14-3-3ζ coordinates adipogenesis of visceral fat

Gareth E. Lim (), Tobias Albrecht, Micah Piske, Karnjit Sarai, Jason T. C Lee, Hayley S. Ramshaw, Sunita Sinha, Mark A. Guthridge, Amparo Acker-Palmer, Angel F. Lopez, Susanne M. Clee, Corey Nislow and James D. Johnson ()
Additional contact information
Gareth E. Lim: University of British Columbia
Tobias Albrecht: University of British Columbia
Micah Piske: University of British Columbia
Karnjit Sarai: University of British Columbia
Jason T. C Lee: University of British Columbia
Hayley S. Ramshaw: The Centre for Cancer Biology, SAPathology and University of South Australia
Sunita Sinha: University of British Columbia
Mark A. Guthridge: Australian Centre for Blood Diseases, Monash University
Amparo Acker-Palmer: Institute of Cell Biology and Neuroscience and Buchmann Institute for Molecular Life Sciences, University of Frankfurt
Angel F. Lopez: The Centre for Cancer Biology, SAPathology and University of South Australia
Susanne M. Clee: University of British Columbia
Corey Nislow: University of British Columbia
James D. Johnson: University of British Columbia

Nature Communications, 2015, vol. 6, issue 1, 1-17

Abstract: 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/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.

Date: 2015
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DOI: 10.1038/ncomms8671

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