The cellular mechanism(s) linking macrophages to norepinephrine (NE)-mediated regulation of thermogenesis has been a topic of debate. Here, we identify sympathetic neuron-associated macrophages (SAMs) as a population of macrophages that mediate clearance of NE via expression of Slc6a2, an NE transporter, and monoamine oxidase A (MAOa), a degradation enzyme. Optogenetic activation of the SNS upregulates NE uptake by SAMs and shifts the SAM profile to a more pro-inflammatory state. NE uptake by SAMs is prevented by genetic depletion ofSlc6a2or inhibition of the transporter. We also found that obesity increases SAM content in the SNS. In two mouse models of obesity, genetic ablation ofSlc6a2in SAMs increases brown adipose tissue (BAT) content, causes browning of white fat, increases thermogenesis and leads to significant and sustained weight loss. We further show that this pathway is conserved as human sympathetic ganglia also contain SAMs and the analogous molecular machinery for NE clearance, thus constituting a potential target for obesity treatment. SOURCE: Christopher Glass (ckg@ucsd.edu) - Glass Lab University of California, San Diego

Pluto Bioinformatics

GSE103847: Sympathetic neuron-associated macrophages contribute to obesity by importing and metabolizing norepinephrine