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Potential mechanisms of obesity related hypertension and increased SNS activity. RAAS indicates renin-angiotensin-aldosterone system; SNS indicates sympathetic nervous system; NO indicates nitric oxide; POMC-MC4R indicates pro-opiomelanocortin-melanocortin 4 receptor.  

Potential mechanisms of obesity related hypertension and increased SNS activity. RAAS indicates renin-angiotensin-aldosterone system; SNS indicates sympathetic nervous system; NO indicates nitric oxide; POMC-MC4R indicates pro-opiomelanocortin-melanocortin 4 receptor.  

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Obesity is recognized as a major health problem throughout the world. Excess weight is a major cause of increased blood pressure in most patients with essential hypertension and greatly increases the risk for diabetes, cardiovascular diseases, and end-stage renal disease. Although the mechanisms by which obesity raises blood pressure are not comple...

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... the rise in arterial pressure caused by excess weight gain is mediated, at least in part, by increased SNS activity, the factors that link obesity with renal sympathetic activation are unclear. Several potential factors have been proposed to contribute to increased SNS activity in obesity, including hyperleptinemia, activation of the central pro-opiomelanocortin/ melanocortin-4 receptor (POMC/MC4R), hyperinsulinemia/insulin resistance, hypoadiponectinemia, hypoghrelinemia, increased angiotensin II levels, and baroreceptor dysfunction ( Figure 1). ...

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... In summary, our data suggest that sympathetic activation of pWAT may increase tissue concentration of NEFA and cytokines. A dysregulated SNS activity during obesity has been reported and might contribute to hyperglycaemia, as insulin secretion is directly inhibited via beta-cell alpha2-adrenergic receptors 26,35,49,50 . In such a situation NEFAs would stimulate glucagon release which further mobilises hepatic glucose production thereby increasing insulin demand and promoting beta-cell exhaustion 34,51,52 . ...
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Inflammatory cytokines and non-esterified fatty acids (NEFAs) are obesity-linked factors that disturb insulin secretion. The aim of this study was to investigate whether pancreatic adipose tissue (pWAT) is able to generate a NEFA/cytokine overload within the pancreatic environment and as consequence to impact on insulin secretion. Pancreatic fat is a minor fat depot, therefore we used high-fat diet (HFD) feeding to induce pancreatic steatosis in mice. Relative Adipoq and Lep mRNA levels were higher in pWAT of HFD compared to chow diet mice. Regardless of HFD, Adipoq and Lep mRNA levels of pWAT were at least 10-times lower than those of epididymal fat (eWAT). Lipolysis stimulating receptors Adrb3 and Npr1 were expressed in pWAT and eWAT, and HFD reduced their expression in eWAT only. In accordance, HFD impaired lipolysis in eWAT but not in pWAT. Despite expression of Npr mRNA, lipolysis was stimulated solely by the adrenergic agonists, isoproterenol and adrenaline. Short term co-incubation of islets with CD/HFD pWAT did not alter insulin secretion. In the presence of CD/HFD eWAT, glucose stimulated insulin secretion only upon isoproterenol-induced lipolysis, i.e. in the presence of elevated NEFA. Isoproterenol augmented Il1b and Il6 mRNA levels both in pWAT and eWAT. These results suggest that an increased sympathetic activity enhances NEFA and cytokine load of the adipose microenvironment, including that of pancreatic fat, and by doing so it may alter beta-cell function.
... Analysis of HR per hour clearly displayed the difference in daily HR pattern for patients compared to controls. The higher HR in the patient group can be explained by sympathetic nervous system overactivation [26,28,29], caused by dysregulation of the release of multiple adipokines (inter alia; leptin, free fatty acids, TNF-α, IL-6, adiponectin) and baroreflex dysfunction [30,31]. In this study, the difference in average nighttime HR between patients and controls increased as a function of age (while no correlation between body mass index SD score and age was found). ...
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Introduction: Clinical research and treatment of childhood obesity is challenging, and objective biomarkers obtained in a home-setting are needed. The aim of this study was to determine the potential of novel digital endpoints gathered by a home-monitoring platform in pediatric obesity. Methods: In this prospective observational study, 28 children with obesity aged 6-16 years were included and monitored for 28 days. Patients wore a smartwatch, which measured physical activity (PA), heart rate (HR), and sleep. Furthermore, daily blood pressure (BP) measurements were performed. Data from 128 healthy children were utilized for comparison. Differences between patients and controls were assessed via linear mixed effect models. Results: Data from 28 patients (average age 11.6 years, 46% male, average body mass index 30.9) and 128 controls (average age 11.1 years, 46% male, average body mass index 18.0) were analyzed. Patients were recruited between November 2018 and February 2020. For patients, the median compliance for the measurements ranged from 55% to 100% and the highest median compliance was observed for the smartwatch-related measurements (81-100%). Patients had a lower daily PA level (4,597 steps vs. 6,081 steps, 95% confidence interval [CI] 862-2,108) and peak PA level (1,115 steps vs. 1,392 steps, 95% CI 136-417), a higher nighttime HR (81 bpm vs. 71 bpm, 95% CI 6.3-12.3) and daytime HR (98 bpm vs. 88 bpm, 95% CI 7.6-12.6), a higher systolic BP (115 mm Hg vs. 104 mm Hg, 95% CI 8.1-14.5) and diastolic BP (76 mm Hg vs. 65 mm Hg, 95% CI 8.7-12.7), and a shorter sleep duration (difference 0.5 h, 95% CI 0.2-0.7) compared to controls. Conclusion: Remote monitoring via wearables in pediatric obesity has the potential to objectively measure the disease burden in the home-setting. The novel endpoints demonstrate significant differences in PA level, HR, BP, and sleep duration between patients and controls. Future studies are needed to determine the capacity of the novel digital endpoints to detect effect of interventions.
... On the other hand, cortisol is also described as a catabolic hormone in the acute setting and, in concert with the release of catecholamines, can induce anorexigenic responses and mobilization of energy stores [54]. In obesity, sympathetic tone is increased due to hyperleptinaemia, and activation of the HPA axis may further elevate it, resulting in increased blood pressure and tachycardia [55]. In the development of agonists or antagonists to NPFFR2, the balance between the acute and chronic stress responses and the tissues engaged must be considered. ...
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Restoring the control of food intake is the key to obesity management and prevention. The arcuate nucleus (ARC) of the hypothalamus is extensively being studied as a potential anti-obesity target. Animal studies showed that neuropeptide FF (NPFF) reduces food intake by its action in neuropeptide Y (NPY) neurons of the hypothalamic ARC, but the detailed mode of action observed in human neurons is missing, due to the lack of a human-neuron-based model for pharmacology testing. Here, we validated and utilized a human-neural-stem-cell-based (hNSC) model of ARC to test the effects of NPFF on cellular pathways and neuronal activity. We found that in the human neurons, decreased cAMP levels by NPFF resulted in a reduced rate of cytoplasmic calcium oscillations, indicating an inhibition of ARC NPY neurons. This suggests the therapeutic potential of NPFFR2 in obesity. In addition, we demonstrate the use of human-stem-cell-derived neurons in pharmacological applications and the potential of this model to address functional aspects of human hypothalamic neurons.
... Instead of a priori developed indices, a template matching method was used to estimate indices that characterized physiologicallyrelevant indices that represent slight deviations in sympathetic and parasympathetic individual responses. These data show that sympathetic amplitude responses significantly increased and parasympathetic responses decreased with increasing BMI, and as such are consistent with past work that actually demonstrated significant sympathetic overactivity and decreased parasympathetic activity in patients with increased BMI greater than 25 (da Silva et al., 2009;Guarino et al., 2017;Molfino et al., 2009). While higher BMI may yield increased energy expenditure necessary for body weight, it has occurred to others that the activation of the sympathetic ANS may be an initial or primary driving force in weight maintenance regulation (Molfino et al., 2009). ...
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Background The autonomic nervous system (ANS) maintains physiological homeostasis in various organ systems via parasympathetic and sympathetic branches. ANS function is altered in common diffuse and focal conditions and heralds the beginning of environmental and disease stresses. Reliable, sensitive, and quantitative biomarkers, first defined in healthy participants, could discriminate among clinically useful changes in ANS function. This framework combines controlled autonomic testing with feature extraction during physiological responses. Methods Twenty-one individuals were assessed in two morning and two afternoon sessions over two weeks. Each session included five standard clinical tests probing autonomic function: squat test, cold pressor test, diving reflex test, deep breathing, and Valsalva maneuver. Noninvasive sensors captured continuous electrocardiography, blood pressure, breathing, electrodermal activity, and pupil diameter. Heart rate, heart rate variability, mean arterial pressure, electrodermal activity, and pupil diameter responses to the perturbations were extracted, and averages across participants were computed. A template matching algorithm calculated scaling and stretching features that optimally fit the average to an individual response. These features were grouped based on test and modality to derive sympathetic and parasympathetic indices for this healthy population. Results A significant positive correlation ( p = 0.000377) was found between sympathetic amplitude response and body mass index. Additionally, longer duration and larger amplitude sympathetic and longer duration parasympathetic responses occurred in afternoon testing sessions; larger amplitude parasympathetic responses occurred in morning sessions. Conclusions These results demonstrate the robustness and sensitivity of an algorithmic approach to extract multimodal responses from standard tests. This novel method of quantifying ANS function can be used for early diagnosis, measurement of disease progression, or treatment evaluation. Trial registration This study registered with Clinicaltrials.gov , identifier NCT04100486 . Registered September 24, 2019, https://www.clinicaltrials.gov/ct2/show/NCT04100486 .
... Adolescent obesity can negatively affect every organ system in the body and increase the risk of developing numerous serious health problems, such as insulin resistance, type 2 diabetes mellitus, atherosclerosis, dyslipidemia, psychological illness, decreased quality of life, and hypertension (6,15). In recent years, documentation reported that the development of hypertension in obese individuals is associated with excessive weight gain, especially with increased visceral adiposity and increased sympathetic nervous system activation that contributes to peripheral vasoconstriction (10,12). An increased heart rate is one of the key mechanisms to induced hypertension. ...
... Interestingly, in obesity, increased heart rate is mediated mainly by reduced parasympathetic activity to the heart (10,12,22). Autonomic dysfunction or the impairment of autonomic cardiac modulation, especially with a reduction in heart rate variability (HRV) has been shown to be often found in obese adolescents and is related to an increased risk of cardiovascular mortality and morbidity (16,70). ...
... Also, studies (47,48) have found that SD-2 is considered an excellent index of inverse sympathetic activity. It has been noted that the decreased values of SD-2 indicate increased sympathetic modulation and parasympathetic withdrawal (10,41). ...
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Diaphragmatic breathing control is an effective physical therapy intervention to alleviate breathing problems and dyspnea. This study examined the effect of diaphragmatic breathing on the immediate alterations of heart rate variability and blood pressure in overweight and obese female adolescents. Fifteen obese or overweight female adolescents were recruited into the study. All subjects' diaphragmatic breathing and spontaneous breathing were performed in a randomly assigned order. Blood pressure parameters were assessed with autonomic function measured via heart rate variability in the time domain (average RR interval, RR), root mean square of the standard deviation (RMSSD) and standard deviation 2 of the Poincaré plot (SD-2), the frequency domain (high frequency, HF), low frequency (LF), and the ratio of LF/HF. 59 RMSSD, SD-2, HF, and LF were significantly greater during diaphragmatic breathing. There was no significant difference in the LF/HF ratio. Diaphragmatic breathing also produced a significant decrease in systolic blood pressure, diastolic blood pressure, and mean arterial pressure. In conclusion, diaphragmatic breathing may be an effective tool to manage obesity-related cardiovascular risk factors by improving cardiac autonomic function and reducing blood pressure in obese female adolescents. A possible mechanism is that diaphragmatic breathing could enhance parasympathetic nervous system activity.
... This hypothesis was revised in later studies, indicating chronic SNS activity as a factor causing weight gain caused by decreased beta-adrenoceptor activity [60]. Chronic SNS hyperactivity occurs primarily in central obesity [61]. Recent studies show increased sympathetic activity in obese patients, especially in the vascular system of muscles and kidneys, which may contribute to an increased cardiovascular risk [62]. ...
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The World Health Organization (WHO) has recognised obesity as one of the top ten threats to human health. Obesity is not only a state of abnormally increased adipose tissue in the body, but also of an increased release of biologically active metabolites. Moreover, obesity predisposes the development of metabolic syndrome and increases the incidence of type 2 diabetes (T2DM), increases the risk of developing insulin resistance, atherosclerosis, ischemic heart disease, polycystic ovary syndrome, hypertension and cancer. The lymphatic system is a one-directional network of thin-walled capillaries and larger vessels covered by a continuous layer of endothelial cells that provides a unidirectional conduit to return filtered arterial and tissue metabolites towards the venous circulation. Recent studies have shown that obesity can markedly impair lymphatic function. Conversely, dysfunction in the lymphatic system may also be involved in the pathogenesis of obesity. This review highlights the important findings regarding obesity related to lymphatic system dysfunction, including clinical implications and experimental studies. Moreover, we present the role of biological factors in the pathophysiology of the lymphatic system and we propose the possibility of a therapy supporting the function of the lymphatic system in the course of obesity.
... In addition, central and peripheral mechanisms are involved in the regulation of metabolism and food intake. In this respect, the hypothalamus plays a vital role in the central mechanisms via the release of hypothalamic neuropeptides such as neuropeptide Y or orexin for the regulation of both energy intake and energy expenditure (96,97), while the sympathetic nervous system and the release of adipokines such as leptin and adiponectin, are involved in peripheral mechanisms (96)(97)(98). Therefore, an imbalance in the regulation of metabolism or in the anatomical structures involved can trigger obesity. ...
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Migraine is a disabling neurovascular disorder, characterized by moderate to severe unilateral headaches, nausea, photophobia, and/or phonophobia, with a higher prevalence in women than in men, which can drastically affect the quality of life of migraine patients. In addition, this chronic disorder is related with metabolic comorbidities associated with the patient's lifestyle, including obesity and diabetes mellitus (DM). Beyond the personal and socioeconomic impact caused by migraine, obesity and DM, it has been suggested that these metabolic disorders seem to be related to migraine since: (i) they are a risk factor for developing cardiovascular disorders or chronic diseases; (ii) they can be influenced by genetic and environmental risk factors; and (iii) while clinical and epidemiological studies suggest that obesity is a risk factor for migraine, DM (i.e., type 1 and type 2 DM) have been reported to be either a protective or a risk factor in migraine. On this basis, and given the high worldwide prevalence of migraine, obesity, and DM, this article provides a narrative review of the current literature related to the association between the etiology and pathophysiology of migraine and these metabolic disorders, considering lifestyle aspects, as well as the possible involvement of neurotransmitters, neuropeptides, and/or sex hormones. While a link between migraine and metabolic disorders has been suggested, many studies are contradictory and the mechanisms involved in this association are not yet sufficiently established. Therefore, further research should be focused on understanding the possible mechanisms involved.
... Following carbohydrate intake, the increased insulin concentration stimulates insulin-mediated glucose metabolism in the same neurons, leading to augmented insulin-mediated glucose metabolism, reduction of the inhibitory pathway, and finally stimulation of the sympathetic centers at the brain-stem levels, with a consequent increase in central sympathetic outflow [3]. This mechanism has been proposed to explain the "pro-hypertensive" effect of insulin in susceptible individuals [10,11], where hypertension could represent the unwanted consequence of a compensatory mechanism recruited in the obese to restore energy balance and limit further weight gain (i.e., IR) ( Figure 2). In other words, obese subjects, while resistant to the effects of insulin on peripheral glucose uptake, should not be resistant to the effect of insulin on the SNS, although this is not invariably associated with increased blood pressure due to a counterbalance of vascular compensatory mechanisms [12]. ...
... Following carbohydrate intake, the increased insulin concentration stimulates insulin-mediated glucose metabolism in the same neurons, leading to augmented insulin-mediated glucose metabolism, reduction of the inhibitory pathway, and finally stimulation of the sympathetic centers at the brain-stem levels, with a consequent increase in central sympathetic outflow [3]. This mechanism has been proposed to explain the ''pro-hypertensive'' effect of insulin in susceptible individuals [10,11], where hypertension could represent the unwanted consequence of a compensatory mechanism recruited in the obese to restore energy balance and limit further weight gain (i.e., IR) ( Figure 2). In other words, obese subjects, while resistant to the effects of insulin on peripheral glucose uptake, should not be resistant to the effect of insulin on the SNS, although this is not invariably associated with increased blood pressure due to a counterbalance of vascular compensatory mechanisms [12]. ...
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The role of the autonomic nervous system in obesity and insulin-resistant conditions has been largely explored. However, the exact mechanisms involved in this relation have not been completely elucidated yet, since most of these mechanisms display a bi-directional effect. Insulin-resistance, for instance, can be caused by sympathetic activation, but, in turn, the associated hyperinsulinemia can activate the sympathetic branch of the autonomic nervous system. The picture is made even more complex by the implicated neural, hormonal and nutritional mechanisms. Among them, leptin plays a pivotal role, being involved not only in appetite regulation and glucose homeostasis but also in energy expenditure. The purpose of this review is to offer a comprehensive view of the complex interplay between leptin and the central nervous system, providing further insights on the impact of autonomic nervous system balance on adipose tissue and insulin-resistance. Furthermore, the link between the circadian clock and leptin and its effect on metabolism and energy balance will be evaluated.
... 24 Overactivation of sympathetic responses resulted in an elevated heart rate which was closely associated with being overweight as well as obesity. [24][25][26] Being overweight and obese served as mediators of increased sodium retention in blood vessels which lead to an increase of blood volume and pressure; this increase of volume and pressure, therefore, hurts cardiovascular health. 24,25 Apart from the relationship between trauma exposure and/or PTSD with excessive weight and obesity, researchers also associated trauma exposure and/or PTSD with other unhealthy behaviours such as alcohol drinking, smoking, and sleeping less that have a significant relationship with adult cardiovascular disease. ...
... [24][25][26] Being overweight and obese served as mediators of increased sodium retention in blood vessels which lead to an increase of blood volume and pressure; this increase of volume and pressure, therefore, hurts cardiovascular health. 24,25 Apart from the relationship between trauma exposure and/or PTSD with excessive weight and obesity, researchers also associated trauma exposure and/or PTSD with other unhealthy behaviours such as alcohol drinking, smoking, and sleeping less that have a significant relationship with adult cardiovascular disease. 27,28 Most of the crosssectional and retrospective study reported that individual with trauma exposure has poorer sleep. ...
... A obesidade é reconhecida como um dos maiores problemas de saúde pública no mundo. (da Silva, A. A., do Carmo, J., Dubinion, J., & Hall, 2009) Segundo a Organização Mundial da Saúde (OMS), a obesidade é uma doença causada pelo acúmulo de gordura, capaz de provocar diversos problemas de saúde. (Nishida C, Barba C, Cavalli-Sforza T, 2004;W. ...
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Introdução: A obesidade é reconhecida como um dos maiores problemas de saúde pública no mundo e está associada a doenças crônicas como diabetes mellitus, dislipidemias e alguns tipos de câncer, além de uma hiperatividade simpática, que pode ser um fator de risco independente de mortalidade. Objetivo: Descrever os perfis autonômico, metabólico e antropométrico de pacientes obesos eletivos à cirurgia bariátrica. Métodos: Estudo corte transversal onde foram analisados os perfis autonômico (SDNN, RMSSD, LF, HF e LF/HF), metabólico (colesterol total, colesterol HDL, triglicérides, glicose, insulina e HOMA – IR) e antropométrico (índice de massa corpórea, circunferência da cintura, circunferência do quadril e gordura relativa) de pacientes no pré-operatório de cirurgia bariátrica, com idade ≥ 21 anos, do Núcleo de Tratamento e Cirurgia de Obesidade (NTCO) da cidade de Salvador-Bahia. Resultados: As médias da idade e IMC foram de 38,1 anos e 40,8 kg/m², respectivamente. As médias da circunferência abdominal e da gordura relativa foram de 119 cm e 48,9%, respectivamente. Em relação ao perfil lipídico, foram encontrados altos valores de colesterol total (191 mg/dL) e triglicérides (159,1 mg/dL). No perfil glicídico, a mediana da dosagem de glicose em jejum foi de 95 mg/dL; insulina: 21,1 mIU/L; HOMA: 5,2. Em relação ao perfil autonômico foram encontrados alteração nos valores, nos domínios do tempo, com predominância dos valores de SDNN sobre RMSSD, e na frequência, predominância dos valores de LH sobre HF. Conclusão: A obesidade esteve relacionada com a alteração do perfil metabólico e do perfil autonômico dessa amostra.