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Modulation of carotid body activity as a therapeutic intervention in metabolic diseases.
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Evaluating the Impact of Different Hypercaloric Diets on Weight Gain, Insulin Resistance, Glucose Intolerance, and its Comorbidities in Rats
Publication . Melo, Bernardete F.; Sacramento, Joana F.; Ribeiro, Maria J.; Prego, Claudia S.; Correia, Miguel C.; Coelho, Joana C.; Cunha-Guimaraes, Joao P.; Rodrigues, Tiago; Martins, Ines B.; Guarino, Maria P.; Seiça, Raquel M.; Matafome, Paulo; Conde, Silvia V.; V Conde, Silvia; NOVA Medical School|Faculdade de Ciências Médicas (NMS|FCM); Centro de Estudos de Doenças Crónicas (CEDOC); MDPI AG
Animal experimentation has a long history in the study of metabolic syndrome-related disorders. However, no consensus exists on the best models to study these syndromes. Knowing that different diets can precipitate different metabolic disease phenotypes, herein we characterized several hypercaloric rat models of obesity and type 2 diabetes, comparing each with a genetic model, with the aim of identifying the most appropriate model of metabolic disease. The effect of hypercaloric diets (high fat (HF), high sucrose (HSu), high fat plus high sucrose (HFHSu) and high fat plus streptozotocin (HF+STZ) during different exposure times (HF 3 weeks, HF 19 weeks, HSu 4 weeks, HSu 16 weeks, HFHSu 25 weeks, HF3 weeks + STZ) were compared with the Zucker fatty rat. Each model was evaluated for weight gain, fat mass, fasting plasma glucose, insulin and C-peptide, insulin sensitivity, glucose tolerance, lipid profile and liver lipid deposition, blood pressure, and autonomic nervous system function. All animal models presented with insulin resistance and dyslipidemia except the HF+STZ and HSu 4 weeks, which argues against the use of these models as metabolic syndrome models. Of the remaining animal models, a higher weight gain was exhibited by the Zucker fatty rat and wild type rats submitted to a HF diet for 19 weeks. We conclude that the latter model presents a phenotype most consistent with that observed in humans with metabolic disease, exhibiting the majority of the phenotypic features and comorbidities associated with type 2 diabetes in humans.
Modulation of carotid body activity as a therapeutic intervention in metabolic diseases
Publication . Sacramento, Joana Filipa Canais da Costa; Conde, Sílvia V.
Type 2 diabetes (T2D) is one of the most common chronic diseases, whose prevalence continues to increase, being expected to affect 629 million people in the world in 2045. The principal defects in T2D are peripheral insulin resistance, abnormal hepatic glucose metabolism and progressive pancreatic beta cell failure. Despite the several different drugs available for T2D treatment, over time, glucose control deteriorates progressively and even with the rearrange of medication, a sizeable proportion of individuals remain poorly control. Therefore, is crucial the development of new therapeutic strategies to control this epidemic. In the last years, the carotid body (CB), a peripheral chemoreceptor that sense changes in blood O2, CO2 and pH, have also been described as a metabolic sensor implicated in the control of energy homeostasis. In fact, it was described that CB overactivity is involved in the genesis of insulin resistance and hypertension induced by the hypercaloric diets. The aims of the present work were to investigate the role of CB in the control of glucose homeostasis and to search a method/approach to modulate CB activity aiming to treat T2D. Chapter I introduces general concepts in T2D field, as the insulin signaling, glucose homeostasis and the therapeutic options for T2D treatment. Additionally, fundamental concepts of CB function and the role of ATP and adenosine in the CB neurotransmission, as well as, the role of CB as a metabolic sensor are also addressed. In chapter II are described the general and specific aims of the present work. In chapter III it was demonstrated that the carotid sinus nerve (CSN), the CB sensitive nerve, resection restores the insulin sensitivity in two prediabetes animal models, an effect that was maintained even when the animals were continuously fed hypercaloric diets. Moreover, it was also demonstrated that CSN resection normalized systemic sympathetic nervous system activity, blood pressure, endothelial function, lipid profile and plasma glucose and insulin levels. Additionally, the mechanism behind the repair of glucohomeostasis involves an improvement in glucose uptake in the liver and perienteric adipose tissue and a restored insulin signaling pathways in skeletal muscle and adipose tissue. In chapter IV it was demonstrated that the bioelectronic modulation of the CSN by using the kilohertz frequency alternating current (KHFAC) is capable to restore the insulin sensitivity and the glucose tolerance in a diet-induced early stage T2D animal model. Furthermore, it was also described that these effects were reversed after discontinuation of the electrical stimulus. This work support a potential role for bioelectronic medicines in the treatment of T2D. Another approach that could be used to modulate the CSN activity is a pharmacological approach. In chapter V, it was explored the role of ATP and adenosine on the basal and CSN chemosensory activity evoked by hypoxia. It was shown that the CSN frequency of discharge is overactivated in a prediabetes animal model, being this effect modulated by ATP and adenosine. Since adenosine contributes more than ATP to generate CSN activity in moderate hypoxia, while ATP shows a more preponderant role during intense hypoxia and knowing that intense hypoxias are less prone to occur, it is suggested that the modulation of ATP signaling in the CB could be a therapeutic target to treat T2D. Finally, in chapter VI, it is presented a general and integrated discussion of this PhD thesis. In conclusion, the data present in this work contribute to strengthen that the modulation of CB/CSN activity represents a novel therapeutic approach for T2D.
Purines and carotid body: New roles in pathological conditions
Publication . Conde, S.V.; V Conde, Silvia; Monteiro, E.C.; Monteiro, E.C.; Sacramento, J.F.; NOVA Medical School|Faculdade de Ciências Médicas (NMS|FCM); Centro de Estudos de Doenças Crónicas (CEDOC); Frontiers Media
It is known that adenosine and adenosine-5'-triphosphate (ATP) are excitatory mediators involved in carotid body (CB) hypoxic signaling. The CBs are peripheral chemoreceptors classically defined by O2, CO2, and pH sensors. When hypoxia activates the CB, it induces the release of neurotransmitters from chemoreceptor cells leading to an increase in the action potentials frequency at the carotid sinus nerve (CSN). This increase in the firing frequency of the CSN is integrated in the brainstem to induce cardiorespiratory compensatory responses. In the last decade several pathologies, as, hypertension, diabetes, obstructive sleep apnea and heart failure have been associated with CB overactivation. In the first section of the present manuscript we review in a concise manner fundamental aspects of purine metabolism. The second section is devoted to the role of purines on the hypoxic response of the CB, providing the state-of-the art for the presence of adenosine and ATP receptors in the CB; for the role of purines at presynaptic level in CB chemoreceptor cells, as well as, its metabolism and regulation; at postsynaptic level in the CSN activity; and on the ventilatory responses to hypoxia. Recently, we have showed that adenosine is involved in CB hypersensitization during chronic intermittent hypoxia (CIH), which mimics obstructive sleep apnea, since caffeine, a non-selective adenosine receptor antagonist that inhibits A2A and A2B adenosine receptors, decreased CSN chemosensory activity in animals subjected to CIH. Apart from this involvement of adenosine in CB sensitization in sleep apnea, it was recently found that P2X3 ATP receptor in the CB contributes to increased chemoreflex hypersensitivity and hypertension in spontaneously hypertension rats. Therefore the last section of this manuscript is devoted to review the recent findings on the role of purines in CB-mediated pathologies as hypertension, diabetes and sleep apnea emphasizing the potential clinical importance of modulating purines levels and action to treat pathologies associated with CB dysfunction. © 2017 Conde, Monteiro and Sacramento.
Micro Computed Tomography Detects Changes in Liver Density in Control and in Prediabetes Rats
Publication . Franco, M. C.; Fonseca, A. R.; Sacramento, J.; Melo, B.; Conde, S. V.; V Conde, Silvia; Guarino, M. P.; NOVA Medical School|Faculdade de Ciências Médicas (NMS|FCM); Centro de Estudos de Doenças Crónicas (CEDOC); Elsevier BV
Fatty liver disease is an early event in the development of insulin resistance that predicts the presence and progression of the metabolic syndrome. In humans, fatty liver diagnosis is usually performed by imaging techniques based on ultrasound, computed tomography and magnetic resonance. Rodent models are often used in metabolic research allowing access to tissue biopsies however, studies describing ex vivo computed tomography of biological samples are scarce. X-ray Micro Computed Tomography (Micro-CT) is an imaging technique that reveals the internal structure of materials in great detail, also allowing a quantitative analysis of properties such as density measured as arbitrary Hounsfield Units (HU). Herein, we tested the hypothesis that Micro-CT detects changes in liver tomographic density induced by metabolic diseases and its reversal upon therapeutic surgical intervention. Two groups of male Wistar rats were used: a group submitted to a hypercaloric diet for 14 weeks to induce prediabetes and the control group submitted to a standard diet). The animals were randomly submitted to a surgical treatment and maintained on their respective diets after the procedure for 11 more weeks. Liver and adipose tissues samples were excised and samples were scanned using a compact X-ray micro-CT scanner. The projection images obtained were analyzed and reconstructed and values of HU density were calculated after calibration for all samples. Results showed that liver density was lower in prediabetes rats (74.8±5.87 HU) than in control animals (97.2±6.3 HU), p<0.05. Liver density was not affected by surgical treatment in control animals however, in prediabetes animals, the surgical therapy restored liver density to control values. Visceral fat density was significantly lower than hepatic density, as expected and was affected, neither by the disease condition nor by the surgical treatment. We concluded that micro-CT detects metabolic disease-induced changes in liver density, but not in visceral adipose tissue density in biopsy samples ex vivo. Changes in hepatic density, assessed by micro-CT, correlate with disease state and with therapeutic interventions.
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Fundação para a Ciência e a Tecnologia
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PD/BD/105890/2014