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Sympathetic neuron–associated macrophages act as a local sink for norepinephrine, leading to reduced thermogenesis and increased obesity. 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.

Human mutations in neuropeptide Y (NPY) have been linked to high body mass index but not altered dietary patterns 1 . Here we uncover the mechanism by which NPY in sympathetic neurons 2 , 3 protects from obesity. Imaging of cleared mouse brown and white adipose tissue (BAT and WAT, respectively) established that NPY + sympathetic axons are a smaller subset that mostly maps to the perivasculature; analysis of single-cell RNA sequencing datasets identified mural cells as the main NPY-responsive cells in adipose tissues. We show that NPY sustains the proliferation of mural cells, which are a source of thermogenic adipocytes in both BAT and WAT 4 – 6 . We found that diet-induced obesity leads to neuropathy of NPY + axons and concomitant depletion of mural cells. This defect was replicated in mice with NPY abrogated from sympathetic neurons. The loss of NPY in sympathetic neurons whitened interscapular BAT, reducing its thermogenic ability and decreasing energy expenditure before the onset of obesity. It also caused adult-onset obesity of mice fed on a regular chow diet and rendered them more susceptible to diet-induced obesity without increasing food consumption. Our results indicate that, relative to central NPY, peripheral NPY produced by sympathetic nerves has the opposite effect on body weight by sustaining energy expenditure independently of food intake. We find that, relative to central neuropeptide Y, peripheral neuropeptide Y produced by sympathetic nerves has the opposite effect on body weight by sustaining energy expenditure independently of food intake.

T helper 17 (T H 17) lymphocytes protect mucosal barriers from infections, but also contribute to multiple chronic inflammatory diseases. Their differentiation is controlled by RORγt, a ligand-regulated nuclear receptor. Here we identify the RNA helicase DEAD-box protein 5 (DDX5) as a RORγt partner that coordinates transcription of selective T H 17 genes, and is required for T H 17-mediated inflammatory pathologies. Surprisingly, the ability of DDX5 to interact with RORγt and coactivate its targets depends on intrinsic RNA helicase activity and binding of a conserved nuclear long noncoding RNA (lncRNA), Rmrp , which is mutated in patients with cartilage-hair hypoplasia. A targeted Rmrp gene mutation in mice, corresponding to a gene mutation in cartilage-hair hypoplasia patients, altered lncRNA chromatin occupancy, and reduced the DDX5–RORγt interaction and RORγt target gene transcription. Elucidation of the link between Rmrp and the DDX5–RORγt complex reveals a role for RNA helicases and lncRNAs in tissue-specific transcriptional regulation, and provides new opportunities for therapeutic intervention in T H 17-dependent diseases. The ability of the DEAD-box RNA helicase DDX5 to interact with master transcription factor RORγt is dependent on binding of the long noncoding RNA Rmrp ; the DDX5–RORγt complex coordinates transcription of selective T H 17 genes and is required for the pathogenicity of T H 17 cells. Modifiers of T H 17 cell pathogenicity The ability of the DEAD-box RNA helicase DDX5 to interact with master transcription factor RORγt is shown to be dependent on binding of the long noncoding RNA Rmrp . The DDX5–RORγt complex coordinates transcription of selective T-helper 17 (T H 17) genes, and is required for the pathogenicity of T H 17 lymphocytes. The discovery of this relationship between an RNA helicase and a long noncoding RNA in complex provide new insight into the role of transcriptional regulation and suggests new avenues for research into T H 17-dependent diseases.

Increased body weight is a major factor that interferes with smoking cessation. Nicotine, the main bioactive compound in tobacco, has been demonstrated to have an impact on energy balance, since it affects both feeding and energy expenditure at the central level. Among the central actions of nicotine on body weight, much attention has been focused on its effect on brown adipose tissue (BAT) thermogenesis, though its effect on browning of white adipose tissue (WAT) is unclear. Here, we show that nicotine induces the browning of WAT through a central mechanism and that this effect is dependent on the κ opioid receptor (KOR), specifically in the lateral hypothalamic area (LHA). Consistent with these findings, smokers show higher levels of uncoupling protein 1 (UCP1) expression in WAT, which correlates with smoking status. These data demonstrate that central nicotine-induced modulation of WAT browning may be a target against human obesity. Nicotine reduces food intake and increases energy expenditure in brown adipose tissue. Here the authors show that nicotine also induces white adipose tissue browning via central kappa opioid receptor action.

Olfactomedin-2 (OLFM2) is a pleiotropic glycoprotein emerging as a regulator of energy homeostasis. We here show the expression of OLFM2 to be adipocyte-specific and inversely associated with obesity. OLFM2 levels increase during adipogenesis and are suppressed in inflamed adipocytes. Functionally, OLFM2 deficiency impairs adipocyte differentiation, while its over-production enhances the adipogenic transformation of fat cell progenitors. Loss and gain of function experiments revealed that OLFM2 modulates key metabolic and structural pathways, including PPAR signaling, citrate cycle, fatty acid degradation, axon guidance and focal adhesion in 3T3 cell lines and primary human adipocytes. On the molecular level, OLFM2 deficiency in differentiated adipocytes predominantly downregulates genes involved in cell cycle. Extending these findings in vivo, both whole-body Olfm2 knockout and adipose-specific Olfm2 depletion in mice resulted in impaired adipose cell cycle gene expression, with the latter also displaying fat mass accretion and metabolic dysfunction. Collectively, our results underscore a critical role for OLFM2 in adipocyte biology, and support a causative link between reduced adipose OLFM2 and the pathophysiology of obesity. Olfactomedin-2 is a pleiotropic glycoprotein emerging as a regulator of energy homeostasis via the hypothalamus. The present findings functionally connect adipose-specific OLFM2 to obesity, and highlight its significance in maintaining adipocyte commitment to avoid metabolic disease.

Sugars that contain glucose, such as sucrose, are generally preferred to artificial sweeteners owing to their post-ingestive rewarding effect, which elevates striatal dopamine (DA) release. While the post-ingestive rewarding effect, which artificial sweeteners do not have, signals the nutrient value of sugar and influences food preference, the neural circuitry that mediates the rewarding effect of glucose is unknown. In this study, we show that optogenetic activation of melanin-concentrating hormone (MCH) neurons during intake of the artificial sweetener sucralose increases striatal dopamine levels and inverts the normal preference for sucrose vs sucralose. Conversely, animals with ablation of MCH neurons no longer prefer sucrose to sucralose and show reduced striatal DA release upon sucrose ingestion. We further show that MCH neurons project to reward areas and are required for the post-ingestive rewarding effect of sucrose in sweet-blind Trpm5 −/− mice. These studies identify an essential component of the neural pathways linking nutrient sensing and food reward. Sales of full-sugar fizzy drinks are almost triple those of diet versions, providing real-world confirmation of the laboratory finding that humans, as well as animals, prefer sugar to artificial sweeteners. However, it is not simply that sugary things taste better. Mice with a mutation that prevents them from perceiving sweet tastes still prefer the natural sugar sucrose over the artificial sweetener sucralose. This is because sugar, unlike artificial sweeteners, has nutritional value, and both humans and animals find it rewarding to consume foods with a high caloric content. Consuming sugar has been known to cause certain parts of the brain to release more of the chemical transmitter dopamine, which is used to signal reward, but exactly how this process produces a preference for sugar has been unclear. Now, Domingos et al. have revealed that a brain region called the lateral hypothalamus is responsible for this effect. This region of the brain—which helps to control appetite and which is also connected to the brain’s reward system—normally contains cells called MCH neurons. Domingos et al. show that the natural preference for sucrose over sucralose can be reversed by stimulating the MCH neurons with light, which in turn stimulates dopamine release in reward centers in the brain. Moreover, mutant mice that do not have any MCH neurons in the lateral hypothalamus show a reduced preference for sucrose over sucralose, compared to normal mice, and they release less dopamine than normal mice when they consume sucrose. By demonstrating that MCH neurons are both necessary and sufficient for sensing the nutritional value of sugar, these results provide new insights into the biological basis of sugar cravings. However, given the health implications of excessive sugar consumption, they may ultimately be used to find ways to make sugar less desirable, or to make artificial sweeteners more closely mimic the real thing.

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. Diphtheria toxin selectively kills cells engineered to express the diphtheria toxin receptor (DTR). Here the authors report a PEGylated version of diphtheria toxin that does not enter the brain, allowing for ablation of only peripheral cells when using Cre lines that drive DTR expression in both the periphery and in the brain.

Hypertension is a major health burden worldwide with many cases resistant to current treatments. Hyperactivity of the sympathetic nervous contributes to the etiology and progression of the disease, where emerging evidence suggests that inflammation may underpin the development of sympathetic dysautonomia. This study examined whether macrophages could drive the sympathetic phenotype in Spontaneously Hypertensive Rats (SHR) before animals develop high pressure. Stellate neurons from wild-type control Wistar rats and SHRs were co-cultured with blood leukocytes from their own strain, and also crossed cultured between strains. The calcium transient response to nicotinic stimulation was recorded using Fura-2 calcium imaging, where SHR neurons had a greater calcium transient compared with Wistar neurons. However, when co-cultured with leukocytes, Wistar neurons began to phenocopy the SHR sympathetic hyperactivity, while the SHR neurons themselves were unaltered. Resident leukocyte populations of the SHR and Wistar stellate ganglia were then compared using flow cytometry, where there was a shift in monocyte-macrophage subset proportions. While classical monocyte-macrophages were predominant in the Wistar, there were relatively more of the non-classical subset in the SHR, which have been implicated in pro-inflammatory roles in a number of diseases. When bone marrow-derived macrophages (BMDMs) were co-cultured with stellate neurons, they made Wistar neurons recapitulate the SHR nicotinic stimulated calcium transient. Wistar BMDMs however, had no effect on SHR neurons, even though SHR BMDMs increased SHR neuron responsiveness further above their hyper-responsive state. Taken together, these findings show that macrophages can be potent enhancers of sympathetic neuronal calcium responsiveness, and thus could conceivably play a role in peripheral sympathetic hyperactivity observed in the early stages of hypertension.

Neuroimmunology and immunometabolism are burgeoning topics of study, but the intersection of these two fields is scarcely considered. This interplay is particularly prevalent within adipose tissue, where immune cells and the sympathetic nervous system (SNS) have an important role in metabolic homeostasis and pathology, namely in obesity. In the present Review, we first outline the established reciprocal adipose–SNS relationship comprising the neuroendocrine loop facilitated primarily by adipose tissue-derived leptin and SNS-derived noradrenaline. Next, we review the extensive crosstalk between adipocytes and resident innate immune cells as well as the changes that occur in these secretory and signalling pathways in obesity. Finally, we discuss the effect of SNS adrenergic signalling in immune cells and conclude with exciting new research demonstrating an immutable role for SNS-resident macrophages in modulating SNS–adipose crosstalk. We posit that the latter point constitutes the existence of a new field — neuroimmunometabolism.

Signals from sympathetic neurons and immune cells regulate adipocytes and thereby contribute to fat tissue biology. Interactions between the nervous and immune systems have recently emerged as important regulators of host defence and inflammation 1 – 4 . Nevertheless, it is unclear whether neuronal and immune cells co-operate in brain–body axes to orchestrate metabolism and obesity. Here we describe a neuro-mesenchymal unit that controls group 2 innate lymphoid cells (ILC2s), adipose tissue physiology, metabolism and obesity via a brain–adipose circuit. We found that sympathetic nerve terminals act on neighbouring adipose mesenchymal cells via the β2-adrenergic receptor to control the expression of glial-derived neurotrophic factor (GDNF) and the activity of ILC2s in gonadal fat. Accordingly, ILC2-autonomous manipulation of the GDNF receptor machinery led to alterations in ILC2 function, energy expenditure, insulin resistance and propensity to obesity. Retrograde tracing and chemical, surgical and chemogenetic manipulations identified a sympathetic aorticorenal circuit that modulates ILC2s in gonadal fat and connects to higher-order brain areas, including the paraventricular nucleus of the hypothalamus. Our results identify a neuro-mesenchymal unit that translates cues from long-range neuronal circuitry into adipose-resident ILC2 function, thereby shaping host metabolism and obesity. Signals from the sympathetic nervous system act via mesenchymal stromal cells to regulate the function of group 2 innate lymphoid cells and control adipocyte metabolism.