Alteration of NCoR Corepressor Splicing in Mice Causes Increased Body Weight and Hepatosteatosis without Glucose Intolerance

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.

SUPPLEMENTAL MATERIAL

Supplemental material for this article may be found at http://dx.doi.org/10.1128/MCB.00554-14.

ACKNOWLEDGMENTS

This work was funded in part by awards NIDDK52528 and ADA712BS151.

We are exceedingly grateful for the technical assistance of Liming Liu. We also thank Sean Adams, Trina Knotts, John Ramsey, Kent Lloyd, Peter Havel, Fawaz Haj, Craig Warren, James Graham, Doug Rowland, Denise Imai, and Stephen Griffey for advice and assistance. We are also grateful for the skills and advice of the University of California at Davis Mouse Biology Program, the Mouse Metabolic Phenotyping Center (Public Health Services/National Institutes of Health grant no. U24 DK09293), the Center for Molecular and Genomic Imaging, the Comparative Pathology Laboratory, and the University of California at Berkeley QB3 Vincent J. Coates Genomics Sequencing Laboratory.