14-3-3ζ coordinates adipogenesis of visceral fat

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. 14-3-3 family proteins are adaptor proteins involved in various cellular functions. Here Lim et al . show that 14-3-3ζ regulates adipogenesis in vitro , and the formation of visceral fat in mice, by reducing autophagic degradation of the adipogenic master transcription factor C/EBP-δ.