF
authors.lastname: Wagner
authors.forename: Georg
authors.initials: G
authors.lastname: Schett
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: David
mesh_terms: D017667:Adipocytes / Q000166:cytology / Q000378:metabolism; D050156:Adipogenesis / Q000235:genetics / Q000502:physiology; D000818:Animals; D015153:Blotting, Western; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics / Q000378:metabolism; D018955:CD36 Antigens / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D047468:Immunoprecipitation; D008060:Lipodystrophy / Q000209:etiology* / Q000235:genetics / Q000378:metabolism*; D008279:Magnetic Resonance Imaging; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism; D010012:Osteogenesis / Q000235:genetics / Q000502:physiology; D016133:Polymerase Chain Reaction; D011485:Protein Binding; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism*; D000099169:Fos-Related Antigen 1
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; D018955:CD36 Antigens; D016760:Proto-Oncogene Proteins c-fos; D000099169:Fos-Related Antigen 1; C530718:CEBPA protein, mouse