The interleukin-6 and noradrenaline mediated inflammation-stress feedback mechanism is dysregulated in metabolic syndrome: Effect of exercise

<p>Abstract</p> <p>Background</p> <p>Metabolic syndrome (MS) is a metabolic disorder associated with obesity, type-II diabetes, and "low grade inflammation", with the concomitant increased risk of cardiovascular events. Removal of the inflammatory mediator signals is a promising strategy to protect against insulin resistance, obesity, and other problems associated with MS such as cardiovascular disease. The aim of the present investigation was to determine the "inflammatory and stress status" in an experimental model of MS, and to evaluate the effect of a program of habitual exercise and the resulting training-induced adaptation to the effects of a single bout of acute exercise.</p> <p>Methods</p> <p>Obese Zucker rats (fa/fa) were used as the experimental model of MS, and lean Zucker rats (Fa/fa) were used for reference values. The habitual exercise (performed by the obese rats) consisted of treadmill running: 5 days/week for 14 weeks, at 35 cm/s for 35 min in the last month. The acute exercise consisted of a single session of 25-35 min at 35 cm/s. Circulating concentrations of IL-6 (a cytokine that regulates the inflammatory and metabolic responses), CRP (a systemic inflammatory marker), and corticosterone (CTC) (the main glucocorticoid in rats) were determined by ELISA, and that of noradrenaline (NA) was determined by HPLC. Glucose was determined by standard methods.</p> <p>Results</p> <p>The genetically obese animals showed higher circulating levels of glucose, IL-6, PCR, and NA compared with the control lean animals. The habitual exercise program increased the concentration of IL-6, PCR, NA, and glucose, but decreased that of CTC. Acute exercise increased IL-6, CRP, and NA in the sedentary obese animals, but not in the trained obese animals. CTC was increased after the acute exercise in the trained animals only.</p> <p>Conclusion</p> <p>Animals with MS present a dysregulation in the feedback mechanism between IL-6 and NA which can contribute to the systemic low-grade inflammation and/or hyperglycaemia of MS. An inappropriate exercise intensity can worsen this dysregulation, contributing to the metabolic, inflammatory, and stress disorders associated with MS. Habitual exercise (i.e., training) induces a positive adaptation in the response to acute exercise.</p

Clonal chromosomal mosaicism and loss of chromosome Y in elderly men increase vulnerability for SARS-CoV-2

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) had an estimated overall case fatality ratio of 1.38% (pre-vaccination), being 53% higher in males and increasing exponentially with age. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, we found 133 cases (1.42%) with detectable clonal mosaicism for chromosome alterations (mCA) and 226 males (5.08%) with acquired loss of chromosome Y (LOY). Individuals with clonal mosaic events (mCA and/or LOY) showed a 54% increase in the risk of COVID-19 lethality. LOY is associated with transcriptomic biomarkers of immune dysfunction, pro-coagulation activity and cardiovascular risk. Interferon-induced genes involved in the initial immune response to SARS-CoV-2 are also down-regulated in LOY. Thus, mCA and LOY underlie at least part of the sex-biased severity and mortality of COVID-19 in aging patients. Given its potential therapeutic and prognostic relevance, evaluation of clonal mosaicism should be implemented as biomarker of COVID-19 severity in elderly people. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, individuals with clonal mosaic events (clonal mosaicism for chromosome alterations and/or loss of chromosome Y) showed an increased risk of COVID-19 lethality

β2 Adrenergic Regulation of the Phagocytic and Microbicide Capacity of Circulating Monocytes: Influence of Obesity and Exercise

Obese individuals present anomalous immune/inflammatory responses with dysregulations in neuroendocrine responses and immune/stress feedback mechanisms. In this context, exercise and &beta;2 adrenergic activation present monocyte-mediated anti-inflammatory effects that are modulated by obesity. However, these anti-inflammatory effects could immunocompromise the monocyte-mediated innate response against a pathogen challenge. Thus, the objective of this work was to evaluate the effect of obesity, and exercise in this condition, on the &beta;2 adrenergic regulation of the phagocytic and microbicide capacity of circulating monocytes. C57BL/6J mice were allocated to different sedentary or exercised, lean or obese groups. Obese mice showed a lower monocyte-mediated innate response than that of lean mice. Globally, selective &beta;2 adrenergic receptor agonist terbutaline decreased the innate response of monocytes from lean and obese sedentary animals, whereas exercise stimulated it. Exercise modulates &beta;2 adrenergic regulation of the innate response in lean and obese animals, with a global stimulatory or neutral effect, thus abolishing the inhibitory effect of terbutaline occurring in sedentary animals. These effects cannot be explained only by changes in the surface expression of toll-like receptors. Therefore, in general, terbutaline does not hinder the effects of regular exercise, but regular exercise does abolish the effects of terbutaline in sedentary individuals

β2 adrenergic regulation of the phagocytic and microbicide capacity of macrophages from obese and lean mice: effects of exercise

Los macrófagos son cruciales en la inflamación asociada a la obesidad. El ejercicio es la principal estrategia no farmacológica contra la obesidad, no sólo por mejorar el deterioro metabólico, sino también por sus efectos antiinflamatorios, en particular los mediados por los receptores adrenérgicos β2 (β2-AR). Sin embargo, estos efectos antiinflamatorios podrían comprometer la respuesta innata frente al desafío patógeno. Así, el objetivo de este trabajo fue evaluar el efecto de la obesidad, y del ejercicio en esta condición, sobre la regulación β2 adrenérgica de la función innata de los macrófagos. Se utilizaron ratones C57BL/6J obesos inducidos por una dieta alta en grasas para evaluar los efectos del ejercicio agudo y regular sobre la capacidad fagocítica y microbicida de los macrófagos peritoneales. El agonista β2-AR selectivo terbutalina (1 µM) disminuyó las actividades fagocíticas y microbicidas de los macrófagos de animales sedentarios magros y obesos de control. Mientras que el ejercicio agudo no modificó la capacidad inhibitoria de la terbutalina, el ejercicio regular abolió este efecto inhibidor. Estos efectos no pueden explicarse únicamente por los cambios en la expresión superficial del β2-AR. En conclusión, (1) la obesidad no altera la disminución de la respuesta innata de los macrófagos mediada por el β2-AR y (2) el ejercicio regular puede revertir el efecto inhibidor de la terbutalina sobre la actividad fagocítica de los macrófagos, aunque la obesidad parece dificultar esta adaptación inmunofisiológica.Macrophages are crucial in the inflammation associated with obesity. Exercise is the main non-pharmacological strategy against obesity, not only for improving metabolic impairment, but also because of its anti-inflammatory effects, particularly those mediated by β2 adrenergic receptors (β2-AR). Nevertheless, these anti-inflammatory effects could immunocompromise the innate response against pathogen challenge. Thus, the objective of this work was to evaluate the effect of obesity, and of exercise in this condition, on the β2 adrenergic regulation of the innate function of macrophages. High fat diet-induced obese C57BL/6J mice were used to evaluate the effects of acute and regular exercise on the phagocytic and microbicide capacities of peritoneal macrophages. Selective β2-AR agonist terbutaline (1 µM) decreased the phagocytic and microbicide activities of macrophages from control lean and obese sedentary animals. While acute exercise did not modify the inhibitory capacity of terbutaline, regular exercise abolished this inhibitory effect. These effects cannot be explained only by changes in the surface expression of β2-AR. In conclusion, (1) obesity does not alter the β2-AR-mediated decrease of the innate response of macrophages and (2) regular exercise can revert the inhibitory effect of terbutaline on the phagocytic activity of macrophages, although obesity seems to hinder this immunophysiological adaptation.• Junta de Extremadura y Fondo Europeo de Desarrollo Regional. Ayudas GR18009 e IB18011 • Ministerio de Ciencia, Innovación y Universidades. Proyecto DEP2015-66093-RpeerReviewe

The Influence of Obesity and Weight Loss on the Bioregulation of Innate/Inflammatory Responses: Macrophages and Immunometabolism

Obesity is characterized by low-grade inflammation and more susceptibility to infection, particularly viral infections, as clearly demonstrated in COVID-19. In this context, immunometabolism and metabolic flexibility of macrophages play an important role. Since inflammation is an inherent part of the innate response, strategies for decreasing the inflammatory response must avoid immunocompromise the innate defenses against pathogen challenges. The concept “bioregulation of inflammatory/innate responses” was coined in the context of the effects of exercise on these responses, implying a reduction in excessive inflammatory response, together with the preservation or stimulation of the innate response, with good transitions between pro- and anti-inflammatory macrophages adapted to each individual’s inflammatory set-point in inflammatory diseases, particularly in obesity. The question now is whether these responses can be obtained in the context of weight loss by dietary interventions (low-fat diet or abandonment of the high-fat diet) in the absence of exercise, which can be especially relevant for obese individuals with difficulties exercising such as those suffering from persistent COVID-19. Results from recent studies are controversial and do not point to a clear anti-inflammatory effect of these dietary interventions, particularly in the adipose tissue. Further research focusing on the innate response is also necessary

Influence of Codiagnosis of Chronic Fatigue Syndrome and Habitual Physical Exercise on the Psychological Status and Quality of Life of Patients with Fibromyalgia

Fibromyalgia (FM) and Chronic Fatigue Syndrome (CFS) are two diseases that are frequently codiagnosed and present many similarities, such as poor tolerance to physical exercise. Although exercise is recommended in their daily routine to improve quality of life, little is known about how CFS codiagnosis affects that. Using scientifically validated questionnaires, we evaluated the psychological state and quality of life of patients with FM (n = 70) and how habitual physical exercise (HPE) reported by patients with only FM (FM-only n = 38) or codiagnosed with CFS (FM + CFS, n = 32) influences those aspects. An age-matched reference group of “healthy” women without FM (RG, n = 70) was used. The FM-only group presented a worse psychological state and quality of life compared to RG, with no influence of CFS codiagnosis. The patients of the FM-only and FM + CFS groups who perform HPE presented better levels of stress and state anxiety, but with no differences between them. Depression and trait anxiety improved only in women with just FM. CFS codiagnosis does not worsen the psychological and quality of life impairment of FM patients and does not have a great influence on the positive effect of HPE

Obesity affects β2 adrenergic regulation of the inflammatory profile and phenotype of circulating monocytes from exercised animals

En la obesidad se producen respuestas inmunitarias/inflamatorias anómalas junto con alteraciones en las respuestas neuroendocrinas y desregulación en los mecanismos de retroalimentación inmunitaria/estrés. El ejercicio es una estrategia antiinflamatoria potencial en este contexto, pero la influencia del ejercicio en la regulación β2 adrenérgica de la respuesta inflamatoria mediada por monocitos en la obesidad sigue siendo completamente desconocida. El primer objetivo de este estudio fue analizar el efecto del ejercicio sobre el perfil inflamatorio y el fenotipo de los monocitos de animales obesos y delgados, y el segundo objetivo era determinar si la obesidad podía afectar a la respuesta inflamatoria de los monocitos a la activación β2 adrenérgica en animales ejercitados. Los ratones C57BL/6J fueron asignados a diferentes grupos magros u obesos: sedentarios, con ejercicio agudo o con ejercicio regular. El perfil inflamatorio y el fenotipo de sus monocitos circulantes se evaluaron por citometría de flujo en presencia o ausencia del agonista selectivo del receptor β2 adrenérgico terbutalina. El ejercicio causó un efecto antiinflamatorio en los individuos obesos y un efecto proinflamatorio en los individuos delgados. La estimulación del receptor adrenérgico β2 ejerció un efecto proinflamatorio global en monocitos de animales obesos ejercitados y un efecto antiinflamatorio en monocitos de animales delgados ejercitados. Así pues, la regulación β2 adrenérgica de la inflamación en monocitos de animales ejercitados parece depender del punto de ajuste inflamatorio basal.Anomalous immune/inflammatory responses in obesity take place along with alterations in the neuroendocrine responses and dysregulation in the immune/stress feedback mechanisms. Exercise is a potential anti-inflammatory strategy in this context, but the influence of exercise on the β2 adrenergic regulation of the monocyte-mediated inflammatory response in obesity remains completely unknown. The first objective of this study was to analyze the e_ect of exercise on the inflammatory profile and phenotype of monocytes from obese and lean animals, and the second aim was to determine whether obesity could a_ect monocytes’ inflammatory response to β2 adrenergic activation in exercised animals. C57BL/6J mice were allocated to di_erent lean or obese groups: sedentary, with acute exercise, or with regular exercise. The inflammatory profile and phenotype of their circulating monocytes were evaluated by flow cytometry in the presence or absence of the selective β2 adrenergic receptor agonist terbutaline. Exercise caused an anti-inflammatory e_ect in obese individuals and a pro-inflammatory e_ect in lean individuals. β2 adrenergic receptor stimulation exerted a global pro-inflammatory e_ect in monocytes from exercised obese animals and an anti-inflammatory e_ect in monocytes from exercised lean animals. Thus, β2 adrenergic regulation of inflammation in monocytes from exercised animals seems to depend on the inflammatory basal set-point.• Junta de Extremadura y Fondo Europeo de Desarrollo Regional. Ayudas GR18009 e IB18011 • Ministerio de Ciencia, Innovación y Universidades. Proyecto FPU15/02395peerReviewe