implications for metabolic diseases

Funding: Joana F. Sacramento and Fatima O. Martins are funded by contracts from the Portuguese Foundation for Science and Technology with reference CEEC IND/02428/2018 and CEECIND/04266/2017, respectivelyNeuro-immune communication has gained enormous interest in recent years due to increasing knowledge of the way in which the brain coordinates functional alterations in inflammatory and autoimmune responses, and the mechanisms of neuron-immune cell interactions in the context of metabolic diseases such as obesity and type 2 diabetes. In this review, we will explain how this relationship between the nervous and immune system impacts the pro- and anti-inflammatory pathways with specific reference to the hypothalamus-pituitary-adrenal gland axis and the vagal reflex and will explore the possible involvement of the carotid body (CB) in the neural control of inflammation. We will also highlight the mechanisms of vagal anti-inflammatory reflex control of immunity and metabolism, and the consequences of functional disarrangement of this reflex in settlement and development of metabolic diseases, with special attention to obesity and type 2 diabetes. Additionally, the role of CB in the interplay between metabolism and immune responses will be discussed, with specific reference to the different stimuli that promote CB activation and the balance between sympathetic and parasympathetic in this context. In doing so, we clarify the multivarious neuronal reflexes that coordinate tissue-specific responses (gut, pancreas, adipose tissue and liver) critical to metabolic control, and metabolic disease settlement and development. In the final section, we will summarize how electrical modulation of the carotid sinus nerve may be utilized to adjust these reflex responses and thus control inflammation and metabolic diseases, envisioning new therapeutics horizons.publishersversionpublishe

Exploring the mediators that promote carotid body dysfunction in type 2 diabetes and obesity related syndromes

Carotid bodies (CBs) are peripheral chemoreceptors that sense changes in blood O2, CO2, and pH levels. Apart from ventilatory control, these organs are deeply involved in the homeostatic regulation of carbohydrates and lipid metabolism and inflammation. It has been described that CB dysfunction is involved in the genesis of metabolic diseases and that CB overactivation is present in animal models of metabolic disease and in prediabetes patients. Additionally, resection of the CB-sensitive nerve, the carotid sinus nerve (CSN), or CB ablation in animals prevents and reverses diet-induced insulin resistance and glucose intolerance as well as sympathoadrenal overactivity, meaning that the beneficial effects of decreasing CB activity on glucose homeostasis are modulated by target-related efferent sympathetic nerves, through a reflex initiated in the CBs. In agreement with our pre-clinical data, hyperbaric oxygen therapy, which reduces CB activity, improves glucose homeostasis in type 2 diabetes patients. Insulin, leptin, and pro-inflammatory cytokines activate the CB. In this manuscript, we review in a concise manner the putative pathways linking CB chemoreceptor deregulation with the pathogenesis of metabolic diseases and discuss and present new data that highlight the roles of hyperinsulinemia, hyperleptinemia, and chronic inflammation as major factors contributing to CB dysfunction in metabolic disorders.publishersversionpublishe

Clinical Implications for Carotid Body Neuromodulation

Funding Information: This study was partially supported by the GlaxoSmithKline Bioelectronics R&D ?Innovation Challenge. JS and BM were supported by a contract and a Ph.D. Grant from the Portuguese Foundation for Science and Technology Reference CEECIND/02428/2018 and PD/BD/128336/2017, respectively. This study received funding from the Fundação para a Ciência e Tecnologia (FCT) (UIDB/05704/2020).Chronic carotid sinus nerve (CSN) electrical modulation through kilohertz frequency alternating current improves metabolic control in rat models of type 2 diabetes, underpinning the potential of bioelectronic modulation of the CSN as a therapeutic modality for metabolic diseases in humans. The CSN carries sensory information from the carotid bodies, peripheral chemoreceptor organs that respond to changes in blood biochemical modifications such as hypoxia, hypercapnia, acidosis, and hyperinsulinemia. In addition, the CSN also delivers information from carotid sinus baroreceptors—mechanoreceptor sensory neurons directly involved in the control of blood pressure—to the central nervous system. The interaction between these powerful reflex systems—chemoreflex and baroreflex—whose sensory receptors are in anatomical proximity, may be regarded as a drawback to the development of selective bioelectronic tools to modulate the CSN. Herein we aimed to disclose CSN influence on cardiovascular regulation, particularly under hypoxic conditions, and we tested the hypothesis that neuromodulation of the CSN, either by electrical stimuli or surgical means, does not significantly impact blood pressure. Experiments were performed in Wistar rats aged 10–12 weeks. No significant effects of acute hypoxia were observed in systolic or diastolic blood pressure or heart rate although there was a significant activation of the cardiac sympathetic nervous system. We conclude that chemoreceptor activation by hypoxia leads to an expected increase in sympathetic activity accompanied by compensatory regional mechanisms that assure blood flow to regional beds and maintenance of hemodynamic homeostasis. Upon surgical denervation or electrical block of the CSN, the increase in cardiac sympathetic nervous system activity in response to hypoxia was lost, and there were no significant changes in blood pressure in comparison to control animals. We conclude that the responses to hypoxia and vasomotor control short-term regulation of blood pressure are dissociated in terms of hypoxic response but integrated to generate an effector response to a given change in arterial pressure.publishersversionpublishe

Primary Effects on Skeletal Muscle

The present study was supported by the Portuguese Society of Diabetes. JS was supported by a PhD Grant from the Portuguese Foundation for Science and Technology, PD/BD/105890/2014.Epidemiological studies showed that chronic caffeine intake decreased the risk of type 2 diabetes. Previously, we described that chronic caffeine intake prevents and reverses insulin resistance induced by hypercaloric diets and aging, in rats. Caffeine has several cellular mechanisms of action, being the antagonism of adenosine receptors the only attained with human coffee consumption. Here, we investigated the subtypes of adenosine receptors involved on the effects of chronic caffeine intake on insulin sensitivity and the mechanisms and sex differences behind this effect. Experiments were performed in male and female Wistar rats fed either a chow or high-sucrose (HSu) diet (35% of sucrose in drinking water) during 28 days, to induce insulin resistance. In the last 15 days of diet the animals were submitted to DPCPX (A1 antagonist, 0.4 mg/kg), SCH58261 (A2A antagonist, 0.5 mg/kg), or MRS1754 (A2B antagonist, 9.5 μg/kg) administration. Insulin sensitivity, fasting glycaemia, blood pressure, catecholamines, and fat depots were assessed. Expression of A1, A2A, A2B adenosine receptors and protein involved in insulin signaling pathways were evaluated in the liver, skeletal muscle, and visceral adipose tissue. UCP1 expression was measured in adipose tissue. Paradoxically, SCH58261 and MRS1754 decreased insulin sensitivity in control animals, whereas they both improved insulin response in HSu diet animals. DPCPX did not alter significantly insulin sensitivity in control or HSu animals, but reversed the increase in total and visceral fat induced by the HSu diet. In skeletal muscle, A1, A2A, and A2B adenosine receptor expression were increased in HSu group, an effect that was restored by SCH58261 and MRS1754. In the liver, A1, A2A expression was increased in HSu group, while A2B expression was decreased, being this last effect reversed by administration of MRS1754. In adipose tissue, A1 and A2A block upregulated the expression of these receptors. A2 adenosine antagonists restored impaired insulin signaling in the skeletal muscle of HSu rats, but did not affect liver or adipose insulin signaling. Our results show that adenosine receptors exert opposite effects on insulin sensitivity, in control and insulin resistant states and strongly suggest that A2 adenosine receptors in the skeletal muscle are the majors responsible for whole-body insulin sensitivity.publishersversionpublishe

High fat diet blunts the effects of leptin on ventilation and on carotid body activity

Funding : This study was supported by the Portuguese Foundation for Science and Technology grant PTDC/SAU-ORG/111417/2009 to S.C. and by Grants BFU2015-70616R from MINECO-FEDER, Spain. J.F.S. and B.F.M. are supported by PhD Grants from FCT, PD/BD/105890/2014 and PD/BD/128336/2017, respectively.Leptin plays a role in the control of breathing, acting mainly on central nervous structures. Leptin receptor is expressed in the carotid body (CB) and this finding has been associated with a putative physiological role of leptin in the regulation of CB function. Since, the CBs are implicated in energy metabolism herein we tested the effects of different concentrations of leptin administration on ventilatory parameters and on carotid sinus nerve (CSN) activity in control and high-fat (HF) diet fed rats, in order to clarify the role of leptin in ventilation control in metabolic disease states. We also investigated the expression of leptin receptors and the neurotransmitters involved in leptin signalling in the CBs. We found that in non-disease conditions, leptin increases minute ventilation both in basal and hypoxic conditions. However, in the HF model, the effect of leptin in ventilatory control is blunted. We also observed that HF rats display an increased frequency of CSN discharge in basal conditions that is not altered by leptin, in contrast to what is observed in control animals. Leptin did not modify intracellular Ca2+ in CB chemoreceptor cells, but it produced an increase in the release of adenosine from the whole CB. We conclude that CBs represent an important target for leptin signalling, not only to coordinate peripheral ventilatory chemoreflexive drive, but probably also to modulate metabolic variables. We also concluded that leptin signalling is mediated by adenosine release and that HF diets blunt leptin responses in the CB, compromising ventilatory adaptation. This article is protected by copyright. All rights reserved.publishersversionpublishe

Type 2 diabetes progression differently affects endothelial function and vascular contractility in the aorta and the pulmonary artery

© The Author(s) 2021. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.Type 2 diabetes (T2D) is associated with cardiovascular and pulmonary disease. How T2D affects pulmonary endothelial function is not well characterized. We investigated the effects of T2D progression on contractility machinery and endothelial function in the pulmonary and systemic circulation and the mechanisms promoting the dysfunction, using pulmonary artery (PA) and aorta. A high-fat (HF, 3 weeks 60% lipid-rich diet) and a high-fat/high-sucrose (HFHSu, combined 60% lipid-rich diet and 35% sucrose during 25 weeks) groups were used as prediabetes and T2D rat models. We found that T2D progression differently affects endothelial function and vascular contractility in the aorta and PA, with the contractile machinery being altered in the PA and aorta in prediabetes and T2D animals; and endothelial function being affected in both models in the aorta but only affected in the PA of T2D animals, meaning that PA is more resistant than aorta to endothelial dysfunction. Additionally, PA and systemic endothelial dysfunction in diabetic rats were associated with alterations in the nitrergic system and inflammatory pathways. PA dysfunction in T2D involves endothelial wall mineralization. The understanding of the mechanisms behind PA dysfunction in T2D can lead to significant advances in both preventative and therapeutic treatments of pulmonary disease-associated diabetes.B.F.M. is supported by PhD Grant from Portuguese Foundation for Science and Technology Reference PD/BD/128336/2017. FOM and JFS are supported by Portuguese Foundation for Science and Technology contracts CEECIND/04266/2017 and CEECIND/02428/2018.info:eu-repo/semantics/publishedVersio

Circulating Dopamine Is Regulated by Dietary Glucose and Controls Glucagon-like 1 Peptide Action in White Adipose Tissue

Funding: This work was supported by a grant from GIFT (Grupo de Investigação Fundamental e Translational) from the Portugal Society of Diabetes and Portugal Foundation for Science and Technology (PEst UID/NEU/04539/2013 and UID/NEU/04539/2019: CNC.IBILI; PEst UIDB/04539/2020 and UIDP/04539/2020: CIBB). G.T. and D.R.S. were supported by Ph.D. Grants from the Portuguese Foundation for Science and Technology (PD/BD/127822/2016 and 2021.08160.BD respectively). J.F.S. is supported by a contract from the Portuguese Foundation for Science and Technology (CEEC IND/02428/2018).Dopamine directly acts in the liver and white adipose tissue (WAT) to regulate insulin signaling, glucose uptake, and catabolic activity. Given that dopamine is secreted by the gut and regulates insulin secretion in the pancreas, we aimed to determine its regulation by nutritional cues and its role in regulating glucagon-like peptide 1 (GLP-1) action in WAT. Solutions with different nutrients were administered to Wistar rats and postprandial dopamine levels showed elevations following a mixed meal and glucose intake. In high-fat diet-fed diabetic Goto-Kakizaki rats, sleeve gastrectomy upregulated dopaminergic machinery, showing the role of the gut in dopamine signaling in WAT. Bromocriptine treatment in the same model increased GLP-1R in WAT, showing the role of dopamine in regulating GLP-1R. By contrast, treatment with the GLP-1 receptor agonist Liraglutide had no impact on dopamine receptors. GLP-1 and dopamine crosstalk was shown in rat WAT explants, since dopamine upregulated GLP-1-induced AMPK activity in mesenteric WAT in the presence of the D2R and D3R inhibitor Domperidone. In human WAT, dopamine receptor 1 (D1DR) and GLP-1R expression were correlated. Our results point out a dietary and gut regulation of plasma dopamine, acting in the WAT to regulate GLP-1 action. Together with the known dopamine action in the pancreas, such results may identify new therapeutic opportunities to improve metabolic control in metabolic disorders.publishersversionpublishe

Propranolol therapy for cerebral cavernous malformations

Funding Information: The present study was funded by IPOLFG EPE and by iNOVA4Health (UID/Multi/04462/2019) a program finan‑ cially supported by Fundação para a Ciência e Tecnologia (FCT)/Ministério da Educação e Ciência, through national funds. The PhD fellowship of FLC was funded by FCT (PD/BD/128337/2017).Cerebral cavernous malformations (CCMs) are vascular malformations characterized by the abnormal growth of vascular structures in the central nervous system. However, the precise mechanism(s) responsible for the development of CCM vascular abnormalities remain poorly understood. Although the mechanisms of action of propranolol in CCM have not yet been fully explored it is not commonly prescribed, it has been shown to be effective in children and appears to play a protective role in the prevention of CCM-derived hemorrhage in adults. The present study performed in vitro and ex vivo assays in order to examine the effects of propranolol on endothelial cells (ECs). The percentage of CD14+/CD31+ cells and the levels of VEGF in the peripheral blood (PB) of a child patient with CCM, with recurrent seizures and hemorrhages, who was maintained under propranolol therapy, were also analyzed. In addition to the effects of propranolol on differentiated ECs, and the decrease angiogenic-related features in vitro and ex vivo, it was observed that in the PB of this patient, propranolol administration decreased the percentage of circulating cells sharing monocytic and EC features (CD14+/CD31+ cells), as well as the VEGF levels; this was concomitant with a good prognosis and with the reversion of CCM lesions. A decrease in VEGF levels by propranolol may also be involved in the impairment of the recruitment of CD14+/CD31+ monocytes functioning as endothelial progenitor cells to sustain the vascular lesion. On the whole, the present study demonstrates that propranolol impairs angiogenesis in vitro and may thus be a useful tool for the clinical management of CCM. Moreover, the present study highlights the monitorization of the levels of CD14+/CD31+ monocytes and VEGF levels as a useful tool for predicting the clinical efficacy of propranolol in patients with CCM.publishersversionepub_ahead_of_prin

Carotid body chemosensitivity: Early biomarker of dysmetabolism in humans

info:eu-repo/semantics/publishedVersio

Exploring the Mediators that Promote Carotid Body Dysfunction in Type 2 Diabetes and Obesity Related Syndromes

Carotid bodies (CBs) are peripheral chemoreceptors that sense changes in blood O2, CO2, and pH levels. Apart from ventilatory control, these organs are deeply involved in the homeostatic regulation of carbohydrates and lipid metabolism and inflammation. It has been described that CB dysfunction is involved in the genesis of metabolic diseases and that CB overactivation is present in animal models of metabolic disease and in prediabetes patients. Additionally, resection of the CB-sensitive nerve, the carotid sinus nerve (CSN), or CB ablation in animals prevents and reverses diet-induced insulin resistance and glucose intolerance as well as sympathoadrenal overactivity, meaning that the beneficial effects of decreasing CB activity on glucose homeostasis are modulated by target-related efferent sympathetic nerves, through a reflex initiated in the CBs. In agreement with our pre-clinical data, hyperbaric oxygen therapy, which reduces CB activity, improves glucose homeostasis in type 2 diabetes patients. Insulin, leptin, and pro-inflammatory cytokines activate the CB. In this manuscript, we review in a concise manner the putative pathways linking CB chemoreceptor deregulation with the pathogenesis of metabolic diseases and discuss and present new data that highlight the roles of hyperinsulinemia, hyperleptinemia, and chronic inflammation as major factors contributing to CB dysfunction in metabolic disorders