Deciphering the extra-telomeric function of Rap1, a metabolic regulator counteracting obesity Agnel Sfeir Project Summary: The telomere-binding protein Rap1 is part of the protective protein complex that binds mammalian telomeres. It was recently found to have additional non-telomeric functions, acting as a transcriptional cofactor for different biological processes. To explore its function more thoroughly, we disrupted mouse Rap1 in vivo and reported its unanticipated role in metabolic regulation and body-weight homeostasis. Rap1 inhibition resulted in dysregulation of hepatic and adipose function, leading to glucose intolerance, insulin resistance, liver steatosis, and excess fat accumulation, resulting in eventual late-onset obesity. At the cellular level, Rap1 appears to play a pivotal role in the transcriptional cascade that controls adipocyte differentiation. Using a separation-of-function allele, we found that the metabolic function of Rap1 is independent of its recruitment to TTAGGG binding elements found at telomeres, we identify a number of possible interactors that might aid Rap1 in its metabolic function. In conclusion, our recent study, together with ongoing experiments, underscores an intriguing function for the most conserved telomere-binding protein, forging an interesting link between telomere biology and metabolic signaling. In this project, we will decipher the underlying mechanism by which Rap1 controls metabolism. Specifically, we will explore the in vivo function and mechanism of Rap1 using a set of molecular and genetic tools. We hypothesize that Rap1 regulates adipose tissue function, mainly by impinging on the transcriptional cascade that controls the remodeling of white-to-beige fat. The impact of Rap1 on metabolic gene expression is most consistent with its propensity to behave as an adaptor protein, acting within the context of a larger transcriptional complex that we plan to characterize. The extra-telomeric function of a bone fide telomere binding protein raises the intriguing possibility of telomeres behaving as a storage site for this transcriptional regulator, thereby regulating Rap1 nucleoplasmic pools available to participate in metabolism. All in all, our study is expected to provide insight into Rap1 function in metabolic control, which is pivotal for understanding dysregulation that arises when this process is mismanaged, for example in age-dependent metabolic disorders. Furthermore, our study might help identify potential therapeutic strategies for regulating excess fat accumulation and protecting against metabolic derangements.

Public Health Relevance

Aberrant regulation of glucose and lipid homeostasis leads to metabolic syndrome and obesity. Our recent data demonstrate that loss of Rap1, a bone fide telomere binding protein that is also capable of acting as a transcription factor leads to dysregulated hepatic function, glucose intolerance, and insulin resistance, ultimately culminating in late-onset obesity in the mouse. In this proposal, we will investigate the mechanism by which Rap1 regulates adipose function and metabolic disorders. This work will provide critical insight into a regulatory mechanism used by telomeres to exert control over metabolism and may identify potential therapeutic strategies for regulating excess fat accumulation and age-dependent metabolic disorders.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Integrative Physiology of Obesity and Diabetes Study Section (IPOD)
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Haft, Carol R
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New York University
Anatomy/Cell Biology
Schools of Medicine
New York
United States
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Lazzerini-Denchi, Eros; Sfeir, Agnel (2016) Stop pulling my strings - what telomeres taught us about the DNA damage response. Nat Rev Mol Cell Biol 17:364-78
Sfeir, Agnel; Symington, Lorraine S (2015) Microhomology-Mediated End Joining: A Back-up Survival Mechanism or Dedicated Pathway? Trends Biochem Sci 40:701-714
Yeung, Frank; Ramírez, Cristina M; Mateos-Gomez, Pedro A et al. (2013) Nontelomeric role for Rap1 in regulating metabolism and protecting against obesity. Cell Rep 3:1847-56
Sfeir, Agnel (2012) Telomeres at a glance. J Cell Sci 125:4173-8