Role of Transcription Factor EB in obesity mediated cardiac dysfunction

Abstract

Lipotoxic complications drive impairment in cardiac function during obesity. Specifically, palmitate toxicity induces ER stress, calcium mishandling and perturbations in lysosomal function by downregulating transcription factor EB (TFEB). This study aims to understand the mechanisms behind palmitate-induced TFEB decline in the heart and the consequences of cardiomyocyte-specific TFEB deletion during obesity. Elevated miR-30b-5p levels were observed in palmitate-treated cells and obese patients' atrial appendages while inhibiting miR-30 prevented TFEB protein decline. Moreover, palmitate significantly accelerated TFEB protein degradation, even in the presence of proteasomal inhibitors, suggesting the involvement of plausible lysosomal degradative mechanisms. Furthermore, cardiomyocyte-specific TFEB deletion in mice fed a high-fat diet resulted in increased body weight, impaired insulin signaling, altered lipid storage, reduced substrate oxidation, changes in calcium transient amplitudes, and cardiac dysfunction, with sex-specific differences. Data from this thesis uncovered the novel role of miR-30b-5p in palmitate-induced TFEB decline and the sex-specific impact of myocyte TFEB insufficiency in the development of obesity-related cardiomyopathy.