The publication data currently available has been vetted by Vanderbilt faculty, staff, administrators and trainees. The data itself is retrieved directly from NCBI's PubMed and is automatically updated on a weekly basis to ensure accuracy and completeness.
If you have any questions or comments, please contact us.
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.
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.
Serotonin (5-HT) is an important neurotransmitter in the central nervous system where it modulates circuits involved in mood, cognition, movement, arousal, and autonomic function. The 5-HT transporter (SERT; SLC6A4) is a key regulator of 5-HT signaling, and genetic variations in SERT are associated with various disorders including depression, anxiety, and autism. This review focuses on the role of SERT in the sympathetic nervous system. Autonomic/sympathetic dysfunction is evident in patients with depression, anxiety, and other diseases linked to serotonergic signaling. Experimentally, loss of SERT function (SERT knockout mice or chronic pharmacological block) has been reported to augment the sympathetic stress response. Alterations to serotonergic signaling in the CNS and thus central drive to the peripheral sympathetic nervous system are presumed to underlie this augmentation. Although less widely recognized, SERT is robustly expressed in chromaffin cells of the adrenal medulla, the neuroendocrine arm of the sympathetic nervous system. Adrenal chromaffin cells do not synthesize 5-HT but accumulate small amounts by SERT-mediated uptake. Recent evidence demonstrated that 5-HT receptors inhibit catecholamine secretion from adrenal chromaffin cells via an atypical mechanism that does not involve modulation of cellular excitability or voltage-gated Ca channels. This raises the possibility that the adrenal medulla is a previously unrecognized peripheral hub for serotonergic control of the sympathetic stress response. As a framework for future investigation, a model is proposed in which stress-evoked adrenal catecholamine secretion is fine-tuned by SERT-modulated autocrine 5-HT signaling.
UNLABELLED - Despite evidence of autonomic disturbances in chronic multisymptom illnesses such as temporomandibular disorder (TMD) and fibromyalgia, additional work is needed to characterize the role of parasympathetic reactivity in these disorders. Given the high levels of comorbidity with psychiatric disorders characterized by stronger parasympathetic decline than controls in safe contexts (leading to higher arousal), it was hypothesized that individuals with TMD and fibromyalgia would respond similarly. In this preliminary investigation, 43 women with TMD (n = 17), TMD + fibromyalgia (n = 11), or neither (controls; n = 15) completed a baseline assessment of respiratory sinus arrhythmia (a measure of parasympathetic activity) followed by ongoing parasympathetic assessment during a questionnaire period. As predicted, patients showed greater parasympathetic decline during psychosocial assessment, suggesting an autonomic stance that supports defensive rather than engagement behaviors. Individual differences in parasympathetic reduction during the questionnaire period were related to a variety of physical and psychosocial variables. Although this study has a number of key limitations, including a convenience sampling approach and small group sizes, if replicated in larger samples, the findings would have important implications for the treatment of patients with these disorders.
PERSPECTIVE - Compared to controls, individuals with TMD or TMD and fibromyalgia demonstrated greater parasympathetic decline during psychosocial assessment, and individual differences in parasympathetic decline predicted negative patient outcomes. Such parasympathetic decline may demonstrate a tendency to readily perceive danger in safe environments.
Copyright © 2015 American Pain Society. Published by Elsevier Inc. All rights reserved.
The inner ear vestibular system has numerous projections on central brain centers that regulate sympathetic outflow, and skeletal sympathetic projections affect bone remodeling by inhibiting bone formation by osteoblasts and promoting bone resorption by osteoclasts. In this study, we show that bilateral vestibular lesions in mice cause a low bone mass phenotype associated with decreased bone formation and increased bone resorption. This reduction in bone mass is most pronounced in lower limbs, is not associated with reduced locomotor activity or chronic inflammation, and could be prevented by the administration of the β-blocker propranolol and by genetic deletion of the β2-adrenergic receptor, globally or specifically in osteoblasts. These results provide novel experimental evidence supporting a functional autonomic link between central proprioceptive vestibular structures and the skeleton. Because vestibular dysfunction often affects the elderly, these results also suggest that age-related bone loss might have a vestibular component and that patients with inner ear pathologies might be at risk for fracture. Lastly, these data might have relevance to the bone loss observed in microgravity, as vestibular function is altered in this condition as well. © 2015 American Society for Bone and Mineral Research.
© 2015 American Society for Bone and Mineral Research.
While hypertension has predominantly been attributed to perturbations of the vasculature, kidney, and central nervous system, research for almost 50 yr has shown that the immune system also contributes to this disease. Inflammatory cells accumulate in the kidneys and vasculature of humans and experimental animals with hypertension and likely contribute to end-organ damage. We and others have shown that mice lacking adaptive immune cells, including recombinase-activating gene-deficient mice and rats and mice with severe combined immunodeficiency have blunted hypertension to stimuli such as ANG II, high salt, and norepinephrine. Adoptive transfer of T cells restores the blood pressure response to these stimuli. Agonistic antibodies to the ANG II receptor, produced by B cells, contribute to hypertension in experimental models of preeclampsia. The central nervous system seems important in immune cell activation, because lesions in the anteroventral third ventricle block hypertension and T cell activation in response to ANG II. Likewise, genetic manipulation of reactive oxygen species in the subfornical organ modulates both hypertension and immune cell activation. Current evidence indicates that the production of cytokines, including tumor necrosis factor-α, interleukin-17, and interleukin-6, contribute to hypertension, likely via effects on both the kidney and vasculature. In addition, the innate immune system also appears to contribute to hypertension. We propose a working hypothesis linking the sympathetic nervous system, immune cells, production of cytokines, and, ultimately, vascular and renal dysfunction, leading to the augmentation of hypertension. Studies of immune cell activation will clearly be useful in understanding this common yet complex disease.
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.
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.
CHF (chronic heart failure) is a multifactorial disease process that is characterized by overactivation of the RAAS (renin-angiotensin-aldosterone system) and the sympathetic nervous system. Both of these systems are chronically activated in CHF. The RAAS consists of an excitatory arm involving AngII (angiotensin II), ACE (angiotensin-converting enzyme) and the AT1R (AngII type 1 receptor). The RAAS also consists of a protective arm consisting of Ang-(1-7) [angiotensin-(1-7)], the AT2R (AngII type 2 receptor), ACE2 and the Mas receptor. Sympatho-excitation in CHF is driven, in large part, by an imbalance of these two arms, with an increase in the AngII/AT1R/ACE arm and a decrease in the AT2R/ACE2 arm. This imbalance is manifested in cardiovascular-control regions of the brain such as the rostral ventrolateral medulla and paraventricular nucleus in the hypothalamus. The present review focuses on the current literature that describes the components of these two arms of the RAAS and their imbalance in the CHF state. Moreover, the present review provides additional evidence for the relevance of ACE2 and Ang-(1-7) as key players in the regulation of central sympathetic outflow in CHF. Finally, we also examine the effects of exercise training as a therapeutic strategy and the molecular mechanisms at play in CHF, in part, because of the ability of exercise training to restore the balance of the RAAS axis and sympathetic outflow.
Changes in bone remodeling induced by pharmacological and genetic manipulation of β-adrenergic receptor (βAR) signaling in osteoblasts support a role of sympathetic nerves in the regulation of bone remodeling. However, the contribution of endogenous sympathetic outflow and nerve-derived norepinephrine (NE) to bone remodeling under pathophysiological conditions remains unclear. We show here that differentiated osteoblasts, like neurons, express the norepinephrine transporter (NET), exhibit specific NE uptake activity via NET and can catabolize, but not generate, NE. Pharmacological blockade of NE transport by reboxetine induced bone loss in WT mice. Similarly, lack of NE reuptake in norepinephrine transporter (Net)-deficient mice led to reduced bone formation and increased bone resorption, resulting in suboptimal peak bone mass and mechanical properties associated with low sympathetic outflow and high plasma NE levels. Last, daily sympathetic activation induced by mild chronic stress was unable to induce bone loss, unless NET activity was blocked. These findings indicate that the control of endogenous NE release and reuptake by presynaptic neurons and osteoblasts is an important component of the complex homeostatic machinery by which the sympathetic nervous system controls bone remodeling. These findings also suggest that drugs antagonizing NET activity, used for the treatment of hyperactivity disorders, may have deleterious effects on bone accrual.