Nontelomeric Role for Rap1 in Regulating Metabolism and Protecting against Obesity

Abstract

SUMMARY 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.

A short leucocyte telomere length is associated with development of insulin resistance

“…Studies in rodents show that shorter telomeres may compromise beta cell function in the pancreas [35,36], but in itself this finding is unlikely to explain the LTL-insulin resistance connection in humans, given that insulin resistance largely reflects a diminished response of peripheral tissues to insulin. In mice, short telomeres contribute to metabolic dysfunction through mitochondrial dysfunction [37], whereas mice with disruption of Rap1, a telomere-binding protein, exhibit accumulation of abdominal fat, insulin resistance and other metabolic abnormalities, suggesting a critical role of telomere biology in body weight homeostasis [38,39]. Notably, in the present study the baseline LTL values were not correlated with baseline insulin resistance values, whereas such a relationship was found in the follow-up measurements.…”

Rap1 induces cytokine production in pro-inflammatory macrophages through NFκB signaling and is highly expressed in human atherosclerotic lesions

“…4 Phenotypic characterization of Rap1 deficient mice indicates that Rap1 is involved in signaling pathways connected to metabolism and contributes to body weight regulation. 7,8 The levels of PPARa and PGC1a are reduced in the liver and gonadal white adipose tissue of Rap1 deficient mice. 7 PPARa-and PGC1a-target genes (including carnitine palmitoyl transferase 1a, solute carrier family 27 member 2 and cluster of differentiation 36), which are involved in fatty acid oxidation and lipid uptake, are decreased in the liver of Rap1 deficient mice.…”

“…7 Such metabolic alterations resulted in the development of hepatic steatosis in these mice, a phenomenon that is more severe in females than in males. 7,8 Mice with genetic deletion of Rap1 also exhibit glucose intolerance, insulin resistance and became obese. 7,8 Furthermore, Rap1 may potenitally contribute to chronic inflammation in ageassoicated diseases.…”

“…7,8 Mice with genetic deletion of Rap1 also exhibit glucose intolerance, insulin resistance and became obese. 7,8 Furthermore, Rap1 may potenitally contribute to chronic inflammation in ageassoicated diseases. 9 Expression of Rap1 was initially believed to be restricted to the nucleus, however it was later found to be expressed in the cytoplasm of breast carcinoma BT476 and epithelial carcinoma HeLa S3 cell lines.…”

Repressor activator protein 1–promoted colorectal cell migration is associated with the regulation of Vimentin

“…Interestingly, RAP1 also localizes to extra-telomeric sites and regulates genes involved in metabolism regulation, cell adhesion, and cancer progression, further highlighting RAP1's role in transcriptional regulation. 8,9,32 It is of note that RAP1 is highly expressed in advanced breast cancer tissues and loss of RAP1 sensitizes breast cancer cells to tumor necrosis factor (TNF)α-induced apoptosis, 10 suggesting the pleiotropic roles of RAP1. In our study, we first showed that RAP1 levels were higher in CRC tissues than in normal mucosa, and importantly, its correlation with distant metastasis.…”