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Sympathetic neuron-associated macrophages contribute to obesity by importing and metabolizing norepinephrine.
Pirzgalska RM, Seixas E, Seidman JS, Link VM, Sánchez NM, Mahú I, Mendes R, Gres V, Kubasova N, Morris I, Arús BA, Larabee CM, Vasques M, Tortosa F, Sousa AL, Anandan S, Tranfield E, Hahn MK, Iannacone M, Spann NJ, Glass CK, Domingos AI
(2017) Nat Med 23: 1309-1318
MeSH Terms: Animals, CX3C Chemokine Receptor 1, Gene Expression Profiling, Homeostasis, Macrophages, Mice, Mice, Inbred C57BL, Mice, Transgenic, Neurons, Norepinephrine, Norepinephrine Plasma Membrane Transport Proteins, Obesity, Sympathetic Nervous System
Show Abstract · Added February 9, 2018
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.
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13 MeSH Terms
Glucose autoregulation is the dominant component of the hormone-independent counterregulatory response to hypoglycemia in the conscious dog.
Gregory JM, Rivera N, Kraft G, Winnick JJ, Farmer B, Allen EJ, Donahue EP, Smith MS, Edgerton DS, Williams PE, Cherrington AD
(2017) Am J Physiol Endocrinol Metab 313: E273-E283
MeSH Terms: Adipose Tissue, Adrenalectomy, Animals, Blood Glucose, Dogs, Gluconeogenesis, Glucose, Glucose Clamp Technique, Homeostasis, Hypoglycemia, Hypoglycemic Agents, Infusions, Intravenous, Insulin, Liver, Liver Glycogen, Muscle, Skeletal, Norepinephrine, Portal Vein, Sympathetic Nervous System
Show Abstract · Added April 23, 2018
The contribution of hormone-independent counterregulatory signals in defense of insulin-induced hypoglycemia was determined in adrenalectomized, overnight-fasted conscious dogs receiving hepatic portal vein insulin infusions at a rate 20-fold basal. Either euglycemia was maintained () or hypoglycemia (≈45 mg/dl) was allowed to occur. There were three hypoglycemic groups: one in which hepatic autoregulation against hypoglycemia occurred in the absence of sympathetic nervous system input (), one in which autoregulation occurred in the presence of norepinephrine (NE) signaling to fat and muscle (), and one in which autoregulation occurred in the presence of NE signaling to fat, muscle, and liver (). Average net hepatic glucose balance (NHGB) during the last hour for was -0.7 ± 0.1, 0.3 ± 0.1 ( < 0.01 vs. ), 0.7 ± 0.1 ( = 0.01 vs. ), and 0.8 ± 0.1 ( = 0.7 vs. ) mg·kg·min, respectively. Hypoglycemia per se () increased NHGB by causing an inhibition of net hepatic glycogen synthesis. NE signaling to fat and muscle () increased NHGB further by mobilizing gluconeogenic precursors resulting in a rise in gluconeogenesis. Lowering glucose per se decreased nonhepatic glucose uptake by 8.9 mg·kg·min, and the addition of increased neural efferent signaling to muscle and fat blocked glucose uptake further by 3.2 mg·kg·min The addition of increased neural efferent input to liver did not affect NHGB or nonhepatic glucose uptake significantly. In conclusion, even in the absence of increases in counterregulatory hormones, the body can defend itself against hypoglycemia using glucose autoregulation and increased neural efferent signaling, both of which stimulate hepatic glucose production and limit glucose utilization.
Copyright © 2017 the American Physiological Society.
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Hyperinsulinemia and Insulin Resistance in Dopamine β-Hydroxylase Deficiency.
Arnold AC, Garland EM, Celedonio JE, Raj SR, Abumrad NN, Biaggioni I, Robertson D, Luther JM, Shibao CA
(2017) J Clin Endocrinol Metab 102: 10-14
MeSH Terms: Adolescent, Animals, Autonomic Nervous System Diseases, Dopamine beta-Hydroxylase, Droxidopa, Female, Humans, Hyperinsulinism, Insulin, Insulin Resistance, Mice, Norepinephrine, Prognosis
Show Abstract · Added March 14, 2018
Context - Dopamine β-hydroxylase (DBH) deficiency is a rare genetic disorder characterized by failure to convert dopamine to norepinephrine. DBH-deficient patients lack sympathetic adrenergic function and are therefore predisposed to orthostatic hypotension. DBH-deficient mice exhibit hyperinsulinemia, lower plasma glucose levels, and insulin resistance due to loss of tonic sympathetic inhibition of insulin secretion. The impact of DBH deficiency on glucose homeostasis in humans is unknown.
Case Description - We describe the metabolic profile of an adolescent female DBH-deficient patient. The patient underwent genetic testing, cardiovascular autonomic function testing, and evaluation of insulin secretion and sensitivity with hyperglycemic clamp under treatment-naive conditions. All procedures were repeated after 1 year of treatment with the norepinephrine prodrug droxidopa (300 mg, 3 times a day). Genetic testing showed a homozygous mutation in the DBH gene (rs74853476). Under treatment-naive conditions, she had undetectable plasma epinephrine and norepinephrine levels, resulting in sympathetic noradrenergic failure and orthostatic hypotension (-32 mm Hg supine to seated). She had high adiposity (41%) and fasting plasma insulin levels (25 μU/mL), with normal glucose (91 mg/dL). Hyperglycemic clamp revealed increased glucose-stimulated insulin secretion and insulin resistance. Droxidopa restored plasma norepinephrine and improved orthostatic tolerance, with modest effects on glucose homeostasis.
Conclusions - We provide evidence for impairment in cardiovascular autonomic regulation, hyperinsulinemia, enhanced glucose-stimulated insulin secretion, and insulin resistance in a DBH-deficient patient. These metabolic derangements were not corrected by chronic droxidopa treatment. These findings provide insight into the pathophysiology and treatment of DBH deficiency and into the importance of catecholaminergic mechanisms to resting metabolism.
Copyright © 2017 by the Endocrine Society
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13 MeSH Terms
Acute blockade of the Caenorhabditis elegans dopamine transporter DAT-1 by the mammalian norepinephrine transporter inhibitor nisoxetine reveals the influence of genetic modifications of dopamine signaling in vivo.
Bermingham DP, Hardaway JA, Snarrenberg CL, Robinson SB, Folkes OM, Salimando GJ, Jinnah H, Blakely RD
(2016) Neurochem Int 98: 122-8
MeSH Terms: Animals, Caenorhabditis elegans, Caenorhabditis elegans Proteins, Dopamine, Dopamine Plasma Membrane Transport Proteins, Dopamine Uptake Inhibitors, Fluoxetine, Gene Deletion, Mutation, Norepinephrine Plasma Membrane Transport Proteins, Paralysis, Plasmids, Signal Transduction, Swimming
Show Abstract · Added February 15, 2016
Modulation of neurotransmission by the catecholamine dopamine (DA) is conserved across phylogeny. In the nematode Caenorhabditis elegans, excess DA signaling triggers Swimming-Induced Paralysis (Swip), a phenotype first described in animals with loss of function mutations in the presynaptic DA transporter (dat-1). Swip has proven to be a phenotype suitable for the identification of novel dat-1 mutations as well as the identification of novel genes that impact DA signaling. Pharmacological manipulations can also induce Swip, though the reagents employed to date lack specificity and potency, limiting their use in evaluation of dat-1 expression and function. Our lab previously established the mammalian norepinephrine transporter (NET) inhibitor nisoxetine to be a potent antagonist of DA uptake conferred by DAT-1 following heterologous expression. Here we demonstrate the ability of low (μM) concentrations of nisoxetine to trigger Swip within minutes of incubation, with paralysis dependent on DA release and signaling, and non-additive with Swip triggered by dat-1 deletion. Using nisoxetine in combination with genetic mutations that impact DA release, we further demonstrate the utility of the drug for demonstrating contributions of presynaptic DA receptors and ion channels to Swip. Together, these findings reveal nisoxetine as a powerful reagent for monitoring multiple dimensions of DA signaling in vivo, thus providing a new resource that can be used to evaluate contributions of dat-1 and other genes linked to DA signaling without the potential for compensations that attend constitutive genetic mutations.
Copyright © 2016 Elsevier Ltd. All rights reserved.
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14 MeSH Terms
Effects of Antecedent GABA A Receptor Activation on Counterregulatory Responses to Exercise in Healthy Man.
Hedrington MS, Tate DB, Younk LM, Davis SN
(2015) Diabetes 64: 3253-61
MeSH Terms: Adult, Alprazolam, Autonomic Nervous System, Bicycling, Blood Glucose, Epinephrine, Exercise, Female, GABA-A Receptor Agonists, Glucagon, Glucose Clamp Technique, Human Growth Hormone, Humans, Hydrocortisone, Lipolysis, Male, Norepinephrine, Pituitary-Adrenal System, Receptors, GABA-A
Show Abstract · Added July 30, 2015
The aim of this study was to determine whether antecedent stimulation of γ-aminobutyric acid (GABA) A receptors with the benzodiazepine alprazolam can blunt physiologic responses during next-day moderate (90 min) exercise in healthy man. Thirty-one healthy individuals (16 male/15 female aged 28 ± 1 year, BMI 23 ± 3 kg/m(2)) were studied during separate, 2-day protocols. Day 1 consisted of morning and afternoon 2-h hyperinsulinemic-euglycemic or hypoglycemic clamps with or without 1 mg alprazolam given 30 min before a clamp. Day 2 consisted of 90-min euglycemic cycling exercise at 50% VO2max. Despite similar euglycemia (5.3 ± 0.1 mmol/L) and insulinemia (46 ± 6 pmol/L) during day 2 exercise studies, GABA A activation with alprazolam during day 1 euglycemia resulted in significant blunting of plasma epinephrine, norepinephrine, glucagon, cortisol, and growth hormone responses. Lipolysis (glycerol, nonesterified fatty acids) and endogenous glucose production during exercise were also reduced, and glucose infusion rates were increased following prior euglycemia with alprazolam. Prior hypoglycemia with alprazolam resulted in further reduction of glucagon and cortisol responses during exercise. We conclude that prior activation of GABA A pathways can play a significant role in blunting key autonomous nervous system, neuroendocrine, and metabolic physiologic responses during next-day exercise in healthy man.
© 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.
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19 MeSH Terms
Development of antimicrobial peptide defenses of southern leopard frogs, Rana sphenocephala, against the pathogenic chytrid fungus, Batrachochytrium dendrobatidis.
Holden WM, Reinert LK, Hanlon SM, Parris MJ, Rollins-Smith LA
(2015) Dev Comp Immunol 48: 65-75
MeSH Terms: Animals, Anti-Infective Agents, Antimicrobial Cationic Peptides, Chytridiomycota, Microbial Sensitivity Tests, Norepinephrine, Ranidae, Skin
Show Abstract · Added February 12, 2015
Amphibian species face the growing threat of extinction due to the emerging fungal pathogen Batrachochytrium dendrobatidis, which causes the disease chytridiomycosis. Antimicrobial peptides (AMPs) produced in granular glands of the skin are an important defense against this pathogen. Little is known about the ontogeny of AMP production or the impact of AMPs on potentially beneficial symbiotic skin bacteria. We show here that Rana (Lithobates) sphenocephala produces a mixture of four AMPs with activity against B. dendrobatidis, and we report the minimum inhibitory concentration (MIC) of synthesized replicates of these four AMPs tested against B. dendrobatidis. Using mass spectrometry and protein quantification assays, we observed that R. sphenocephala does not secrete a mature suite of AMPs until approximately 12 weeks post-metamorphosis, and geographically disparate populations produce a different suite of peptides. Use of norepinephrine to induce maximal secretion significantly reduced levels of culturable skin bacteria.
Copyright © 2014 Elsevier Ltd. All rights reserved.
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8 MeSH Terms
Striatal dopamine homeostasis is altered in mice following Roux-en-Y gastric bypass surgery.
Reddy IA, Wasserman DH, Ayala JE, Hasty AH, Abumrad NN, Galli A
(2014) ACS Chem Neurosci 5: 943-51
MeSH Terms: Adiposity, Anastomosis, Roux-en-Y, Animals, Body Weight, Caloric Restriction, Corpus Striatum, Diet, High-Fat, Dopamine, Gastric Bypass, Homeostasis, Immunoblotting, Male, Mice, Inbred C57BL, Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinase 3, Norepinephrine, Obesity, Phosphorylation, Receptor, Insulin, Tyrosine 3-Monooxygenase
Show Abstract · Added January 21, 2015
Roux-en-Y gastric bypass (RYGB) is an effective treatment for obesity. Importantly, weight loss following RYGB is thought to result in part from changes in brain-mediated regulation of appetite and food intake. Dopamine (DA) within the dorsal striatum plays an important role in feeding behavior; we therefore hypothesized that RYGB alters DA homeostasis in this subcortical region. In the current study, obese RYGB-operated mice consumed significantly less of a high-fat diet, weighed less by the end of the study, and exhibited lower adiposity than obese sham-operated mice. Interestingly, both RYGB and caloric restriction (pair feeding) resulted in elevated DA and reduced norepinephrine (NE) tissue levels compared with ad libitum fed sham animals. Consequently, the ratio of NE to DA, a measure of DA turnover, was significantly reduced in both of these groups. The RYGB mice additionally exhibited a significant increase in phosphorylation of tyrosine hydroxylase at position Ser31, a key regulatory site of DA synthesis. This increase was associated with augmented expression of extracellular-signal-regulated kinases ERK1/2, the kinase targeting Ser31. Additionally, RYGB has been shown in animal models and humans to improve insulin sensitivity and glycemic control. Curiously, we noted a significant increase in the expression of insulin receptor-β in RYGB animals in striatum (a glucosensing brain region) compared to sham ad libitum fed mice. These data demonstrate that RYGB surgery is associated with altered monoamine homeostasis at the level of the dorsal striatum, thus providing a critical foundation for future studies exploring central mechanisms of weight loss in RYGB.
1 Communities
4 Members
1 Resources
20 MeSH Terms
Excitatory drive onto dopaminergic neurons in the rostral linear nucleus is enhanced by norepinephrine in an α1 adrenergic receptor-dependent manner.
Williams MA, Li C, Kash TL, Matthews RT, Winder DG
(2014) Neuropharmacology 86: 116-24
MeSH Terms: Animals, Dopaminergic Neurons, Electric Capacitance, Electric Impedance, Excitatory Postsynaptic Potentials, Glutamic Acid, Green Fluorescent Proteins, Male, Membrane Potentials, Mice, Mice, Inbred C57BL, Mice, Transgenic, Miniature Postsynaptic Potentials, Norepinephrine, Promoter Regions, Genetic, Raphe Nuclei, Receptors, Adrenergic, alpha-1, Receptors, Adrenergic, alpha-2, Tyrosine 3-Monooxygenase, Ventral Tegmental Area
Show Abstract · Added August 21, 2014
Dopaminergic innervation of the extended amygdala regulates anxiety-like behavior and stress responsivity. A portion of this dopamine input arises from dopamine neurons located in the ventral lateral periaqueductal gray (vlPAG) and rostral (RLi) and caudal linear nuclei of the raphe (CLi). These neurons receive substantial norepinephrine input, which may prime them for involvement in stress responses. Using a mouse line that expresses eGFP under control of the tyrosine hydroxylase promoter, we explored the physiology and responsiveness to norepinephrine of these neurons. We find that RLi dopamine neurons differ from VTA dopamine neurons with respect to membrane resistance, capacitance and the hyperpolarization-activated current, Ih. Further, we found that norepinephrine increased the frequency of spontaneous excitatory postsynaptic currents (sEPSCs) on RLi dopamine neurons. This effect was mediated through the α1 adrenergic receptor (AR), as the actions of norepinephrine were mimicked by the α1-AR agonist methoxamine and blocked by the α1-AR antagonist prazosin. This action of norepinephrine on sEPSCs was transient, as it did not persist in the presence of prazosin. Methoxamine also increased the frequency of miniature EPSCs, indicating that the α1-AR action on glutamatergic transmission likely has a presynaptic mechanism. There was also a modest decrease in sEPSC frequency with the application of the α2-AR agonist UK-14,304. These studies illustrate a potential mechanism through which norepinephrine could recruit the activity of this population of dopaminergic neurons.
Copyright © 2014 Elsevier Ltd. All rights reserved.
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20 MeSH Terms
Substance P increases sympathetic activity during combined angiotensin-converting enzyme and dipeptidyl peptidase-4 inhibition.
Devin JK, Pretorius M, Nian H, Yu C, Billings FT, Brown NJ
(2014) Hypertension 63: 951-7
MeSH Terms: Adult, Angiotensin-Converting Enzyme Inhibitors, Blood Pressure, Bradykinin, Cross-Over Studies, Dipeptidyl Peptidase 4, Double-Blind Method, Enalaprilat, Enzyme Inhibitors, Female, Heart Rate, Humans, Male, Middle Aged, Neurotransmitter Agents, Norepinephrine, Peptidyl-Dipeptidase A, Pyrazines, Sitagliptin Phosphate, Substance P, Sympathetic Nervous System, Triazoles, Vascular Resistance
Show Abstract · Added January 20, 2015
UNLABELLED - Dipeptidyl peptidase-4 inhibitors prevent the degradation of incretin hormones and reduce postprandial hyperglycemia in patients with type 2 diabetes mellitus. Dipeptidyl peptidase-4 degrades other peptides with a penultimate proline or alanine, including bradykinin and substance P, which are also substrates of angiotensin-converting enzyme (ACE). During ACE inhibition, substance P is inactivated primarily by dipeptidyl peptidase-4, whereas bradykinin is first inactivated by aminopeptidase P. This study tested the hypothesis that dipeptidyl peptidase-4 inhibition potentiates vasodilator and fibrinolytic responses to substance P when ACE is inhibited. Twelve healthy subjects participated in this randomized, double-blinded, placebo-controlled crossover study. On each study day, subjects received sitagliptin 200 mg by mouth or placebo. Substance P and bradykinin were infused via brachial artery before and during intra-arterial enalaprilat. Sitagliptin and enalaprilat each reduced forearm vascular resistance and increased forearm blood flow without affecting mean arterial pressure, but there was no interactive effect of the inhibitors. Enalaprilat increased bradykinin-stimulated vasodilation and tissue plasminogen activator release; sitagliptin did not affect these responses to bradykinin. The vasodilator response to substance P was unaffected by sitagliptin and enalaprilat; however, substance P increased heart rate and vascular release of norepinephrine during combined ACE and dipeptidyl peptidase-4 inhibition. In women, sitagliptin diminished tissue plasminogen activator release in response to substance P both alone and during enalaprilat. Substance P increases sympathetic activity during combined ACE and dipeptidyl peptidase-4 inhibition.
CLINICAL TRIAL REGISTRATION - - URL: http://www.clinicaltrials.gov. Unique identifier: NCT01413542.
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23 MeSH Terms
Melatonin reduces tachycardia in postural tachycardia syndrome: a randomized, crossover trial.
Green EA, Black BK, Biaggioni I, Paranjape SY, Bagai K, Shibao C, Okoye MC, Dupont WD, Robertson D, Raj SR
(2014) Cardiovasc Ther 32: 105-12
MeSH Terms: Administration, Oral, Adult, Anti-Arrhythmia Agents, Blood Pressure, Cross-Over Studies, Drug Administration Schedule, Female, Heart Rate, Humans, Male, Melatonin, Norepinephrine, Postural Orthostatic Tachycardia Syndrome, Sympathetic Nervous System, Tennessee, Time Factors, Treatment Outcome, Young Adult
Show Abstract · Added March 21, 2014
BACKGROUND - Postural tachycardia syndrome (POTS) induces disabling chronic orthostatic intolerance with an excessive increase in heart rate (HR) upon standing, and many POTS patients have a hyperadrenergic state. Medications that restrain HR are a promising approach to this problem.
OBJECTIVE - We tested the hypothesis that melatonin will attenuate the tachycardia and improve symptom burden in patients with POTS.
METHODS - Patients with POTS (n = 78) underwent acute drug trials with melatonin 3 mg orally and placebo, on separate mornings, in a randomized crossover design. Blood pressure, HR, and symptoms were assessed while seated and after standing for up to 10 min prior to, and hourly for 4 h following study drug administration.
RESULTS - The reduction in standing HR was significantly greater 2 h after melatonin compared with placebo (P = 0.017). There was no significant difference in the reduction of systolic blood pressure between melatonin and placebo, either with standing or while seated. The symptom burden was not improved with melatonin compared with placebo.
CONCLUSION - Oral melatonin produced a modest decrease in standing tachycardia in POTS. Further research is needed to determine the effects of regular night-time use of this medication in POTS.
© 2014 John Wiley & Sons Ltd.
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18 MeSH Terms