Abstract 14169: Deletion of P21 Activated Kinase-1 Modulates Energy Homeostasis and Affects Cardiac Function

Abstract

Introduction: We investigated the consequences of P21-activated kinase-1 (PAK1) deletion on cardiac function, body weight, body composition, and energy balance using a mouse model of global PAK1 knock out. PAK1 is a protein kinase that plays a role in multiple aspects of cardiac health. We hypothesize that PAK1 plays a role in cardiometabolic health including cardiac function and adipose tissue homeostasis. Methods: We used PAK1 -/- in the FVB/N background. We included 10-12-week-old male and female mice. Age and sex-matched FVB/N mice were used as wild-type (WT) controls. Most results included both male and female mice together, as no differences were found between sexes. Ca 2+ kinetics was measured in neonatal cardiomyocytes. Results: Deletion of PAK1 was found to have a significant impact on cardiac function. Specifically, slower Ca 2+ release and reuptake kinetics accompanied with decreased phospholamban phosphorylation was observed in PAK1 -/- mice. These changes affected cardiac systolic (EF, s’) and lusitropy parameters (E/e’, IVRT). Moreover, our findings revealed body weight differences between PAK1 -/- and WT at 12 weeks, accompanied with increased % fat mass and decreased % lean mass in PAK1 -/- , indicating a shift towards adiposity. Further analysis revealed that PAK1 -/- mice had increased weights of white adipose tissue (WAT), and brown adipose tissue (BAT). Moreover, we found increased food intake, increased number of feeding bouts and decreased energy expenditure accompanied with decreased thermogenic markers in subcutaneous WAT and BAT in PAK1 -/- , further contributing to the obesogenic phenotype (see table for results). Conclusions: Deletion of PAK1 affected systolic and diastolic functions, and resulted in increased energy intake, decreased energy expenditure, and increased adiposity. Therefore, targeting PAK1 signaling pathways may represent a promising therapeutic strategy for improving cardiometabolic diseases.