For the past few decades, obesity has emerged as one of the major complex diseases affecting human
populations. Despite recent breakthroughs in ameliorating some of the complications associated with this
disease, there are still no effective therapies against obesity
To understand obesity one must know how the adipose tissue (AT) is regulated in normal and affected
conditions. Our knowledge on AT biology has grown significantly in the last few years. This knowledge
has resulted in a clearer picture of how obesity shapes the AT. In this regard, we have decided to focus
our work on one important aspect of AT biology: its neuro-immune regulation. More specifically, we set
out to understand if signals originating from the sympathetic nervous system (SNS) can modulate the
adipose mass, and if such signaling may be regulated at the immunological level.
Here we show that sympathetic nerve bundles target the subcutaneous white AT (WAT). Furthermore,
we demonstrate that the sympathetic axons in the WAT mediate the lipolytic response to leptin.
Importantly, local ablation of the SNS in WAT resulted in decreased leptin activity and blunted lipolysis.
Conversely, by using optogenetics to selectively activate these sympathetic bundles, we observed a local
release of the neurotransmitter norepinephrine (NE) and subsequent fat loss. Our data provide evidence
supporting that sympathetic axons in the AT are both necessary and sufficient for leptin-driven lipolysis
in WAT.
Obesity has long been associated with low-grade inflammation in peripheral tissues and in the central
nervous system (CNS). We have observed that obesity-associated low-grade inflammation also occurs in
the SNS. By using multiphoton microscopy tools, we demonstrate that sympathetic axons in WAT are
populated by a discrete population of macrophages with cellular characteristics different from those of the
macrophages in the surrounding AT. Such Sympathetic-neuron Associated Macrophages (SAM) exhibit
profuse dendritiform processes, which dynamically extend and retract over time. On the other hand, AT
macrophages (ATMs) were smaller, round and had a substantially different cellular displacement. Our
study demonstrates that obesity-induced inflammation of the AT preferentially affects the sympathetic
nerve fibers targeting the WAT and is closely associated with the accumulation of SAMs. Furthermore,
we also observed that obesity drove the up-regulation of pro-inflammatory profiles in both SAMs and
ATMs.
We provide some insight into the possible mechanism that may link macrophages in the AT to the neurotransmitter NE. Our results suggest that SAMs possess the machinery to incorporate NE (via the
Norepinephrine Transporter SLC6A2) and to catabolize it (via the enzyme Monoamine Oxidase-A). Of
note, this machinery was not present in any other macrophage population we studied. In this regard,
the deletion of SLC6A2 in the hematopoietic compartment (by bone marrow transfer from SLC6A2-
KO mice into genetically obese ob/ob mice), improved thermogenic capacities and fat oxidation in this
mouse model of obesity. Overall, our results demonstrate the functional significance of the neuro-immune
interface for the regulation of the adipose tissue during obesity
