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.

Leptin is a hormone produced by the adipose tissue that acts in the brain, stimulating white fat breakdown. We find that the lipolytic effect of leptin is mediated through the action of sympathetic nerve fibers that innervate the adipose tissue. Using intravital two-photon microscopy, we observe that sympathetic nerve fibers establish neuro-adipose junctions, directly "enveloping" adipocytes. Local optogenetic stimulation of sympathetic inputs induces a local lipolytic response and depletion of white adipose mass. Conversely, genetic ablation of sympathetic inputs onto fat pads blocks leptin-stimulated phosphorylation of hormone-sensitive lipase and consequent lipolysis, as do knockouts of dopamine β-hydroxylase, an enzyme required for catecholamine synthesis. Thus, neuro-adipose junctions are necessary and sufficient for the induction of lipolysis in white adipose tissue and are an efferent effector of leptin action. Direct activation of sympathetic inputs to adipose tissues may represent an alternative approach to induce fat loss, circumventing central leptin resistance. PAPERCLIP.

Conditional expression of diphtheria toxin receptor (DTR) is widely used for tissue-specific ablation of cells. However, diphtheria toxin (DT) crosses the blood–brain barrier, which limits its utility for ablating peripheral cells using Cre drivers that are also expressed in the central nervous system (CNS). Here we report the development of a brain-sparing DT, termed BRAINSPAReDT, for tissue-specific genetic ablation of cells outside the CNS. We prevent blood–brain barrier passage of DT through PEGylation, which polarizes the molecule and increases its size. We validate BRAINSPAReDT with regional genetic sympathectomy: BRAINSPAReDT ablates peripheral but not central catecholaminergic neurons, thus avoiding the Parkinson-like phenotype associated with full dopaminergic depletion. Regional sympathectomy compromises adipose tissue thermogenesis, and renders mice susceptible to obesity. We provide a proof of principle that BRAINSPAReDT can be used for Cre/DTR tissue-specific ablation outside the brain using CNS drivers, while consolidating the link between adiposity and the sympathetic nervous system.

Summary Anti-obesity drugs in the amphetamine (AMPH) class act in the brain to reduce appetite and increase locomotion. They are also characterized by adverse cardiovascular effects with origin that, despite absence of any in vivo evidence, is attributed to a direct sympathomimetic action in the heart. Here, we show that the cardiac side effects of AMPH originate from the brain and can be circumvented by PEGylation (PEGyAMPH) to exclude its central action. PEGyAMPH does not enter the brain and facilitates SNS activity via theβ 2 -adrenoceptor, protecting mice against obesity by increasing lipolysis and thermogenesis, coupled to higher heat dissipation, which acts as an energy sink to increase energy expenditure without altering food intake or locomotor activity. Thus, we provide proof-of-principle for a novel class of exclusively peripheral anti-obesity sympathofacilitators that are devoid of any cardiovascular and brain-related side effects.

Since 1980, the incidence of obesity in the world has more than doubled (1), but most prescribed treatments still rely on voluntary modifications of eating behavior (dieting). Longterm compliance to dieting is difficult (2) as it requires eating less and forcefully deciding about what foods to eat. Sugar restriction, for instance, is a common theme in many weightcontrol diets and a must for patients with diabetes. The appetite for sugar is mediated by nutrient-sensing circuits in the brain, which play a role that seems to be conserved across species (3-5). These brain nutrient-sensing circuits are regulated to allow adaptive food intake behavior in response to the metabolic state and hormones such as leptin (6-9).Leptin is an adipose tissue hormone that functions as an afferent signal in a negative feedback loop that maintains homeostatic control of adipose tissue mass (10,11). Leptin is synthesized by adipose tissue and released into the bloodstream in amounts that are proportional to the amount of fat, thus informing the brain about the status of energy reserves. Leptin is a primordial hormone in the regulation of energy homeostasis that acts in hypothalamic neurons to increase energy expenditure and reduce appetite (12). Moreover, leptin controls sugar reward via the central nervous system by acting on glucose-sensing neural circuitry (8,13,14).While most studies have made progress in the identification of leptin action in the brain, Yoshida et al. (15) present a study revealing a role for leptin outside of the brain-in taste buds. They discovered that leptin regulates sweet taste responses in taste buds, thus putting forward the first peripheral mechanism linking sweetness to leptin.In this study, the authors used in situ hybridization to investigate which types of taste cells (TCs) express the long form of the leptin receptor (Ob-Rb). Ob-Rb colocalizes with approximately 40% of taste receptor family 1 member 3 (T1R3)-expressing TCs, which are the sweet-sensing TCs. The study also included electrophysiological analyses of the effect of leptin on TC responses to different taste stimuli: sweet, sour, or bitter. Yoshida et al. discovered that leptin exhibits selective action on T1R3-expressing TCs, suppressing their response to natural sweet sweeteners, such as sucrose, and artificial sweeteners, such as sucralose and saccharin. This suppressive effect of leptin was reversible, dose-dependent, and did not extend to other sensory modalities, such as bitter or sour perception. The authors used mutant mice lacking Ob-Rb (db/db) to discover that the suppressive effect of leptin on TC responses to saccharin was mediated by Ob-Rb. In addition, the study demonstrated by in situ hybridization that the gene SUR1, which encodes for a K ATP channel, was expressed in Ob-Rb/T1R3-expressing TCs. Pharmacological inhibition of this K ATP channel blunts the suppressive effect of leptin on T1R3-expressing TC responses to saccharin. Reciprocally, pharmacological activation of K ATP channels phenocopied the effect of leptin on sac...