Ana Domingos

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). The role of SAMs at steady state and obesity will be discussed.

• [1] Zeng W, Pirzgalska RM, Pereira MMA, Kubasova N, Barateiro A, Seixas E, Lu YH, Kozlova A, Voss H, Martins GG, Friedman JM, Domingos AI: Sympathetic Neuro-Adipose Connections Mediate Leptin-Driven Lipolysis. Cell 163 (1): 84–94, 2015 
• [2] Pereira MMA, Mahú I, Seixas E, Martinéz-Sánchez N, Kubasova N, Pirzgalska RM, Cohen P, Dietrich MO, López M, Bernardes GJL, Domingos, AI: A brain-sparing diphtheria toxin for chemical genetic ablation of peripheral cell lineages. Nature Communications 8: 15673, 2017 
• [3] Pirzgalska RM, Seixas E, Seidman JS, Link VM, Sánchez NM , Mahú I, Mendes R, Gres V, Kubasova N, Morris I, Arús BA, Larabee CM, Vasques M, Tortosa F, Sousa AL , Anandan S, Tranfield E, Hahn MK, Iannacone M, Spann NJ, Glass CK, Domingos AI: Sympathetic neuron–associated macrophages contribute to obesity by importing and metabolizing norepinephrine. Nature Medicine 23 (11): 1309-1318, 2017.