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

Abstract

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 cells 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 deletion of Slc6a2 or inhibition of the transporter. We also observed increased SAM content in the SNS of two obesity mouse models. Genetic ablation of Slc6a2 in SAMs increases brown adipose tissue (BAT) content, causes browning of white fat, increases thermogenesis, and leads to significant and sustained weight loss of obese mice. We further show that this pathway is conserved, as human sympathetic ganglia also contain SAMs expressing the analogous molecular machinery for NE clearance, thus constituting a potential target for obesity treatment.