Nontelomeric Role for Rap1 in Regulating Metabolism and Protecting against Obesity

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. [Display omitted] •Loss of mouse Rap1 leads to mature-onset obesity•Metabolic defects include glucose intolerance and insulin resistance•Multisystemic derangement due to impaired hepatic and white adipose tissue function•The metabolic function of Rap1 is independent of TRF2-mediated TTAGGG recruitment The telomere-binding protein Rap1 is highly conserved from yeast to humans. Mammalian Rap1 inhibits the unwanted activity of homologous recombination at telomeres and was recently shown to have extratelomeric functions. Here, Sfeir and colleagues find that Rap1 is involved in regulating metabolism and counteracting obesity. The authors use a separation-of-function allele to show that the metabolic role of Rap1 is independent of its association with TRF2, its telomeric repeat binding partner. These data allude to an important link between telomere biology and metabolism.