Graduate Student Dalhousie University Saint John , New Brunswick, Canada
Disclosure(s): I do not have a relationship with a for-profit and/or a not-for-profit organization to disclose
Blinded Abstract: Obesity-related heart disease is associated with metabolic remodeling and defective organelle function in the cardiomyocyte. Transcription factor EB (TFEB) is the bonafide regulator of lysosomal function. Fatty acid overload depletes TFEB, perturbing lysosomal function. We tested the hypothesis that a decline in cardiomyocyte TFEB during diet-induced obesity (DIO) remodels energy metabolism and triggers cardiac dysfunction. Wild type (TFEBfl/fl -/-) and cardiomyocyte TFEB knockout (TFEBfl/fl Cre/-) mice were fed low fat (LF;10 kcal% from fat) or high fat (HF; 60 kcal% from fat) diet for 20 weeks. Cardiac-specific TFEB deletion led to increased atrial weight and ventricular weight to tibial length ratio, collagen score, myocyte length, and protein markers of hypertrophy in mice fed an HF diet. Cardiomyocytes from HF diet-fed TFEBfl/fl Cre/- mice displayed increased Ca2+ transient amplitude, intracellular Ca2+, increased oleate-induced lipid droplet accumulation, and decreased fatty acid-linked mitochondrial oxygen consumption, suggesting decreased fatty acid oxidation. Isovolumetric relaxation (IVRT) and contraction time (IVCT), readouts of diastolic dysfunction, increased in male and female TFEBfl/fl Cre/- mice upon 20 weeks of HF diet feeding. Notably, female TFEBfl/fl Cre/- mice but not males exhibit aggravated HF diet-induced IVRT and IVCT prolongation, body weight gain, and glucose intolerance. Therefore, during DIO, TFEB insufficiency remodels mitochondrial metabolism and calcium handling, causing cardiac dysfunction. Characterizing metabolic pathways regulated by TFEB will uncover novel druggable targets for obesity-related heart disease.
