5:00 p.m. CT Saturday, June 13
The Domingos laboratory investigates sympathetic neuroimmune mechanisms underlying obesity. They discovered neuro-adipose junctions between white adipocytes and the sympathetic nervous system that are necessary and sufficient for fat mass reduction via norepinephrine (NE) signalling (Cell 2015, Nature Comm 2017). They discovered Sympathetic neuron-Associated Macrophages (SAMs) that import and metabolize NE. Abrogation of SAM function promotes long-term amelioration of obesity independently of food intake (Nature Medicine, 2017). This anti-obesity effect relied on genetic loss of function of one of the targets of amphetamine outside of the brain. This genetic result inspired the development of “PEGyAMPH,” a brain-spared anti-obesity amphetamine that facilitates sympathetic activity without cardiovascular side effects via physiological mechanisms, which are unrelated to those of centrally acting amphetamines (Cell Metab 2020). PEGyAMPH couples heat production to its simultaneous dissipation to act as a whole-body energy sink. It acts via β2-adrenoceptors to promote vasodilation, while facilitating the activity of fat burning sympathetic neurons. These findings provide proof-of principle for the development of anti-obesity sympathofacilitators that act peripherally, while circumventing the brain. Ana Domingos is funded by HHMI, Wellcome Trust, ERC, HFSP, EMBO.