# Elucidating the mechanism by which Rap1 protects from obesity - Resubmission - 1

> **NIH NIH F30** · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · 2020 · $36,756

## Abstract

Project Summary
 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.

## Key facts

- **NIH application ID:** 9998662
- **Project number:** 5F30DK118901-02
- **Recipient organization:** NEW YORK UNIVERSITY SCHOOL OF MEDICINE
- **Principal Investigator:** Raymond Mario Barry-Herrera
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $36,756
- **Award type:** 5
- **Project period:** 2019-08-01 → 2021-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9998662

## Citation

> US National Institutes of Health, RePORTER application 9998662, Elucidating the mechanism by which Rap1 protects from obesity - Resubmission - 1 (5F30DK118901-02). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/9998662. Licensed CC0.

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