Metabolic dysregulation is linked to aging; however, the molecular mechanisms that mediate this time- dependent decline in metabolic homeostasis remain elusive. With an increasingly aging and obese population, it is critical to understand these mechanisms to develop effective therapies to combat metabolic disorders. Recent evidence from our lab and others has identified Rap1 (Repressor/Activator Protein 1), a conserved telomere binding protein with additional extratelomeric functions in gene activation/repression, as a novel regulator of metabolic gene transcription. Rap1 knockout mice (Rap1KO) exhibit adult-onset obesity coincident with metabolic breakdown characterized by glucose intolerance, insulin resistance, dyslipidemia, and hepatosteatosis. Principally, these mice suffer from altered hepatic and white adipose tissue (WAT) function evidenced morphologically and at the level of gene transcription. Gross examination upon surgical dissection shows significant expansion of WAT compartments and ectopic fat deposition in multiple vital organs. In addition, parallel ex vivo experiments suggest a cell-autonomous role for Rap1 in promoting an anti-adipogenic transcriptional program. Altogether, we hypothesize that WAT dysfunction due to improper transcriptional control is a major driver of metabolic derangement in Rap1-deficient mice. How Rap1, which is primarily found at telomeres, can maintain proper metabolic gene transcription of WAT in vivo remains unclear. We hypothesize that Rap1 promotes its metabolic functions by associating at discrete extratelomeric loci with a specific set of partners. To pursue this avenue of inquiry, cutting edge proteomics and high-throughput sequencing approaches will be employed to molecularly characterize Rap1 mechanism of action in regulating transcriptional networks. In addition, mouse model studies will be used to test these mechanisms in vivo. Specifically, this proposal aims to test whether: (i) Extra-telomeric Rap1 functions independent of telomere binding in vivo to control from obesity due to WAT dysfunction (ii) Rap1 acts as an adaptor protein to recruit transcriptional regulatory factors to metabolic gene promoters. By bridging gene promoters to telomeres, Rap1 provides an unprecedented link between telomere biology and metabolic signaling. Thus, this study will provide important insight into how aging and, thus, telomere shortening, drives changes in metabolic homeostasis and supply a potential new therapeutic target for treating metabolic disorders such as obesity and diabetes.
As rates of obesity and diabetes continue to rise, we now find ourselves, for the first time, in a world where the global burden due to overnutrition outpaces that due to undernutrition. Prevalence of obesity increases with age in part due to functional decline of tissues that ensure nutritional balance and energy homeostasis; however, the molecular mechanisms responsible for this decline in function are poorly understood. Elucidating the mechanisms of Rap1 function to protect from obesity and metabolic dysregulation will provide a potential new therapeutic target to combat the obesity epidemic and also further our understanding of the link between physiological dysfunction and aging when telomeres become short.
