Abstract 213: Fat Tissue specific Adipose Triglyceride Lipase as a major determinant for the development of pressure overload-induced heart failure

Introduction: Myocardial metabolism undergoes change in response to pathological cardiac hypertrophy (PH), characterized by increased reliance on glucose oxidation, decreased free fatty acid (FFA) oxidation and a loss of metabolic flexibility. Cardiac metabolism is influenced by other organs such as adipose tissue. Hence, we aimed to investigate the effect of Adipose Triglyceride Lipase (ATGL) in adipose tissue on the development of PH and heart failure (HF) in a pressure overload-induced cardiac hypertrophy model in mice. Methods: Male adipose tissue specific ATGL-knock out (atATGL-KO) and wild type mice (WT) underwent sham surgery (sham) or transverse aortic constriction (TAC). After 11 weeks, mice were sacrificed and organs were harvested. We performed echocardiography one week before and 11 weeks after surgery. Left ventricular mass (LVM), left ventricular mass/tibia length (LVM/TL) and ejection fraction (EF) were calculated. Beta-myosin heavy chain (β-MyHC) was measured in RNA of hearts. Insulin resistance was assessed by an intraperitoneal glucose tolerance test (GTT) and an insulin tolerance test (ITT). FFAs were measured in serum in total. Results: LVM and LVM/TL in WT was significantly higher compared to atATGL-KO after TAC (LVM/TL [mg/mm] WT-TAC: 18,0±2,2; atATGL-KO-TAC: 13,1±2,3; p Beta-MyHC, a marker for PH, was markedly higher in WT-TAC than in atATGL-KO-TAC (WT-TAC: 11,3±3,6; atATGL-KO-TAC: 1.9±0,6; p While WT-TAC showed higher Serum FFA-levels than atATGL-KO-TAC ([mmol/l] WT-TAC: 0,97±0,086; atATGL-KO-TAC: 0,49±0,032; p Conclusion: The present study demonstrates that atATGL is a crucial determinant for the development of pressure overload-induced PH and HI. The lack of ATGL in adipose tissue, the associated reduction of fatty acid release in the circulation and subsequent switches in cardiac energy substrates from free fatty acids to glucose are potential underlying mechanisms of this process.