title: An alternative splicing program promotes adipose tissue thermogenesis.
abstract: Alternative pre-mRNA splicing expands the complexity of the transcriptome and controls isoform-specific gene expression. Whether alternative splicing contributes to metabolic regulation is largely unknown. Here we investigated the contribution of alternative splicing to the development of diet-induced obesity. We found that obesity-induced changes in adipocyte gene expression include alternative pre-mRNA splicing. Bioinformatics analysis associated part of this alternative splicing program with sequence specific NOVA splicing factors. This conclusion was confirmed by studies of mice with NOVA deficiency in adipocytes. Phenotypic analysis of the NOVA-deficient mice demonstrated increased adipose tissue thermogenesis and improved glycemia. We show that NOVA proteins mediate a splicing program that suppresses adipose tissue thermogenesis. Together, these data provide quantitative analysis of gene expression at exon-level resolution in obesity and identify a novel mechanism that contributes to the regulation of adipose tissue function and the maintenance of normal glycemia.
authors.affiliation: Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, United States.
authors.forename: Santiago
authors.initials: S
authors.lastname: Vernia
authors.affiliation: Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, United States.
authors.forename: Yvonne Jk
authors.initials: YJ
authors.lastname: Edwards
authors.affiliation: Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, United States.
authors.forename: Myoung Sook
authors.initials: MS
authors.lastname: Han
authors.affiliation: Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, United States.|Howard Hughes Medical Institute, Worcester, United States.
authors.forename: Julie
authors.initials: J
authors.lastname: Cavanagh-Kyros
authors.affiliation: Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, United States.|Howard Hughes Medical Institute, Worcester, United States.
authors.forename: Tamera
authors.initials: T
authors.lastname: Barrett
authors.affiliation: Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, United States.
authors.forename: Jason K
authors.initials: JK
authors.lastname: Kim
authors.affiliation: Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, United States.|Howard Hughes Medical Institute, Worcester, United States.
authors.forename: Roger J
authors.identifier: 0000-0002-0130-1652
authors.initials: RJ
authors.lastname: Davis
mesh_terms: D000273:Adipose Tissue / Q000502:physiology*; D017398:Alternative Splicing; D000818:Animals; D000951:Antigens, Neoplasm / Q000032:analysis* / Q000235:genetics; D019295:Computational Biology; D006943:Hyperglycemia; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000090682:Neuro-Oncological Ventral Antigen; D009765:Obesity / Q000503:physiopathology; D016601:RNA-Binding Proteins / Q000032:analysis* / Q000235:genetics; D022722:Thermogenesis
chemical_list: D000951:Antigens, Neoplasm; D000090682:Neuro-Oncological Ventral Antigen; C000608219:Nova1 protein, mouse; C515624:Nova2 protein, mouse; D016601:RNA-Binding Proteins
keywords: JNK; NOVA; adipocyte; cell biology; high fat diet; human; mouse; pre-mRNA splicing; thermogenesis