Friday, November 22, 2024
11/22/2024
Project Summary/Abstract Type II diabetes (TIID) is the most prevalent form of diabetes and doubles a patient’s risk for cardiovascular disease (CVD) heart failure, independent of additional risk factors. In fact, CVD that occurs in patients with TIID is termed, ‘diabetic cardiomyopathy’ (DC). While impaired cardiac insulin signaling, or insulin resistance, is a major factor in DC pathogenesis, current therapies focus on reducing blood glucose versus restoring insulin sensitivity. Our overall objective to identify the major mediators of cardiac insulin sensitivity and resistance in an effort to identify novel therapeutic targets for DC. Using unbiased genome-wide approaches, we uncovered ‘regulated in development and DNA damage 1’ (Redd1, also known as Ddit4) as the most transcriptionally active, insulin- inducible gene in the murine heart. This correlated with insulin-inducible increases in REDD1 gene and protein expression. REDD1 is an established inhibitor of mTORC1 signaling, however, the mechanisms by which this occurs remain unclear. In addition, REDD1 has been implicated in both insulin sensitivity and resistance, but with no consensus. Our preliminary data demonstrate that, in addition to insulin, fatty acids and high fat diet (HFD) selectively induce REDD1 expression. We also show that insulin increases, while HFD prevents, REDD1 nuclear localization in the heart. Our data also outline a novel potential mechanism whereby insulin increases REDD1 expression, nuclear localization, and chromatin binding, enhancing the transcription of REDD1-bound oxidative metabolic genes and inhibiting the transcription of REDD1-bound autophagic and mitophagic genes in the heart. It is our central hypothesis that high fat drives insulin resistance by preventing insulin-mediated REDD1 nuclear localization, which results in suppressed oxidative metabolism and activated autophagy and mitophagy, mainly via loss of nuclear REDD1-dependent transcriptional regulation, as well as enhanced mTORC1 inhibition. We will test this hypothesis with three specific aims. We will (1) determine the cytosolic role of REDD1 in mediating cardiac insulin resistance, (2) investigate the mechanism of REDD1 nuclear localization and its role in mediating cardiac insulin sensitivity, and (3) examine the effects of REDD1 on insulin-dependent cardiac transcription and gene expression. Here, we will use a novel mouse model with cardiomyocyte REDD1 deletion, as well as isolate these cardiomyocytes for in vitro studies. These mice or cardiomyocytes will be subjected to high fat to induce insulin resistance, using well established models. We will also employ four novel REDD1 mutants to examine the contributions of REDD1-dependent mTORC1 inhibition, nuclear localization, and chromatin binding to cardiac insulin sensitivity versus resistance. Overall, we expect that high fat will prevent insulin-inducible nuclear localization, chromatin binding, and activation of oxidative metabolic and suppression of autophagic and mitophagic genes. Accordingly, we predict that this is a major mechanism by which high fat drives insulin resistance. These studies are critical as we predict that restoring nuclear REDD1 will restore insulin sensitivity and prevent cardiac dysfunction. Investigation of these critical pathways is essential for the developing novel therapies for TIID and DC.
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