title: Nontelomeric role for Rap1 in regulating metabolism and protecting against obesity.
abstract: The mammalian telomere-binding protein Rap1 was recently found to have additional nontelomeric functions, acting as a transcriptional cofactor and a regulator of the NF-κB pathway. Here, we assess the effect of disrupting mouse Rap1 in vivo and report on its unanticipated role in metabolic regulation and body-weight homeostasis. Rap1 inhibition causes dysregulation in hepatic as well as adipose function, leading to glucose intolerance, insulin resistance, liver steatosis, and excess fat accumulation. Furthermore, Rap1 appears to play a pivotal role in the transcriptional cascade that controls adipocyte differentiation in vitro. Using a separation-of-function allele, we show that the metabolic function of Rap1 is independent of its recruitment to TTAGGG binding elements found at telomeres and at other interstitial loci. In conclusion, our study underscores an additional function for the most conserved telomere-binding protein, forging a link between telomere biology and metabolic signaling.
authors.affiliation: The Helen L. and Martin S. Kimmel Center for Biology and Medicine, Skirball Institute of Biomolecular Medicine, Department of Cell Biology, NYU School of Medicine, New York, NY 10016, USA.
authors.forename: Frank
authors.initials: F
authors.lastname: Yeung
authors.forename: Cristina M
authors.initials: CM
authors.lastname: Ramírez
authors.forename: Pedro A
authors.initials: PA
authors.lastname: Mateos-Gomez
authors.forename: Alexandra
authors.initials: A
authors.lastname: Pinzaru
authors.forename: Giovanni
authors.initials: G
authors.lastname: Ceccarini
authors.forename: Shaheen
authors.initials: S
authors.lastname: Kabir
authors.forename: Carlos
authors.initials: C
authors.lastname: Fernández-Hernando
authors.forename: Agnel
authors.initials: A
authors.lastname: Sfeir
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001835:Body Weight / Q000235:genetics*; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D009765:Obesity / Q000235:genetics* / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D000089804:Shelterin Complex; D016615:Telomere / Q000378:metabolism*; D034501:Telomere-Binding Proteins / Q000235:genetics / Q000378:metabolism; D020827:rap1 GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D000089804:Shelterin Complex; C440809:TERF2IP protein, human; D034501:Telomere-Binding Proteins; D020827:rap1 GTP-Binding Proteins