Nontelomeric Role for Rap1 in Regulating Metabolism and Protecting against Obesity
Frank Yeung,
Cristina M. Ramírez,
Pedro A. Mateos-Gomez,
Alexandra Pinzaru,
Giovanni Ceccarini,
Shaheen Kabir,
Carlos Fernández-Hernando,
Agnel Sfeir
Affiliations
Frank Yeung
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
Cristina M. Ramírez
Departments of Medicine and Cell Biology, NYU School of Medicine, New York, NY 10016, USA
Pedro A. Mateos-Gomez
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
Alexandra Pinzaru
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
Giovanni Ceccarini
Obesity Center at the Endocrine Unit, Department of Clinical and Experimental Medicine, University Hospital of Pisa, Via Paradisa 2, 56100 Pisa, Italy
Shaheen Kabir
Laboratory of Cell Biology and Genetics, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA
Carlos Fernández-Hernando
Departments of Medicine and Cell Biology, NYU School of Medicine, New York, NY 10016, USA
Agnel Sfeir
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
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.