Abstract 20251: A Novel Role for Brown Adipose Tissue in Cardioprotection

Abstract

Introduction: Brown adipose tissue (BAT), upon activation by natriuretic peptides and catecholamines, converts the energy of free fatty acids and glucose oxidation into heat (thermogenesis) through uncoupling protein 1 (UCP1). BAT activation has also been reported to increase triglyceride uptake and improve insulin resistance in obesity. Hypothesis: We hypothesized that activated BAT limits myocardial injury and remodeling in a catecholamine-induced cardiomyopathy model. Methods: Isoproterenol (ISO, 60 mg/kg/day) or saline were infused in wild type (WT, n=12) and UCP1-deficient (UCP1-/-, n=11) mice for 14 days using an osmotic minipump. Plasma cardiac troponin I levels (cTnI) were measured after 3 days of treatment. Echocardiograms were performed before and after treatment for 14 days. BAT and LV were harvested for RNA and histology. The experiments were repeated in mice that had undergone prior BAT transplantation (WT to WT n=8; WT to UCP1-/- n=7; UCP1-/- to UCP1-/- n=6). Results: At baseline LV size, mass and ejection fraction (LVEF) were similar in WT and UCP1-/- mice, cTnI was undetectable. Gene expression in BAT of UCP1-/- mice revealed decreased lipid metabolism and oxidative phosphorylation. After 3 days of ISO treatment plasma cTnI was markedly increased in UCP1-/- mice compared to WT (Table). After 14 days of ISO infusion UCP1-/- mice developed greater LV hypertrophy and fibrosis than WT mice (Table). Transplantation of UCP1-/- BAT to UCP1-/- or WT mice did not decrease isoproterenol-induced cTnI release, however, transplantation of WT BAT to UCP1-/- mice reversed the increased cTnI and adverse remodeling. Conclusions: UCP1-deficiency causes BAT dysfunction, and increases cardiomyocyte injury and adverse LV remodeling in a mouse model of catecholamine-induced cardiomyopathy. Cardiomyocyte injury and adverse LV remodeling are rescued by transplantation of functional BAT in to UCP1-/- mice, suggesting that functional BAT is cardioprotective.