title: 14-3-3ζ coordinates adipogenesis of visceral fat.
abstract: The proteins that coordinate complex adipogenic transcriptional networks are poorly understood. 14-3-3ζ is a molecular adaptor protein that regulates insulin signalling and transcription factor networks. Here we report that 14-3-3ζ-knockout mice are strikingly lean from birth with specific reductions in visceral fat depots. Conversely, transgenic 14-3-3ζ overexpression potentiates obesity, without exacerbating metabolic complications. Only the 14-3-3ζ isoform is essential for adipogenesis based on isoform-specific RNAi. Mechanistic studies show that 14-3-3ζ depletion promotes autophagy-dependent degradation of C/EBP-δ, preventing induction of the master adipogenic factors, Pparγ and C/EBP-α. Transcriptomic data indicate that 14-3-3ζ acts upstream of hedgehog signalling-dependent upregulation of Cdkn1b/p27(Kip1). Indeed, concomitant knockdown of p27(Kip1) or Gli3 rescues the early block in adipogenesis induced by 14-3-3ζ knockdown in vitro. Adipocyte precursors in 14-3-3ζKO embryos also appear to have greater Gli3 and p27(Kip1) abundance. Together, our in vivo and in vitro findings demonstrate that 14-3-3ζ is a critical upstream driver of adipogenesis.
authors.affiliation: Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z3.
authors.forename: Gareth E
authors.initials: GE
authors.lastname: Lim
authors.affiliation: Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z3.
authors.forename: Tobias
authors.initials: T
authors.lastname: Albrecht
authors.affiliation: Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z3.
authors.forename: Micah
authors.initials: M
authors.lastname: Piske
authors.affiliation: Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z3.
authors.forename: Karnjit
authors.initials: K
authors.lastname: Sarai
authors.affiliation: Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z3.
authors.forename: Jason T C
authors.identifier: http://orcid.org/0000-0001-8681-8257
authors.initials: JTC
authors.lastname: Lee
authors.affiliation: The Centre for Cancer Biology, SAPathology and University of South Australia, Adelaide, SA 5000, Australia.
authors.forename: Hayley S
authors.initials: HS
authors.lastname: Ramshaw
authors.affiliation: Department of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z3.
authors.forename: Sunita
authors.initials: S
authors.lastname: Sinha
authors.affiliation: Division of Blood Cancers, Australian Centre for Blood Diseases, Monash University, Melbourne, Victoria, VIC 3004, Australia.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Guthridge
authors.affiliation: Institute of Cell Biology and Neuroscience and Buchmann Institute for Molecular Life Sciences, University of Frankfurt, Frankfurt am Main 60438, Germany.
authors.forename: Amparo
authors.initials: A
authors.lastname: Acker-Palmer
authors.affiliation: The Centre for Cancer Biology, SAPathology and University of South Australia, Adelaide, SA 5000, Australia.
authors.forename: Angel F
authors.initials: AF
authors.lastname: Lopez
authors.affiliation: Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z3.
authors.forename: Susanne M
authors.initials: SM
authors.lastname: Clee
authors.affiliation: Department of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z3.
authors.forename: Corey
authors.initials: C
authors.lastname: Nislow
authors.affiliation: Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z3.
authors.forename: James D
authors.initials: JD
authors.lastname: Johnson
mesh_terms: D048948:14-3-3 Proteins / Q000235:genetics* / Q000378:metabolism; D041721:3T3-L1 Cells; D050156:Adipogenesis / Q000235:genetics*; D000818:Animals; D001343:Autophagy / Q000235:genetics; D051743:CCAAT-Enhancer-Binding Protein-delta / Q000378:metabolism; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics / Q000378:metabolism; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D053823:Hedgehog Proteins / Q000378:metabolism; D015151:Immunoblotting; D066298:In Vitro Techniques; D050152:Intra-Abdominal Fat / Q000378:metabolism*; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D041681:NIH 3T3 Cells; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009765:Obesity / Q000235:genetics* / Q000378:metabolism; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction; D000074290:Zinc Finger Protein Gli3
chemical_list: D048948:14-3-3 Proteins; D051743:CCAAT-Enhancer-Binding Protein-delta; D022762:CCAAT-Enhancer-Binding Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D053823:Hedgehog Proteins; D051741:Kruppel-Like Transcription Factors; D009419:Nerve Tissue Proteins; D047495:PPAR gamma; D000074290:Zinc Finger Protein Gli3; C000590975:Ywhaz protein, mouse; C530718:CEBPA protein, mouse; C493961:Cdkn1b protein, mouse; C497253:Cebpd protein, mouse; C465571:Gli3 protein, mouse