Role of PERM1 in the Development of Insulin Resistance and Diabetic Cardiomyopathy During High-Fat Diet Feeding

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dc.contributor.authorJames, Amina N.'Kechien
dc.contributor.committeechairWarren, Junkoen
dc.contributor.committeememberKarch, Jessica Maryen
dc.contributor.committeememberDavy, Kevin P.en
dc.contributor.committeememberDrake, Joshua Chadwicken
dc.contributor.departmentHuman Nutrition, Foods and Exerciseen
dc.date.accessioned2025-03-21T08:00:16Zen
dc.date.available2025-03-21T08:00:16Zen
dc.date.issued2025-03-20en
dc.description.abstractHeart failure is a leading cause of death in the United States, impacting approximately 6.7 million people. Several comorbidities are associated with heart failure, contributing to adverse clinical outcomes. Among these comorbidities, diabetes is highlighted as a prominent risk factor for heart failure, with approximately 20-40% of heart failure patients having type 2 diabetes. As the prevalence of heart failure continues to rise, there is a need for novel therapeutic methods to address this concern. PPARGC1 and ESRR Induced Regulator in Muscle 1 (PERM1) is a striated muscle-specific regulator of mitochondrial bioenergetics, predominantly expressed in skeletal and cardiac muscle. Our group has previously demonstrated that PERM1 is downregulated in both human and mouse failing hearts, and that Perm1-knockout mice exhibit reduced cardiac contractility and energy reserve. However, the role of PERM1 in cardiac dysfunction in diabetes remains unknown. We hypothesized that loss of PERM1 increases vulnerability to metabolic insults and exacerbates diet-induced insulin resistance and cardiac dysfunction. To test this, C57BL/6N male wild-type (WT) and Perm1-knockout (Perm1-KO) mice were fed either a normal diet or a high-fat diet (HFD; 60% calories from fat) for up to 43 weeks. We found that PERM1 expression was upregulated in the hearts of WT mice after 8 weeks of HFD feeding, coinciding with an increased level of carnitine palmitoyltransferase 2 (CPT2), a key enzyme involved in mitochondrial fatty acid uptake. Importantly, both WT and Perm1-KO mice exhibited similar increases in total body weight, fat mass, and fasting blood glucose levels throughout 43 weeks of HFD feeding, suggesting that loss of PERM1 did not accelerate the development of either obesity or diabetes. Echocardiographic assessments showed that WT mice maintained systolic and diastolic function, despite moderate cardiac remodeling, manifested as a subtle but significant increase of left ventricle posterior (LVPW) wall thickness. Unexpectedly, 8 weeks HFD feeding partially restored systolic function in Perm1-KO mice with no change in LVPW thickening. These findings show that while HFD feeding induced obesity and insulin resistance, its effect on cardiac function was relatively moderate and neither was exacerbated by the loss of PERM1. Unexpectedly, this study suggests that HFD feeding in Perm1-KO mice could partially compensate for cardiac dysfunction.en
dc.description.abstractgeneralHeart failure is a major health issue in the U.S, affecting 6.7 million people. About 20-40% of heart failure patients also have type-2 diabetes, making their condition worse. Due to its high prevalence, there is a need for new treatments to address this problem. One potential therapeutic strategy is a protein called PPARGC1 and ESRR Induced Regulator in Muscle 1 (PERM1), which plays a role in energy production in the heart and skeletal muscle. Our group has previously shown that levels of PERM1 drop in the failing heart, leading to weaker heart function. However, the role that PERM1 plays in heart failure with diabetes is unknown. We hypothesized that loss of PERM1 increases metabolic stress, insulin resistance, and cardiac dysfunction. To study how PERM1 affects the heart, we used mice with and without the PERM1 gene and fed them either a normal diet or a high-fat diet (HFD) to mimic conditions like obesity and diabetes. After 8 weeks of a HFD, we found that, while both groups of mice developed obesity and insulin resistance, the absence of PERM1 did not make these issues worse. Interestingly, we also found that HFD increased levels of PERM1 in the heart and increased levels of the protein carnitine palmitoyltransferase 2 (CPT2), which promotes fatty acid uptake in cells. In addition, HFD feeding appeared to partially improve systolic heart function in the mice lacking PERM1. Overall, this study suggests that losing PERM1 does not worsen heart problems in response to a high-fat diet, and in some cases, the diet might even help compensate for heart failure. These findings could lead to new insights into how the heart adapts to stress and metabolic changes.en
dc.description.degreeMaster of Scienceen
dc.format.mediumETDen
dc.identifier.othervt_gsexam:42573en
dc.identifier.urihttps://hdl.handle.net/10919/124894en
dc.language.isoenen
dc.publisherVirginia Techen
dc.rightsCreative Commons Attribution-NonCommercial-ShareAlike 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by-nc-sa/4.0/en
dc.subjectHeart Failureen
dc.subjectDiabetesen
dc.subjectObesityen
dc.subjectHigh-Fat Dieten
dc.subjectPERM1en
dc.subjectCardiac Energeticsen
dc.titleRole of PERM1 in the Development of Insulin Resistance and Diabetic Cardiomyopathy During High-Fat Diet Feedingen
dc.typeThesisen
thesis.degree.disciplineHuman Nutrition, Foods, and Exerciseen
thesis.degree.grantorVirginia Polytechnic Institute and State Universityen
thesis.degree.levelmastersen
thesis.degree.nameMaster of Scienceen

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