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.
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
. 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.
In recent decades, obesity has become a global public health crisis irrespective of age or gender 20. But according to historic records, concerns over appropriate maintenance of body size have been ...long established. For more than to 2 millennia, the main therapeutic approach to curb excess weight has been to recommend dietary restrictions and regular exercise (Haslam, 2016). Nevertheless, more contemporary studies indicate that the employment of such approaches in the treatment of severely obese patients causes metabolic adaptions which impair their long-term success in weight management 8. These evidences highlight thus, the urgency in the search for a more comprehensive knowledge of the mechanisms that underlie the control of body weight, which would be essential for the development of effective strategies for the treatment of obesity and its comorbidities. Importantly, the discovery of the hormone leptin 33and the use of novel techniques in targeted transgenesis 32 have enabled progress in defining some of the key players and the molecular mechanisms that are involved in the processes that control body size homeostasis and energy balance, and how obesity may disrupt leptin's feedback loop and lead to the pathology of metabolic syndrome. On the light of such findings, here we review how the sympathetic nervous system modulates adipose tissue metabolism downstream of leptin's action on the CNS, with particular focus on how this system may be disrupted in the context of excess adiposity, plus highlight the potential clinical implications arising from a better understanding of the physiologic control of the sympathetic neuro-adipose connection.
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.
Hypoglycemia is a clinical hallmark of severe malaria, the often-lethal outcome of Plasmodium falciparum infection. Here, we report that malaria-associated hypoglycemia emerges from a non-canonical ...resistance mechanism, whereby the infected host reduces glycemia to starve Plasmodium. This hypometabolic response is elicited by labile heme, a byproduct of hemolysis that induces illness-induced anorexia and represses hepatic glucose production. While transient repression of hepatic glucose production prevents unfettered immune-mediated inflammation, organ damage, and anemia, when sustained over time it leads to hypoglycemia, compromising host energy expenditure and adaptive thermoregulation. The latter arrests the development of asexual stages of Plasmodium via a mechanism associated with parasite mitochondrial dysfunction. In response, Plasmodium activates a transcriptional program associated with the reduction of virulence and sexual differentiation toward the generation of transmissible gametocytes. In conclusion, malaria-associated hypoglycemia represents a trade-off of a hypometabolic-based defense strategy that balances parasite virulence versus transmission.
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•Repression of hepatic gluconeogenesis by labile heme drives malarial hypoglycemia•Hypoglycemia lowers Plasmodium virulence•Malarial hypoglycemia compromises host energy metabolism and thermoregulation•Plasmodium undergoes gametocytogenesis in response to hypoglycemia
Malaria-associated hypoglycemia develops as a trade-off of a non-canonical resistance mechanism against Plasmodium infection based on restricting parasite access to glucose. In response, Plasmodium reduces its virulence in favor of transmission, an evolutionarily conserved host-pathogen cooperative metabolic behavior.
The ‘Crosstalks of immunity and metabolism’ Symposium was focused on how the intercommunication between different organs and the immune system affects organismal health. At this meeting, experts in ...immunology and metabolic research provided novel insights into the growing field of immunometabolism. This report attempts to review and integrate views, ideas, propositions, and conclusions that emanated from the symposium.
The recent interest in exploring interactions between immunity and metabolism has inspired the theme of the symposium, which we summarize in this report. This intersection has proven a fruitful approach in the dissection of mechanisms that regulate whole‐body physiology. A multidisciplinary panel of speakers presented research focused on the immunometabolic crosstalks that regulate health in the context of a variety of pathologic insults, such as infections, tissue damage, cancer, and obesity.
Hyperpolarization in nuclear magnetic resonance boosts the signals by several orders of magnitude. Using the singlet spin order of parahydrogen to create large non-equilibrium spin polarization is a ...fast approach to obtain hyperpolarized metabolites in seconds. In recent years, it has attracted particular interest in the field of biomedicine because signal-enhanced and
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C-enriched metabolites allow for real-time metabolic investigations in combination with imaging in vivo. With this, metabolism can be traced and characterized with spatial selectivity in the body. Here, we introduce a method to use signal-enhanced metabolites to study multiple organs in separate injections to obtain real-time kinetics in vivo of these organs. Using hyperpolarized 1-
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C-pyruvate, we measured the kinetics of the conversion from pyruvate to lactate in the brain and the liver of mice. This we did by injecting the hyperpolarized pyruvate two times within half an hour and using each injection to measure the spectra of one region of interest. Organ cross-talk and especially how different organs affect each other in diseases is of major interest and poorly understood, because of the high complexity of biological systems. With the proof-of-principle study provided here, we are introducing a new tool to study organ-related interaction in vivo. It allows the characterization of different organs of the same animal within half an hour, which is enabled by the fast signal enhancement achieved with parahydrogen.
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 theβ2-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.
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•PEGylated amphetamine (PEGyAMPH) does not enter the brain, nor has behavioral effects•PEGyAMPH promotes weight loss, by coupling thermogenesis to heat dissipation•PEGyAMPH is a sympathofacilitator, requiring β2-adrenoceptor function•PEGyAMPH is cardioprotective, unless directly delivered into the brain
PEGyAMPH is a brain-sparing modified amphetamine that is a cardioneutral anti-obesity drug. Unlike amphetamines, which act in the brain to increase satiety and locomotion, PEGyAMPH couples thermogenesis to heat dissipation, activating a whole-body energy sink by simultaneously promoting vasodilation and facilitating the activity of sympathetic neurons.
Nature Communications 8: Article number: 14967 (2017); Published 3 April 2017; Updated 17 May 2017 The financial support for this Article was not fully acknowledged. The Acknowledgements should have ...included the following: ***Human Frontiers Science Program (HFSP) funds the labs of A.I.D. and P.C. ***.
The ferritin heavy/heart chain (FTH) gene encodes the ferroxidase component of the iron (Fe) sequestering ferritin complex, which plays a central role in the regulation of cellular Fe metabolism. ...Here we tested the hypothesis that ferritin regulates organismal Fe metabolism in a manner that impacts energy balance and thermal homeostasis.
We developed a mouse strain, referred herein as FthR26 fl/fl, expressing a tamoxifen-inducible Cre recombinase under the control of the Rosa26 (R26) promoter and carrying two LoxP (fl) sites: one at the 5′end of the Fth promoter and another the 3' end of the first Fth exon. Tamoxifen administration induces global deletion of Fth in adult FthR26Δ/Δ mice, testing whether FTH is required for maintenance of organismal homeostasis.
Under standard nutritional Fe supply, Fth deletion in adult FthR26Δ/Δ mice led to a profound deregulation of organismal Fe metabolism, oxidative stress, inflammation, and multi-organ damage, culminating in death. Unexpectedly, Fth deletion was also associated with a profound atrophy of white and brown adipose tissue as well as with collapse of energy expenditure and thermogenesis. This was attributed mechanistically to mitochondrial dysfunction, as assessed in the liver and in adipose tissue.
The FTH component of ferritin acts as a master regulator of organismal Fe homeostasis, coupling nutritional Fe supply to organismal redox homeostasis, energy expenditure and thermoregulation.
•Ferritin acts as a master regulator of organismal iron metabolism.•Regulation of Fe metabolism by Ferritin sustains organismal redox homeostasis.•Ferritin is essential to support organismal energy expenditure and thermogenesis.•Ferritin is essential to support mitochondrial function and integrity in parenchymal tissues.
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