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J Biol Chem. 2018 Sep 7;293(36):14100-14111. doi: 10.1074/jbc.RA118.003678. Epub 2018 Jul 20.

The regulatory protein SnoN antagonizes activin/Smad2 protein signaling and thereby promotes adipocyte differentiation and obesity in mice.

Author information

1
From the Department of Molecular and Cell Biology, University of California, Berkeley, California 94720.
2
the Department of Cellular and Molecular Pharmacology, Howard Hughes Medical Institute, University of California, San Francisco, California 94158-2140.
3
From the Department of Molecular and Cell Biology, University of California, Berkeley, California 94720, kluo@berkeley.edu.
4
the Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California 94720 and.

Abstract

Ski-related oncogene SnoN (SnoN or SKIL) regulates multiple signaling pathways in a tissue- and developmental stage-dependent manner and has broad functions in embryonic angiogenesis, mammary gland alveologenesis, cancer, and aging. Here, we report that SnoN also plays a critical role in white adipose tissue (WAT) development by regulating mesenchymal stem cell (MSC) self-renewal and differentiation. We found that SnoN promotes MSC differentiation in the adipocyte lineage by antagonizing activin A/Smad2, but not TGFβ/Smad3 signaling. Mice lacking SnoN or expressing a mutant SnoN defective in binding to the Smads were protected from high-fat diet-induced obesity and insulin resistance, and MSCs lacking a functional SnoN exhibited defective differentiation. We further demonstrated that activin, via Smad2, appears to be the major regulator of WAT development in vivo We also noted that activin A is abundantly expressed in WAT and adipocytes through an autocrine mechanism and promotes MSC self-renewal and inhibits adipogenic differentiation by inducing expression of the gene encoding the homeobox transcription factor Nanog. Of note, SnoN repressed activin/Smad2 signaling and activin A expression, enabling expression of adipocyte-specific transcription factors and promoting adipogenic differentiation. In conclusion, our study has revealed that SnoN plays an important in vivo role in adipocyte differentiation and WAT development in vivo by decreasing activity in the activin/Smad2 signaling pathway.

KEYWORDS:

SKI like proto-oncogene; SKIL; SMAD transcription factor; Smad2; SnoN; activin; adipocyte; adipose tissue; differentiation; obesity; transforming growth factor β (TGF-β)

PMID:
30030373
PMCID:
PMC6130966
[Available on 2019-09-07]
DOI:
10.1074/jbc.RA118.003678
[Indexed for MEDLINE]

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