Sympathetic Neuroimmunity for Obesity

The brain controls adiposity via central and peripheral neural circuits. We used molecular genetic tools such as optogenetics to probe the connection between peripheral sympathetic neurons and adipocytes. Further, we found this neuro-adipose junction to drive lipolysis via norepinephrine (NE) signaling (1) and that the SNS is necessary and sufficient for fat mass reduction (1,2). As obesity is a chronic inflammatory state, we set to define neuroimmune mechanisms that link inflammation to SNS neurons (3). We report the discovery of Sympathetic neuron-Associated Macrophages (SAMs) that directly regulate the extracellular availability of norepinephrine (NE). We identified the molecular mechanism by which SAMs import and metabolize norepinephrine (NE). Abrogation of the mechanism for the uptake of NE by SAMs increases NE availability, which in turn promotes thermogenesis and browning, and long-term amelioration of obesity independently of food intake (3). These results suggested that blockade of NE uptake outside the brain is sufficient to promote weight loss role thus we chemically modified an amphetamine, which targets the NE transporter, such that it does not cross the BBB. The anti-obesity effect of this novel drug will be discussed.