14-3-3[zeta] coordinates adipogenesis of visceral fat

• Published in: Nature communications 2015-07, Vol.6, p.7671
• Main Authors: Lim, Gareth E, Albrecht, Tobias, Piske, Micah, Sarai, Karnjit, Lee, Jason T C, Ramshaw, Hayley S, Sinha, Sunita, Guthridge, Mark A, Acker-palmer, Amparo, Lopez, Angel F, Clee, Susanne M, Nislow, Corey, Johnson, James D
• Format: Article
• Language: English
• Subjects: 14-3-3 protein; Adipogenesis; Autophagy; CCAAT/enhancer-binding protein; Complications; Cyclin-dependent kinase inhibitor p27; Depletion; Embryos; Hedgehog protein; Insulin; Phagocytosis; Proteins; RNA-mediated interference; Rodents; Signaling; Upstream
• ISSN: 2041-1723
• DOI: 10.1038/ncomms8671

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/p27Kip1 . Indeed, concomitant knockdown of p27Kip1 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 p27Kip1 abundance. Together, our in vivo and in vitro findings demonstrate that 14-3-3ζ is a critical upstream driver of adipogenesis.