Investigating the role of leptin signaling under various metabolic conditions on apoptotic cell death and cellular hypertrophy in a cellular model of diabetic cardiomyopathy

Increasing evidence suggests that leptin, beyond its well-studied function as a satiety hormone, directly mediates cardiac-specific effects by modulating lipid and glucose metabolism. This role of leptin could be of importance for clinical situations, in which leptin levels are tremendously increased, such as in obesity, insulin resistance and diabetes. Direct evidence for leptin-mediated cardiac effects comes mainly from studies performed in rodents, showing that leptin administration caused structural and functional alterations in the heart, including increase in cell surface area, left ventricular hypertrophy, apoptosis, and oxidative stress. Loss of metabolic flexibility due to alterations in leptin signaling observed in ob/ob or db/db mice resulted in reduced glucose oxidation but increased fatty acid utilization, thus promoting accumulation of lipids (di-and triacylglycerols, ceramides), DNA damage and increased cardiomyocyte apoptosis. However, leptin administration could reverse cardiomyocyte apoptosis in ob/ob but not in db/db mice, indicating that leptin signaling may exert cardioprotective effects. Although rodent models demonstrate a cardioprotective role of leptin, such a role remains controversially discussed in the clinical situation. Therefore, a deeper analysis of the exact mechanisms underlying the proposed cardioprotective role of leptin is required to relate the findings from animal studies to the human situation, thereby helping to overcome existing translational barriers.

The project aims to investigate the impact of leptin signaling on cellular hypertrophy and apoptosis in a diabetic cell culture model, a patient specific leptin receptor (LEPR) mutation known to cause early onset of obesity was introduced into human induced pluripotent stem cells (iPSCs) using CRISPR/Cas9 genome editing. Cultivation of iPSC-derived cardiomyocytes (iPSC-CMs) under various metabolic conditions, stimulation of iPSC-CMs with leptin and/or insulin at (patho-)physiological levels, and readouts to determine trophic and apoptotic signaling will be used to analyze the impact of leptin signaling on cardiac remodeling in diabetic cardiomyopathy.

The experiments performed will provide important insights to uncover the role of leptin signaling in myocardial survival and in cardiac hypertrophy under metabolic conditions, which in the clinical situation are correlated with the development of diabetic cardiomyopathy.