title: RAP1 protects from obesity through its extratelomeric role regulating gene expression.
abstract: RAP1 is part of shelterin, the protective complex at telomeres. RAP1 also binds along chromosome arms, where it is proposed to regulate gene expression. To investigate the nontelomeric roles of RAP1 in vivo, we generated a RAP1 whole-body knockout mouse. These mice show early onset of obesity, which is more severe in females than in males. Rap1-deficient mice show accumulation of abdominal fat, hepatic steatosis, and high-fasting plasma levels of insulin, glucose, cholesterol, and alanine aminotransferase. Gene expression analyses of liver and visceral white fat from Rap1-deficient mice before the onset of obesity show deregulation of metabolic programs, including fatty acid, glucose metabolism, and PPARα signaling. We identify Pparα and Pgc1α as key factors affected by Rap1 deletion in the liver. We show that RAP1 binds to Pparα and Pgc1α loci and modulates their transcription. These findings reveal a role for a telomere-binding protein in the regulation of metabolism.
authors.affiliation: Telomeres and Telomerase Group, Molecular Oncology Program, Spanish National Cancer Research Centre (CNIO), Melchor Fernández Almagro 3, Madrid 28029, Spain.
authors.forename: Paula
authors.initials: P
authors.lastname: Martínez
authors.forename: Gonzalo
authors.initials: G
authors.lastname: Gómez-López
authors.forename: Fernando
authors.initials: F
authors.lastname: García
authors.forename: Evi
authors.initials: E
authors.lastname: Mercken
authors.forename: Sarah
authors.initials: S
authors.lastname: Mitchell
authors.forename: Juana M
authors.initials: JM
authors.lastname: Flores
authors.forename: Rafael
authors.initials: R
authors.lastname: de Cabo
authors.forename: Maria A
authors.initials: MA
authors.lastname: Blasco
mesh_terms: D052436:Adipose Tissue, White / Q000378:metabolism; D000818:Animals; D005260:Female; D015870:Gene Expression; D006801:Humans; D050152:Intra-Abdominal Fat / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009765:Obesity / Q000235:genetics* / Q000378:metabolism; D000089804:Shelterin Complex; D034501:Telomere-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D014162:Transfection; D020827:rap1 GTP-Binding Proteins
chemical_list: D000089804:Shelterin Complex; C440809:TERF2IP protein, human; D034501:Telomere-Binding Proteins; D020827:rap1 GTP-Binding Proteins