Alteration of NCoR corepressor splicing in mice causes increased body weight and hepatosteatosis without glucose intolerance

Michael L. Goodson, Briana M. Young, Chelsea A. Snyder, Amy C. Schroeder, Martin L. Privalsky

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

Alternative mRNA splicing is an important means of diversifying function in higher eukaryotes. Notably, both NCoR and SMRT corepressors are subject to alternative mRNA splicing, yielding a series of distinct corepressor variants with highly divergent functions. Normal adipogenesis is associated with a switch in corepressor splicing from NCoRω to NCoRδ, which appears to help regulate this differentiation process. We report here that mimicking this development switch in mice by a splice-specific whole-animal ablation of NCoRω is very different from a whole-animal or tissue-specific total NCoR knockout and produces significantly enhanced weight gain on a high-fat diet. Surprisingly, NCoRω-/- mice are protected against diet-induced glucose intolerance despite enhanced adiposity and the presence of multiple additional, prodiabetic phenotypic changes. Our results indicate that the change in NCoR splicing during normal development both helps drive normal adipocyte differentiation and plays a key role in determining a metabolically appropriate storage of excess calories. We also conclude that whole-gene "knockouts" fail to reveal how important gene products are customized, tailored, and adapted through alternative mRNA splicing and thus do not reveal all the functions of the protein products of that gene.

Original languageEnglish (US)
Pages (from-to)4104-4114
Number of pages11
JournalMolecular and Cellular Biology
Volume34
Issue number22
DOIs
StatePublished - 2014

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Co-Repressor Proteins
Glucose Intolerance
Alternative Splicing
Body Weight
Messenger RNA
Nuclear Receptor Co-Repressor 2
Adipogenesis
Gene Knockout Techniques
Adiposity
High Fat Diet
Eukaryota
Adipocytes
Weight Gain
Diet
Genes
Proteins

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Alteration of NCoR corepressor splicing in mice causes increased body weight and hepatosteatosis without glucose intolerance. / Goodson, Michael L.; Young, Briana M.; Snyder, Chelsea A.; Schroeder, Amy C.; Privalsky, Martin L.

In: Molecular and Cellular Biology, Vol. 34, No. 22, 2014, p. 4104-4114.

Research output: Contribution to journalArticle

Goodson, Michael L. ; Young, Briana M. ; Snyder, Chelsea A. ; Schroeder, Amy C. ; Privalsky, Martin L. / Alteration of NCoR corepressor splicing in mice causes increased body weight and hepatosteatosis without glucose intolerance. In: Molecular and Cellular Biology. 2014 ; Vol. 34, No. 22. pp. 4104-4114.
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