Brown adipose tissue dysfunction promotes heart failure via a trimethylamine N-oxide-dependent mechanism
Low body temperature predicts a poor outcome in patients with heart failure, but the underlying pathological mechanisms and implications are largely unknown. While brown adipose tissue (BAT) was initially characterized as a thermogenic organ, recent studies have suggested it has a crucial role in maintaining systemic metabolic health. Thoracic aortic constriction (TAC) or myocardial infarction (MI) induced BAT dysfunction in mice, leading to significant reduction of body temperature. Metabolomic analysis showed that BAT dysfunction was associated with elevation of plasma trimethylamine N-oxide (TMAO) levels. Administration of TMAO to mice led to significant reduction of phosphocreatine and ATP levels in cardiac tissue via suppression of mitochondrial complex IV activity. In patients with dilated cardiomyopathy, body temperature was low along with elevation of plasma choline and TMAO levels, and positron emission tomography (PET) showed BAT was not detectable in patients with heart failure. These results suggest that maintenance of BAT homeostasis and reducing TMAO production could be potential next generation therapies for heart failure.