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14-3-3? coordinates adipogenesis of visceral fat.

ABSTRACT: The proteins that coordinate complex adipogenic transcriptional networks are poorly understood. 14-3-3? is a molecular adaptor protein that regulates insulin signalling and transcription factor networks. Here we report that 14-3-3?-knockout mice are strikingly lean from birth with specific reductions in visceral fat depots. Conversely, transgenic 14-3-3? overexpression potentiates obesity, without exacerbating metabolic complications. Only the 14-3-3? isoform is essential for adipogenesis based on isoform-specific RNAi. Mechanistic studies show that 14-3-3? depletion promotes autophagy-dependent degradation of C/EBP-?, preventing induction of the master adipogenic factors, Ppar? and C/EBP-?. Transcriptomic data indicate that 14-3-3? 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 14-3-3? knockdown in vitro. Adipocyte precursors in 14-3-3?KO embryos also appear to have greater Gli3 and p27(Kip1) abundance. Together, our in vivo and in vitro findings demonstrate that 14-3-3? is a critical upstream driver of adipogenesis.

SUBMITTER: Lim GE

PROVIDER: S-EPMC4532800 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature

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14-3-3ζ coordinates adipogenesis of visceral fat.

Lim Gareth E GE Albrecht Tobias T Piske Micah M Sarai Karnjit K Lee Jason T C JTC Ramshaw Hayley S HS Sinha Sunita S Guthridge Mark A MA Acker-Palmer Amparo A Lopez Angel F AF Clee Susanne M SM Nislow Corey C Johnson James D JD

Nature communications 20150729

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 ...[more]

PMID: 26220403

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Project description:ObjectiveMetabolic stress primes monocytes for accelerated chemokine-mediated adhesion, migration, and recruitment into vascular lesions by increasing actin remodeling. The mechanism linking metabolic stress to accelerated actin turnover and enhanced monocyte migration was not known. We tested the hypothesis that in metabolically primed monocytes, the acceleration of monocyte chemoattractant protein-1-induced chemotaxis is mediated by the hyperactivation of cofilin.Approach and resultsMetabolic priming was induced by exposing human THP-1 monocytes to diabetic conditions, that is, human native low-density lipoprotein plus high glucose concentrations. In healthy monocytes, monocyte chemoattractant protein-1 induced the phosphorylation and inactivation of cofilin. This response was completely blocked in metabolically primed monocytes but restored by overexpression of the thiol transferase, glutaredoxin 1. Cofilin kinase, LIM kinase 1, and cofilin phosphatase, Slingshot-1L, were not affected by metabolic stress. However, metabolic priming increased 3.8-fold the S-glutathionylation of the Slingshot-1L-binding protein 14-3-3ζ (zeta), resulting in its caspase-dependent degradation. Glutaredoxin 1 overexpression inhibited low-density lipoprotein plus high glucose-induced S-glutathionylation and degradation of 14-3-3ζ. The C25S mutant of 14-3-3ζ was resistant to both S-glutathionylation and degradation induced by low-density lipoprotein plus high glucose. Overexpression of the C25S mutant restored monocyte chemoattractant protein-1-induced cofilin phosphorylation and prevented accelerated migration of metabolically stressed monocytes, suggesting that loss of 14-3-3ζ increases the pool of free Slingshot-1L phosphatase, thereby preventing the phosphorylation and deactivation of cofilin in response to chemokine activation.ConclusionsBy preventing the inactivation of cofilin, metabolic stress-induced degradation of 14-3-3ζ promotes the conversion of blood monocytes into a hypermigratory, proatherogenic phenotype.

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14-3-3? coordinates adipogenesis of visceral fat.

Publications

14-3-3ζ coordinates adipogenesis of visceral fat.

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