Brown Adipose Tissue Function Plays a Critical Role in the Development of Heart Failure during Pressure Overload

Heart failure (HF) is one of the main causes of mortality worldwide. It has been reported that low body temperature is linked to cardiac systolic dysfunction as well as to poor clinical outcome in patients with HF; however the underlying mechanisms and pathological implications are largely unknown. Brown adipose tissue (BAT) was initially characterized as an organ involved in thermogenic response, and studies suggest that BAT has crucial roles for the maintenance of systemic metabolism in obesity. Here we show that BAT dysfunction develops with heart failure and promotes cardiac remodeling by inducing systemic metabolic dysfunction. We generated a left ventricular (LV) pressure-overload model in mice with a thoracic aortic constriction (TAC). Cardiac systolic dysfunction developed in four weeks after operation, together with a reduction of the thermogenic response to acute cold exposure and an increase of TUNEL-positive cells in BAT. In-vitro studies with differentiated brown adipocytes suggested that the chronic activation of adrenergic signaling reduced mitochondrial membrane potential and increased apoptotic cells. The transplantation of healthy BAT into mice undergoing TAC improved thermogenic response and ameliorated cardiac dysfunction. Studies with metabolome analyses indicated that BAT dysfunction has a causal role for accumulation of one metabolite which contributes to the progression of cardiac metabolic remodeling and dysfunction. Maintenance of BAT homeostasis would become a novel therapeutic target for heart failure.