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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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14-3-3 Proteins / genetics*
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14-3-3 Proteins / metabolism
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3T3-L1 Cells
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Adipogenesis / genetics*
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Animals
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Autophagy / genetics
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CCAAT-Enhancer-Binding Protein-delta / metabolism
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CCAAT-Enhancer-Binding Proteins / genetics
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CCAAT-Enhancer-Binding Proteins / metabolism
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Cyclin-Dependent Kinase Inhibitor p27 / genetics
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Cyclin-Dependent Kinase Inhibitor p27 / metabolism
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Flow Cytometry
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Gene Expression Profiling
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Hedgehog Proteins / metabolism
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Immunoblotting
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In Vitro Techniques
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Intra-Abdominal Fat / metabolism*
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Kruppel-Like Transcription Factors / genetics
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Kruppel-Like Transcription Factors / metabolism
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Mice
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Mice, Knockout
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Microscopy, Fluorescence
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NIH 3T3 Cells
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Nerve Tissue Proteins / genetics
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Nerve Tissue Proteins / metabolism
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Obesity / genetics*
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Obesity / metabolism
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PPAR gamma / genetics
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PPAR gamma / metabolism
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Real-Time Polymerase Chain Reaction
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Signal Transduction
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Zinc Finger Protein Gli3
Substances
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14-3-3 Proteins
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14-3-3zeta protein, mouse
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CCAAT-Enhancer-Binding Proteins
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CEBPA protein, mouse
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Cdkn1b protein, mouse
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Cebpd protein, mouse
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Gli3 protein, mouse
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Hedgehog Proteins
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Kruppel-Like Transcription Factors
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Nerve Tissue Proteins
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PPAR gamma
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Zinc Finger Protein Gli3
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CCAAT-Enhancer-Binding Protein-delta
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Cyclin-Dependent Kinase Inhibitor p27
Associated data
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GEO/GSE60745
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GEO/GSE66716