Project 451182

The obesity epidemic is a serious public health concern. Obesity occurs when energy from food consumption exceeds energy expenditure. Sustaining weight loss with diet and exercise shows limited success because metabolic processes are triggered to resist the maintenance of that lowered weight. Hence, there is a major clinical need to develop new approaches to counter obesity-linked metabolic complications and sustain weight loss. Brown adipose tissue (BAT) wastes energy from food by transforming it to heat in a process called thermogenesis. BAT can offset the adverse effects of obesity by removing sugar and fat from the blood to fuel its thermogenic properties. However, the molecular mechanisms that regulate BAT thermogenesis are not fully understood. Noradrenaline (NA) is the physiological activator of BAT thermogenesis. NA works by binding alpha-adrenergic receptors (alpha-ARs) and beta-adrenergic receptors (beta-ARs). Upon binding NA, these receptors stimulate metabolic pathways inside of brown adipocytes to promote thermogenesis. Beta-AR signaling has received the most attention in the thermogenesis field. However, mice lacking all three forms of beta-AR's can still mount a thermogenic response, indicating that additional thermogenic signaling cascades and metabolic pathways of thermogenesis remain to be discovered. Given that the full thermogenic response of brown adipocytes to NA has been understood for decades to require alpha-AR and beta-AR pathways, the large focus on beta-AR signaling has left the alpha-AR-dependent component a vastly under-explored area of adipocyte biology. Most importantly, the metabolic effector pathways that lie downstream of the cooperative activity of alpha-AR and beta-AR signaling in brown adipocyte thermogenesis have remained elusive. We have now identified this thermogenic pathway. We aim to study the relevance of alpha-AR signaling in BAT thermogenesis and to explore its impact on obesity and metabolic disease.