Abstract 5254: Dependence of Beta-3 Adrenergic Signaling on the Adipokine Leptin in Cardiac Myocytes
Introduction: The adipokine leptin modulates cardiac contractility via a NO-dependent mechanism. Beta-3 adrenergic receptors (B3AR) negatively regulate B-adrenergic signaling via NO and are dependent on leptin for normal expression in adipocytes, making B3AR an attractive candidate for crosstalk with leptin in the heart. Accordingly, we tested the hypothesis that cardiac B3AR signaling is dependent on leptin and is severely diminished in leptin-deficient ob/ob mice.
Methods and Results: We studied fura-loaded isolated cardiac myocytes (n=11–25 cells/strain) from B3−/−, ob/ob, and their respective background strains of WT mice (FVB and C57BL6) with a combined treatment of the nonspecific B-agonist isoproterenol (ISO) and the B3-specific agonist BRL37344 (BRL). Continuous administration of ISO “primes” cells to elicit a maximal response from subsequent B3-specific stimulation. Stepwise increases in BRL produced dose-dependent reductions of sarcomere shortening and calcium transients in myocytes from both WT strains. Negative inotropic effects of BRL were absent in B3−/− as expected. Importantly, effects of BRL were markedly diminished in ob/ob myocytes. To confirm that B3AR signaling is dependent on leptin, we performed qPCR of B3AR mRNA in WT and ob/ob myocardial extracts. B3AR mRNA levels were indeed decreased by 78±5% (n=4–5 hearts) in ob/ob vs. WT, and 4 weeks of in vivo leptin repletion restored B3AR mRNA in ob/ob to WT levels.
Conclusions: These findings demonstrate a novel role for leptin in cardiac myocyte physiology, specifically, leptin dependence of B3AR signaling. Our results offer new insight into the mechanisms of obesity-related cardiac dysfunction.