14-3-3ζ coordinates adipogenesis of visceral fat
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Date
2015
Authors
Lim, G.
Albrecht, T.
Piske, M.
Sarai, K.
Lee, J.
Ramshaw, H.
Sinha, S.
Guthridge, M.
Acker-Palmer, A.
Lopez, A.
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Journal article
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Nature Communications, 2015; 6(1):7671-1-7671-17
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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, James D. Johnson
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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.
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