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 have 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 solute carrier family 6 member 2 (SLC6A2), an NE transporter, and monoamine oxidase A (MAOA), a degradation enzyme. Optogenetic activation of the sympathetic nervous system (SNS) upregulates NE uptake by SAMs and shifts the SAM profile to a more proinflammatory state. NE uptake by SAMs is prevented by genetic deletion of Slc6a2 or inhibition of the encoded transporter. We also observed an increased proportion of SAMs in the SNS of two mouse models of obesity. Genetic ablation of Slc6a2 in SAMs increases brown adipose tissue (BAT) content, causes browning of white fat, increases thermogenesis, and leads to substantial and sustained weight loss in 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, which thus constitutes a potential target for obesity treatment.

Contributions of innate type 2 inflammation to adipose function

“…These findings were disputed in a multilaboratory paper providing strong evidence that WAT macrophages cannot express TH and therefore can't produce catecholamines to beige WAT [97], which called into question the upstream role of eosinophils in beiging as well. Additional studies have provided further insight by revealing the presence of nerve-associated macrophages (NAMs/SAMs) that line TH-producing sympathetic nerves within WAT [98,99]. It was found that the NAMs/SAMs could collect and catabolize catecholamines secreted by nerves, and in this way modulate the available pool of catecholamines that could otherwise act on proximal adipocytes (Figure 1).…”

Nerves in Bone: Evolving Concepts in Pain and Anabolism

“…In bone metastasis, sympathetic signaling via activation of β 2 ‐AR on osteoblasts leads directly to cancer cell recruitment and indirectly to vascular changes that promote colonization of metastatic cancer cells in the bone marrow . Last, NE uptake by bone and immune cells may also contribute to extraneuronal control of local NE homeostasis and actions on the skeleton …”

Leptin and brain–adipose crosstalks

“…However, it is difficult to determine whether these ganglia are part of the SNS, owing to the lack of tyrosine hydroxylase (TH) counterstaining in these studies. Sympathetic thoracic chain ganglia innervating WAT were recently described in mice using TH-specific antibody staining 211 . Thus, coupling tract tracers and retrograde labelling to TH immunostaining will be useful to further determine the nature of the SNS ganglia projection to adipose tissues.…”

“…4). However, there is a caveat associated with PRV tracing studies: glial or phagocytic cells of the immune compartment might accumulate PRV particles, populate the SNS ganglia and be incorrectly interpreted as neurons 211 . Moreover, studies in rats failed to identify innervation of inguinal BAT from ganglion cells in the T13 and the L1–L3 ganglia 110 , again reinforcing the need for further investigations into species-specific innervation differences.…”