# Investigating REDD1 as a mediator of cardiac insulin resistance

> **NIH NIH F31** · VIRGINIA POLYTECHNIC INST AND ST UNIV · 2024 · $42,503

## Abstract

Project Summary/Abstract
Cardiovascular disease (CVD) and type II diabetes (TIID) are intimately linked, as TIID more than doubles a
patient’s risk of developing CVD. This pathology is termed ‘diabetic cardiomyopathy’ (DC), and occurs
independent of other risk factors. A major but poorly understood component of DC pathogenesis is impaired
insulin signaling, or insulin resistance (IR). However, current therapeutics center on blood glucose management
and reduction, rather than insulin sensitivity restoration. As such, this proposal centers upon the identification
and investigation of putative major molecular mediators of cardiac insulin sensitivity and resistance, in an effort
to identify novel therapeutic targets for DC to reduce disease burden. Utilizing unbiased genome-wide studies,
my laboratory identified ‘regulated in development and DNA damage 1’ (Redd1, also Ddit4) as the most
transcriptionally active, insulin-inducible gene in the murine heart. This increase in transcriptional activity
translated to increases in both REDD1 gene and protein expression. REDD1 is known to inhibit mTORC1
signaling, but the exact mechanism by which this occurs is unknown. Notably, REDD1 is shown to be involved
in both insulin sensitivity and resistance. Our preliminary data indicate that high fat diet (HFD) and fatty acids
increase REDD1 expression, further suggesting a role for REDD1 in IR. Our data also outline a novel mechanism
in which insulin increases REDD1 expression, nuclear localization, and chromatin binding. This increase in
chromatin binding is associated with alterations in transcriptional activity, enhancing the transcriptional activity
of oxidative metabolic genes in the heart. Thus, it is our hypothesis that high fat diet prevents REDD1 nuclear
localization, resulting in suppressed oxidative metabolism mainly via the loss of REDD1-dependent
transcriptional regulation, as well as enhanced inhibition of mTORC1, ultimately driving IR. We will test this
hypothesis with two specific aims. We will, first, determine the role of REDD1 in mediating cardiac insulin
resistance and, second, investigate the mechanism of REDD1 nuclear localization and its transcriptional role in
mediating cardiac insulin sensitivity. Here, we will utilize a novel murine model with cardiac REDD1 deletion for
in vivo studies and isolate cardiomyocytes for in vitro studies. These mice or cardiomyocytes will be subjected
to high fat/fatty acids to induce insulin resistance. We will also employ a novel REDD1 mutant to examine the
contribution of REDD1 nuclear localization to cardiac insulin sensitivity and resistance. Overall, we expect that
high fat will prevent insulin-inducible REDD1 nuclear localization, chromatin binding, and activation of oxidative
metabolic genes. We hypothesize that this is a major mechanism by which high fat mediates IR. These studies
are critical, as we predict that restoration of nuclear REDD1 will restore cardiac sensitivity to insulin, prevent
subsequ...

## Key facts

- **NIH application ID:** 10902616
- **Project number:** 1F31HL174075-01
- **Recipient organization:** VIRGINIA POLYTECHNIC INST AND ST UNIV
- **Principal Investigator:** Mason Wheeler
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $42,503
- **Award type:** 1
- **Project period:** 2024-09-10 → 2027-09-09

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10902616

## Citation

> US National Institutes of Health, RePORTER application 10902616, Investigating REDD1 as a mediator of cardiac insulin resistance (1F31HL174075-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10902616. Licensed CC0.

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