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Interoception entails perceiving or being aware of the internal state of the body, playing a pivotal role in regulating processes such as heartbeat, digestion, glucose metabolism, and respiration. The carotid body (CB) serves as an interoceptive organ, transmitting information to the brain via its sensitive nerve, the carotid sinus nerve, to maintain homeostasis. While traditionally known for sensing oxygen, carbon dioxide, and pH levels, the CB is now recognized to possess additional interoceptive properties, detecting various mediators involved in blood pressure regulation, inflammation, and glucose homeostasis, among other physiological functions. Furthermore, in the last decades CB dysfunction has been linked to diseases like sleep apnea, essential hypertension, and diabetes. In this review manuscript, we make a concise overview of the traditional interoceptive functions of the CB, acting as a sensor for oxygen levels, carbon dioxide levels, and pH, and introduce the novel interoceptive properties of the CB related to vascular, glucose and energy regulation. Additionally, we revise the contribution of the CB to the onset and progression of metabolic diseases, delving into the potential dysfunction of its interoceptive metabolic functions as a contributing factor to pathophysiology. Finally, we postulate the use of therapeutic interventions targeting the metabolic interoceptive properties of the CB as a potential avenue for addressing metabolic diseases., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Bioelectronic medicine are an emerging class of treatments aiming to modulate body nervous activity to correct pathological conditions and restore health. Recently, it was shown that the high frequency electrical neuromodulation of the carotid sinus nerve (CSN), a small branch of the glossopharyngeal nerve that connects the carotid body (CB) to the brain, restores metabolic function in type 2 diabetes (T2D) animal models highlighting its potential as a new therapeutic modality to treat metabolic diseases in humans. In this manuscript, we review the current knowledge supporting the use of neuromodulation of the CSN to treat T2D and discuss the future perspectives for its clinical application. Firstly, we review in a concise manner the role of CB chemoreceptors and of CSN in the pathogenesis of metabolic diseases. Secondly, we describe the findings supporting the potential therapeutic use of the neuromodulation of CSN to treat T2D, as well as the feasibility and reversibility of this approach. A third section is devoted to point up the advances in the neural decoding of CSN activity, in particular in metabolic disease states, that will allow the development of closed-loop approaches to deliver personalized and adjustable treatments with minimal side effects. And finally, we discuss the findings supporting the assessment of CB activity in metabolic disease patients to screen the individuals that will benefit therapeutically from this bioelectronic approach in the future., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Conde, Sacramento, Zinno, Mazzoni, Micera and Guarino.)

Maternal obesity and gestational diabetes predispose the next generation to metabolic disturbances. Moreover, the lactation phase also stands as a critical phase for metabolic programming. Nevertheless, the precise mechanisms originating these changes remain unclear. Here, we investigate the consequences of a maternal lipid-rich diet during gestation and lactation and its impact on metabolism and behavior in the offspring. Two experimental groups of Wistar female rats were used: a control group (NC) that was fed a standard diet during the gestation and lactation periods and an overnutrition group that was fed a high-fat diet (HF, 60% lipid-rich) during the same phases. The offspring were analyzed at postnatal days 21 and 28 and at 2 months old (PD21, PD28, and PD60) for their metabolic profiles (weight, fasting glycemia insulin sensitivity, and glucose tolerance) and euthanized for brain collection to evaluate metabolism and inflammation in the hypothalamus, hippocampus, and prefrontal cortex using Western blot markers of synaptic dynamics. At 2 months old, behavioral tests for anxiety, stress, cognition, and food habits were conducted. We observed that the female offspring born from HF mothers exhibited increased weight gain and decreased glucose tolerance that attenuated with age. In the offspring males, weight gain increased at P21 and worsened with age, while glucose tolerance remained unchanged. The offspring of the HF mothers exhibited elevated levels of anxiety and stress during behavioral tests, displaying decreased predisposition for curiosity compared to the NC group. In addition, the offspring from mothers with HF showed increased food consumption and a lower tendency towards food-related aggression. We conclude that exposure to an HF diet during pregnancy and lactation induces dysmetabolism in the offspring and is accompanied by heightened stress and anxiety. There was sexual dimorphism in the metabolic traits but not behavioral phenotypes.

The association between obstructive sleep apnea (OSA) and metabolic disorders is well-established; however, the underlying mechanisms that elucidate this relationship remain incompletely understood. Since the liver is a major organ in the maintenance of metabolic homeostasis, we hypothesize that liver dysfunction plays a crucial role in the pathogenesis of metabolic dysfunction associated with obstructive sleep apnea (OSA). Herein, we explored the underlying mechanisms of this association within the liver. Experiments were performed in male Wistar rats fed with a control or high fat (HF) diet (60% lipid-rich) for 12 weeks. Half of the groups were exposed to chronic intermittent hypoxia (CIH) (30 hypoxic (5% O 2 ) cycles, 8 h/day) that mimics OSA, in the last 15 days. Insulin sensitivity and glucose tolerance were assessed. Liver samples were collected for evaluation of lipid deposition, insulin signaling, glucose homeostasis, hypoxia, oxidative stress, antioxidant defenses, mitochondrial biogenesis and inflammation. Both the CIH and HF diet induced dysmetabolism, a state not aggravated in animals submitted to HF plus CIH. CIH aggravates hepatic lipid deposition in obese animals. Hypoxia-inducible factors levels were altered by these stimuli. CIH decreased the levels of oxidative phosphorylation complexes in both groups and the levels of SOD-1. The HF diet reduced mitochondrial density and hepatic antioxidant capacity. The CIH and HF diet produced alterations in cysteine-related thiols and pro-inflammatory markers. The results obtained suggest that hepatic mitochondrial dysfunction and oxidative stress, leading to inflammation, may be significant factors contributing to the development of dysmetabolism associated with OSA.

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.

Individuals who develop type 2 diabetes (T2D) at an early age are at higher risk of developing neurodegenerative disorders such as Alzheimer's and Parkinson's disease. A shared dysfunctional characteristic between T2D and these neurodegenerative disorders is insulin resistance. Recently, it was shown that prediabetes animals and patients exhibited increased carotid body (CB) activity. Moreover, these organs are deeply involved in the development of metabolic diseases, since upon abolishment of their activity via carotid sinus nerve (CSN) resection, several dysmetabolic features of T2D were reverted. Herein, we investigated if CSN resection may also prevent cognitive impairment associated with brain insulin resistance. We explored a diet-induced prediabetes animal model where Wistar rats are kept in a high fat-high sucrose (HFHSu) diet for 20 weeks. We evaluated CSN resection effects on behavioral parameters and on insulin signaling-related proteins levels, in the prefrontal cortex and the hippocampus. HFHSu animals exhibited impaired short-term memory evaluated by the y-maze test. Remarkably, CSN resection prevented the development of this phenotype. HFHSu diet or CSN resection did not promote significant alterations in insulin signaling-associated proteins levels. Our findings suggest that CBs modulation might have a role in preventing short-term spatial memory deficits associated with peripheral dysmetabolic states., (© 2023. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Endothelial dysfunction is an essential intermediary for development of cardiovascular diseases associated with diabetes and hypertension (HT). The carotid body (CB) dysfunction contributes to dysmetabolic states, and the resection of carotid sinus nerve (CSN) prevents and reverts dysmetabolism and HT. Herein, we investigated if CSN denervation ameliorates systemic endothelial dysfunction in an animal model of type 2 diabetes mellitus (T2DM).We used Wistar male rats submitted to HFHSu diet during 25 weeks and the correspondent age-matched controls fed with a standard diet. CSN resection was performed in half of the groups after 14 weeks of diet. In vivo insulin sensitivity, glucose tolerance and blood pressure, ex vivo aortic artery contraction and relaxation and nitric oxide (NO) levels in plasma and aorta, aorta nitric oxide synthase (NOS) isoforms, and PGF2αR levels were evaluated.We demonstrated that, alongside to dysmetabolism and HT reversion, CSN resection restores endothelial function in the aorta and decreases the NO levels in plasma and aorta at the same time that restores normal levels of iNOS in aorta without changing eNOS or PGF2αR levels.These results suggest that the modulation of CB activity can be important for the treatment of HT and endothelial dysfunction related with T2DM., (© 2023. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Metformin is a glucose-lowering, insulin-sensitizing drug that is commonly used in the treatment of type 2 diabetes (T2D). In the last decade, the carotid body (CB) has been described as a metabolic sensor implicated in the regulation of glucose homeostasis, being CB dysfunction crucial for the development of metabolic diseases, such as T2D. Knowing that metformin could activate AMP-activated protein kinase (AMPK) and that AMPK has been described to have an important role in CB hypoxic chemotransduction, herein we have investigated the effect of chronic metformin administration on carotid sinus nerve (CSN) chemosensory activity in basal and hypoxic and hypercapnic conditions in control animals. Experiments were performed in male Wistar rats subjected to 3 weeks of metformin (200 mg/kg) administration in the drinking water. The effect of chronic metformin administration was tested in spontaneous and hypoxic (0% and 5% O 2 ) and hypercapnic (10% CO 2 ) evoked CSN chemosensory activity. Metformin administration for 3 weeks did not modify the basal CSN chemosensory activity in control animals. Moreover, the CSN chemosensory response to intense and moderate hypoxia and hypercapnia was not altered by the chronic metformin administration. In conclusion, chronic metformin administration did not modify chemosensory activity in control animals., (© 2023. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Obesity is a worldwide epidemic being the main cause of cardiovascular, metabolic disturbances and chronic pulmonary diseases. The increase in body weight may affect the respiratory system due to fat deposition and systemic inflammation. Herein, we evaluated the sex differences in the impact of obesity and high abdominal circumference on basal ventilation. Thirty-five subjects, 23 women and 12 men with a median age of 61 and 67, respectively, were studied and classified as overweight and obese according to body mass index (BMI) and were also divided by the abdominal circumference. Basal ventilation, namely, respiratory frequency, tidal volume, and minute ventilation, was evaluated. In normal and overweight women, basal ventilation did not change, but obese women exhibited a decrease in tidal volume. In men, overweight and obese subjects did not exhibit altered basal ventilation. In contrast, when subjects were subdivided based on the abdominal perimeter, a higher circumference did not change the respiratory frequency but induced a decrease in tidal volume and minute ventilation in women, while in men these two parameters increased. In conclusion, higher abdominal circumference rather than BMI is associated with alterations in basal ventilation in women and men., (© 2023. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Carotid bodies (CBs) are metabolic sensors whose dysfunction is involved in the genesis of dysmetabolic states. Ageing induces significant alterations in CB function also prompting to metabolic deregulation. On the other hand, metabolic disease can accelerate ageing processes. Taking these into account, we evaluated the effect of long-term hypercaloric diet intake and CSN resection on age-induced dysmetabolism and CB function. Experiments were performed in male Wistar rats subjected to 14 or 44 weeks of high-fat high-sucrose (HFHSu) or normal chow (NC) diet and subjected to either carotid sinus nerve (CSN) resection or a sham procedure. After surgery, the animals were kept on a diet for more than 9 weeks. Metabolic parameters, basal ventilation, and hypoxic and hypercapnic ventilatory responses were evaluated. CB type I and type II cells, HIF-1α and insulin receptor (IR), and GLP-1 receptor (GLP1-R)-positive staining were analyzed by immunofluorescence. Ageing decreased by 61% insulin sensitivity in NC animals, without altering glucose tolerance. Short-term and long-term HFHSu intake decreased insulin sensitivity by 55 and 62% and glucose tolerance by 8 and 29%, respectively. CSN resection restored insulin sensitivity and glucose tolerance. Ageing decreased spontaneous ventilation, but short-term or long-term intake of HFHSu diet and CSN resection did not modify basal ventilatory parameters. HFHSu diet increased hypoxic ventilatory responses in young and adult animals, effects attenuated by CSN resection. Ageing, hypercaloric diet, and CSN resection did not change hypercapnic ventilatory responses. Adult animals showed decreased type I cells and IR and GLP-1R staining without altering the number of type II cells and HIF-1α. HFHSu diet increased the number of type I and II cells and IR in young animals without significantly changing these values in adult animals. CSN resection restored the number of type I cells in HFHSu animals and decreased IR-positive staining in all the groups of animals, without altering type II cells, HIF-1α, or GLP-1R staining. In conclusion, long-term hypercaloric diet consumption exacerbates age-induced dysmetabolism, and both short- and long-term hypercaloric diet intakes promote significant alterations in CB function. CSN resection ameliorates these effects. We suggest that modulation of CB activity is beneficial in exacerbated stages of dysmetabolism., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Melo, Sacramento, Capucho, Sampaio-Pires, Prego and Conde.)

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., Competing Interests: Part of this study, in particular Figures 1, 3 were funded by GlaxoSmithKline Bioelectronics R&D unit. The funder had the following involvement with the study: decision to publish. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Conde, Sacramento, Melo, Fonseca-Pinto, Romero-Ortega and Guarino.)

Background and Objectives: The therapeutic effects of the dopamine D2 receptor (D2R) agonist, bromocriptine, in type 2 diabetes (T2D) have been attributed to central nervous system actions. However, peripheral dopamine directly modulates glucose uptake in insulin-sensitive tissues and lipid metabolism in adipose tissue (AT). We hypothesized that the dopaminergic system may be impaired in the adipose tissue of patients with T2D and that the therapeutic actions of bromocriptine could involve the modulation of metabolism in this tissue., Methods: The expression of dopamine receptors was evaluated in visceral AT samples from patients with obesity and stratified in several groups: insulin sensitive (IS); insulin resistance (IR) normoglycaemic; insulin resistant prediabetic; insulin resistant diabetic, according to Ox-HOMA2IR, fasting glycaemia and HbA1c levels. T2D Goto-Kakizaki rats (GK) were fed a high-caloric diet (HCD) for five months and treated with bromocriptine (10 mg/kg/day, i.p.) in the last month. The levels of dopaminergic system mediators and markers of insulin sensitivity and glucose and lipid metabolism were assessed in the peri-epididymal adipose tissue (pEWAT) and brown (BAT) adipose tissues, liver, and skeletal muscle., Results: Patients with IR presented a decreasing trend of DRD1 expression in the visceral adipose tissue, being correlated with the expression of UCP1, PPARA, and insulin receptor (INSR) independently of insulin resistance and body mass index. Although no differences were observed in DRD2, DRD4 expression was significantly decreased in patients with prediabetes and T2D. In HCD-fed diabetic rats, bromocriptine increased D1R and tyrosine hydroxylase (TH) levels in pEWAT and the liver. Besides reducing adiposity, bromocriptine restored GLUT4 and PPARγ levels in pEWAT, as well as postprandial InsR activation and postabsorptive activation of lipid oxidation pathways. A reduction of liver fat, GLUT2 levels and postprandial InsR and AMPK activation in the liver was observed. Increased insulin sensitivity and GLUT4 levels in BAT and an improvement of the overall metabolic status were observed., Conclusions: Bromocriptine treatment remodels adipose tissue and the liver dopaminergic system, with increased D1R and TH levels, resulting in higher insulin sensitivity and catabolic function. Such effects may be involved in bromocriptine therapeutic effects, given the impaired expression of dopamine receptors in the visceral adipose tissue of IR patients, as well as the correlation of D1R expression with InsR and metabolic mediators., (Copyright © 2021 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Several studies demonstrated a link between obstructive sleep apnea (OSA) and the development of insulin resistance. However, the main event triggering insulin resistance in OSA remains to be clarified. Herein, we investigated the effect of mild and severe chronic intermittent hypoxia (CIH) on whole-body metabolic deregulation and visceral adipose tissue dysfunction. Moreover, we studied the contribution of obesity to CIH-induced dysmetabolic states. Experiments were performed in male Wistar rats submitted to a control and high-fat (HF) diet. Two CIH protocols were tested: A mild CIH paradigm (5/6 hypoxic (5% O 2 ) cycles/h, 10.5 h/day) during 35 days and a severe CIH paradigm (30 hypoxic (5% O 2 ) cycles, 8 h/day) during 15 days. Fasting glycemia, insulinemia, insulin sensitivity, weight, and fat mass were assessed. Adipose tissue hypoxia, inflammation, angiogenesis, oxidative stress, and metabolism were investigated. Mild and severe CIH increased insulin levels and induced whole-body insulin resistance in control animals, effects not associated with weight gain. In control animals, CIH did not modify adipocytes perimeter as well as adipose tissue hypoxia, angiogenesis, inflammation or oxidative stress. In HF animals, severe CIH attenuated the increase in adipocytes perimeter, adipose tissue hypoxia, angiogenesis, and dysmetabolism. In conclusion, adipose tissue dysfunction is not the main trigger for initial dysmetabolism in CIH. CIH in an early stage might have a protective role against the deleterious effects of HF diet on adipose tissue metabolism.

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.

Neuro-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.

Carotid bodies (CBs) are peripheral chemoreceptors that sense changes in blood O 2 , CO 2 , 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.

Objective: The carotid bodies (CBs) are peripheral chemoreceptor organs classically described as being O2 sensors, which are increasingly emerging as core players in metabolic control. Herein we evaluated CB activity in prediabetes patients and determined its correlation with dysmetabolism clinical features., Design and Methods: Prediabetes patients were recruited at the Cardiology Service, Hospital Santa Marta, Centro Hospitalar Lisboa Central, EPE (CHLC-EPE). The study was approved by CHLC-EPE and NOVA Medical School Ethics Committee. Thirty-three prediabetic and 14 age-matched, non-prediabetic, volunteers had their peripheral chemosensitivity evaluated by the Dejours test. Serum biomarkers of metabolic disease, insulin sensitivity (HOMA-IR), blood pressure, carotid intima-media thickness (cIMT) and glucose tolerance were assessed., Results: CB chemosensitivity was significantly increased in prediabetic group (P < 0.01). Fasting blood, glucose intolerance, fasting insulin and HOMA-IR were significantly higher in prediabetes patients. Insulin resistance correlated both with peripheral chemosensitivity, assessed by the Dejours test (P < 0.05) and with abdominal circumference (P < 0.01). HbA1c correlated with HOMA-IR (P < 0.05) and left cIMT (P < 0.05) in prediabetes patients., Conclusions: We conclude that CB is overactive in prediabetes subjects and that peripheral chemosensitivity correlates with fasting insulin and insulin resistance representing a novel non-invasive functional biomarker to forecast early metabolic disease.

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 (A 1 antagonist, 0.4 mg/kg), SCH58261 (A 2A antagonist, 0.5 mg/kg), or MRS1754 (A 2B antagonist, 9.5 μg/kg) administration. Insulin sensitivity, fasting glycaemia, blood pressure, catecholamines, and fat depots were assessed. Expression of A 1 , A 2A , A 2B 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, A 1 , A 2A , and A 2B adenosine receptor expression were increased in HSu group, an effect that was restored by SCH58261 and MRS1754. In the liver, A 1 , A 2A expression was increased in HSu group, while A 2B expression was decreased, being this last effect reversed by administration of MRS1754. In adipose tissue, A 1 and A 2A block upregulated the expression of these receptors. A 2 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 A 2 adenosine receptors in the skeletal muscle are the majors responsible for whole-body insulin sensitivity., (Copyright © 2020 Sacramento, Martins, Rodrigues, Matafome, Ribeiro, Olea and Conde.)

Key Points: Adenosine and ATP are excitatory neurotransmitters involved in the carotid body (CB) response to hypoxia. During ageing the CB exhibits a decline in its functionality, demonstrated by decreased hypoxic responses. In aged rats (20-24 months old) there is a decrease in: basal and hypoxic release of adenosine and ATP from the CB; expression of adenosine and ATP receptors in the petrosal ganglion; carotid sinus nerve (CSN) activity in response to hypoxia; and ventilatory responses to ischaemic hypoxia. There is also an increase in SNAP25, ENT1 and CD73 expression. It is concluded that, although CSN activity and ventilatory responses to hypoxia decrease with age, adjustments in purinergic metabolism in the CB in aged animals are present aiming to maintain the contribution of adenosine and ATP. The possible significance of the findings in the context of ageing and in CB-associated pathologies is considered., Abstract: During ageing the carotid body (CB) exhibits a decline in its functionality. Here we investigated the effect of ageing on functional CB characteristics as well as the contribution of adenosine and ATP to CB chemosensory activity. Experiments were performed in 3-month-old and 20- to 24-month-old male Wistar rats. Ageing decreased: the number of tyrosine hydroxylase immune-positive cells, but not type II cells or nestin-positive cells in the CB; the expression of P2X 2 and A 2A receptors in the petrosal ganglion; and the basal and hypoxic release of adenosine and ATP from the CB. Ageing increased ecto-nucleotidase (CD73) immune-positive cells and the expression of synaptosome associated protein 25 (SNAP25) and equilibrative nucleoside transporter 1 (ENT1) in the CB. Additionally, ageing did not modify basal carotid sinus nerve (CSN) activity or the activity in response to hypercapnia, but decreased CSN activity in hypoxia. The contribution of adenosine and ATP to stimuli-evoked CSN chemosensory activity in aged animals followed the same pattern of 3-month-old animals. Bilateral common carotid occlusions during 5, 10 and 15 s increased ventilation proportionally to the duration of ischaemia, an effect decreased by ageing. ATP contributed around 50% to ischaemic-ventilatory responses in young and aged rats; the contribution of adenosine was dependent on the intensity of ischaemia, being maximal in ischaemias of 5 s (50%) and much smaller in 15 s ischaemias. Our results demonstrate that both ATP and adenosine contribute to CB chemosensory activity in ageing. Though CB responses to hypoxia, but not to hypercapnia, decrease with age, the relative contribution of both ATP and adenosine for CB activity is maintained., (© 2019 The Authors. The Journal of Physiology © 2019 The Physiological Society.)

Recent studies showed that the carotid sinus nerve (CSN) and the sympathetic nervous system (SNS) are overactivated in type 2 diabetes and that restoring the correct CSN neural activity can re-establish the proper metabolism. However, a robust characterization of the relationship between CSN and SNS neural activities and metabolism in type 2 diabetes is still missing. Here, we investigated the relationship between neural activity of CSN and SNS in control rats and in rats with diet-induced type 2 diabetes and the animal condition during metabolic challenges. We found that the diabetic condition can be discriminated on the basis of CSN and SNS neural activities due to a high-frequency shift in both spectra. This shift is suppressed in the SNS in case of CSN denervation, confirming the role of CSN in driving sympathetic overactivation in type 2 diabetes. Interestingly, the Inter-Burst-Intervals (IBIs) calculated from CSN bursts strongly correlate with perturbations in glycaemia levels. This finding, held for both control and diabetic rats, indicates the possibility of detecting metabolic information from neural recordings even in pathological conditions. Our results suggest that CSN activity could serve as a marker to monitor glycaemic alterations and, therefore, it could be used for closed-loop control of CSN neuromodulation. This paves the way to the development of novel and effective bioelectronic therapies for type 2 diabetes.

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.

Key Points: Leptin plays a role in the control of breathing, acting mainly on central nervous system; however, leptin receptors have been recently shown to be expressed in the carotid body (CB), and this finding suggests a physiological role for leptin in the regulation of CB function. Leptin increases minute ventilation in both basal and hypoxic conditions in rats. It increases the frequency of carotid sinus nerve discharge in basal conditions, as well as the release of adenosine from the CB. However, in a metabolic syndrome animal model, the effects of leptin in ventilatory control, carotid sinus nerve activity and adenosine release by the CB are blunted. Although leptin may be involved in triggering CB overactivation in initial stages of obesity and dysmetabolism, resistance to leptin signalling and blunting of responses develops in metabolic syndrome animal models., Abstract: Leptin plays a role in the control of breathing, acting mainly on central nervous system structures. Leptin receptors are 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, here 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 in both 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 Ca 2+ 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., (© 2017 The Authors. The Journal of Physiology © 2017 The Physiological Society.)

The carotid body is now looked at as a multipurpose sensor for blood gases, blood pH, and several hormones. The matter of glucose sensing by the carotid body has been debated for several years in the literature, and these days there is a consensus that carotid body activity is modified by metabolic factors that contribute to glucose homeostasis. However, the sensing ability for glucose is still being pondered: are the carotid bodies low glucose sensors or, in contrast, are they overresponsive in high-glucose conditions? Herein, we debate the glucose and insulin sensing capabilities of the carotid body as key early events in the overactivation of the carotid body, which is increasingly recognized as an important feature of metabolic diseases. Additionally, we dedicate a final section to discuss new outside-the-box therapies designed to decrease carotid body activity that may be used for treating metabolic diseases.

Aims/hypothesis: A new class of treatments termed bioelectronic medicines are now emerging that aim to target individual nerve fibres or specific brain circuits in pathological conditions to repair lost function and reinstate a healthy balance. Carotid sinus nerve (CSN) denervation has been shown to improve glucose homeostasis in insulin-resistant and glucose-intolerant rats; however, these positive effects from surgery appear to diminish over time and are heavily caveated by the severe adverse effects associated with permanent loss of chemosensory function. Herein we characterise the ability of a novel bioelectronic application, classified as kilohertz frequency alternating current (KHFAC) modulation, to suppress neural signals within the CSN of rodents., Methods: Rats were fed either a chow or high-fat/high-sucrose (HFHSu) diet (60% lipid-rich diet plus 35% sucrose drinking water) over 14 weeks. Neural interfaces were bilaterally implanted in the CSNs and attached to an external pulse generator. The rats were then randomised to KHFAC or sham modulation groups. KHFAC modulation variables were defined acutely by respiratory and cardiac responses to hypoxia (10% O 2  + 90% N 2 ). Insulin sensitivity was evaluated periodically through an ITT and glucose tolerance by an OGTT., Results: KHFAC modulation of the CSN, applied over 9 weeks, restored insulin sensitivity (constant of the insulin tolerance test [K ITT ] HFHSu sham, 2.56 ± 0.41% glucose/min; K ITT HFHSu KHFAC, 5.01 ± 0.52% glucose/min) and glucose tolerance (AUC HFHSu sham, 1278 ± 20.36 mmol/l × min; AUC HFHSu KHFAC, 1054.15 ± 62.64 mmol/l × min) in rat models of type 2 diabetes. Upon cessation of KHFAC, insulin resistance and glucose intolerance returned to normal values within 5 weeks., Conclusions/interpretation: KHFAC modulation of the CSN improves metabolic control in rat models of type 2 diabetes. These positive outcomes have significant translational potential as a novel therapeutic modality for the purpose of treating metabolic diseases in humans.

The carotid body (CB) is organized in clusters of lobules containing type I cells and type II cells, in a ratio of approximately 4:1. The CB undergoes structural and functional changes during perinatal development, in response to a variety of environmental stimuli and in pathological conditions. Knowing that the CB acts as a metabolic sensor involved in the control of peripheral insulin sensitivity and that its overactivation contributes to the genesis of metabolic disturbances, herein we tested if diet-induced insulin resistance is associated with morphological alterations in the proportion of type I and type II cells in the CB. Diet induced insulin resistant model (HFHSu) was obtained by submitting Wistar rats to 14 weeks of 60% lipid-rich diet and 35% of sucrose in drinking water. The HFHSu group was compared with an aged-matched control group. Glucose tolerance and insulin sensitivity were measured in conscious animals before diet administration and 14 weeks after the diet protocol. The expression of tyrosine hydroxylase (TH) and nestin were assessed by immunohistochemistry to identify type I and type II cells, respectively. TH expression was also quantified by Western blot. As expected, 14 weeks of HFHSu diet induced a decrease in insulin sensitivity as well as in glucose tolerance. HFHsu diet increased the number of TH-positive type I cells by 192% and decreased nestin-postive type 2 cells by 74%. This increase in type II cells observed by immunohistochemistry correlates with an increase by 107% in TH expression quantified by Western blot. These results suggest that changes in CB morphology are associated with metabolic disturbances invoked by administration of a hypercaloric diet.

Adenosine is one of the key neurotransmitters involved in hypoxic signaling in the carotid body (CB), and it was recently found to have a modulatory role in mediating hypercapnic sensitivity in the CB. Herein we have investigated the contribution of adenosine to the hypercapnic response in the rat CB and studied the adenosine receptors responsible for this effect. Experiments were performed in Wistar rats. Adenosine release in normoxia (21% O 2 ) and in response to hypercapnia (10% CO 2 ) was quantified by HPLC. Carotid sinus nerve (CSN) chemosensory activity was evaluated in response to hypercapnia in the absence and presence of ZM241385 (300 nM), an A 2 antagonist, and SCH58261 (20 nM), a selective A 2A antagonist. Hypercapnia increased the extracellular concentrations of adenosine by 50.01%. Both, ZM241385 and SCH58261, did not modify significantly the basal frequency of discharges of the CSN. Also, ZM241385 and SCH58261 did not modify the latency time and the time to peak in CSN chemosensory activity. CSN activity evoked by hypercapnia decreased by 58.82 and 33.59% in response to ZM241385 and to SCH58261, respectively. In conclusion, the effect of adenosine in mediating the hypercapnic response in the rat CB involves an effect on A 2A and A 2B adenosine receptors.

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 O 2 , CO 2 , 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 A 2A and A 2B 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.

Aims/hypothesis: We recently described that carotid body (CB) over-activation is involved in the aetiology of insulin resistance and arterial hypertension in animal models of the metabolic syndrome. Additionally, we have demonstrated that CB activity is increased in animal models of insulin resistance, and that carotid sinus nerve (CSN) resection prevents the development of insulin resistance and arterial hypertension induced by high-energy diets. Here, we tested whether the functional abolition of CB by CSN transection would reverse pre-established insulin resistance, dyslipidaemia, obesity, autonomic dysfunction and hypertension in animal models of the metabolic syndrome. The effect of CSN resection on insulin signalling pathways and tissue-specific glucose uptake was evaluated in skeletal muscle, adipose tissue and liver., Methods: Experiments were performed in male Wistar rats submitted to two high-energy diets: a high-fat diet, representing a model of insulin resistance, hypertension and obesity, and a high-sucrose diet, representing a lean model of insulin resistance and hypertension. Half of each group was submitted to chronic bilateral resection of the CSN. Age-matched control rats were also used., Results: CSN resection normalised systemic sympathetic nervous system activity and reversed weight gain induced by high-energy diets. It also normalised plasma glucose and insulin levels, insulin sensitivity lipid profile, arterial pressure and endothelial function by improving glucose uptake by the liver and perienteric adipose tissue., Conclusions/interpretation: We concluded that functional abolition of CB activity restores insulin sensitivity and glucose homeostasis by positively affecting insulin signalling pathways in visceral adipose tissue and liver.

Metabolic diseases affect millions of individuals across the world and represent a group of chronic diseases of very high prevalence and relatively low therapeutic success, making them suitable candidates for pathophysiological studies. The sympathetic nervous system (SNS) contributes to the regulation of energy balance and energy expenditure both in physiological and pathological states. For instance, drugs that stimulate sympathetic activity decrease food intake, increase resting metabolic rate and increase the thermogenic response to food, while pharmacological blockade of the SNS has opposite effects. Likewise, dysmetabolic features such as insulin resistance, dyslipidaemia and obesity are characterized by a basal overactivation of the SNS. Recently, a new line of research linking the SNS to metabolic diseases has emerged with the report that the carotid bodies (CBs) are involved in the development of insulin resistance. The CBs are arterial chemoreceptors that classically sense changes in arterial blood O 2 , CO 2 and pH levels and whose activity is known to be increased in rodent models of insulin resistance. We have shown that selective bilateral resection of the nerve of the CB, the carotid sinus nerve (CSN), totally prevents diet-induced insulin resistance, hyperglycaemia, dyslipidaemia, hypertension and sympathoadrenal overactivity. These results imply that the beneficial effects of CSN resection on insulin action and glucoregulation are modulated by target-related efferent sympathetic nerves through a reflex that is initiated in the CBs. It also highlights modulation of CB activity as a putative future therapeutic intervention for metabolic diseases., (© 2016 The Authors. The Journal of Physiology © 2016 The Physiological Society.)

Chronic intermittent hypoxia (CIH) is a feature of obstructive sleep apnea (OSA). Whereas clinical studies have demonstrated the association between OSA and insulin resistance, the molecular mechanisms behind it are still unknown. Herein we investigated the effect of mild CIH on insulin sensitivity and we evaluated the changes in insulin and HIF signaling pathways that occur in CIH-induced insulin resistance. We showed that mild CIH obtained by 5/6 hypoxic (5%O2) cycles/h, 10.5h/day during 28 and 35 days increased arterial blood pressure. Insulin resistance and insulinemia increased with CIH duration, being significantly different after 35 days of CIH. Thirty-five days of CIH decreased insulin receptor expression and phosphorylation in skeletal muscle and adipose tissue, but not in the liver. Conversely, Glut2 expression increased in the liver of CIH-animals. Thirty-five days of CIH up-regulated HIF-1α in the liver and down-regulated HIF-1α and HIF-2α in skeletal muscle. We concluded that the effect of CIH on insulin sensitivity and signaling is time-dependent and is associated with changes in HIF signaling in insulin-sensitive tissues., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Caffeine, a non-selective adenosine antagonist, has distinct effects on insulin sensitivity when applied acutely or chronically. Herein, we investigated the involvement of adenosine receptors on insulin resistance induced by single-dose caffeine administration. Additionally, the mechanism behind adenosine receptor-mediated caffeine effects in skeletal muscle was assessed. The effect of the administration of caffeine, 8-cycle-1,3-dipropylxanthine (DPCPX, A1 antagonist), 2-(2-Furanyl)-7-(2-phenylethyl)-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine (SCH58261, A2A antagonist) and 8-(4-{[(4-cyanophenyl)carbamoylmethyl]-oxy}phenyl)-1,3-di(n-propyl)xanthine (MRS1754, A2B antagonist) on whole-body insulin sensitivity was tested. Skeletal muscle Glut4,5'-AMP activated protein kinase (AMPK) and adenosine receptor protein expression were also assessed. The effect of A1 and A2B adenosine agonists on skeletal muscle glucose uptake was evaluated in vitro. Sodium nitroprussiate (SNP, 10nM), a nitric oxide (NO) donor, was used to evaluate the effect of NO on insulin resistance induced by adenosine antagonists. Acute caffeine decreased insulin sensitivity in a concentration dependent manner (Emax=55.54±5.37%, IC50=11.61nM), an effect that was mediated by A1 and A2B adenosine receptors. Additionally, acute caffeine administration significantly decreased Glut4, but not AMPK expression, in skeletal muscle. We found that A1, but not A2B agonists increased glucose uptake in skeletal muscle. SNP partially reversed DPCPX and MRS1754 induced-insulin resistance. Our results suggest that insulin resistance induced by acute caffeine administration is mediated by A1 and A2B adenosine receptors. Both Glut4 and NO seem to be downstream effectors involved in insulin resistance induced by acute caffeine., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Adenosine is a key excitatory neurotransmitter at the synapse between O(2)-sensing chemoreceptor cells-carotid sinus nerve (CSN) endings in the carotid body (CB). Herein, we have investigated the significance of adenosine, through the blockade of its receptors with caffeine, on the CB hypoxic sensitization induced by chronic intermittent hypoxia (CIH) in the rat. CIH animals were obtained by submitting rats during 15 days from 8:00 to 16:00 to 10 %O(2) for 40 s and 20 % O(2) for 80 s (i.e., 30 episodes/h). Caffeine (1 mM) was tested in spontaneous and 5 %O(2) evoked-CSN chemosensory activity in normoxic and CIH animals. CIH decreased basal spontaneous activity but increased significantly CSN activity evoked by acute hypoxia. Caffeine did not modify basal spontaneous activity in normoxic rats, but decreased significantly by 47.83 % basal activity in CIH animals. In addition, acute application of caffeine decreased 49.31 % and 56.01 % the acute hypoxic response in normoxic and CIH animals, respectively. We demonstrate that adenosine contributes to fix CSN basal activity during CIH, being also involved in hypoxic CB chemotransduction. It is concluded that adenosine participates in CB sensitization during CIH.

The carotid bodies (CB) are peripheral chemoreceptors that sense changes in arterial blood O2, CO2, and pH levels. Hypoxia, hypercapnia, and acidosis activate the CB, which respond by increasing the action potential frequency in their sensory nerve, the carotid sinus nerve (CSN). CSN activity is integrated in the brain stem to induce a panoply of cardiorespiratory reflexes aimed, primarily, to normalize the altered blood gases, via hyperventilation, and to regulate blood pressure and cardiac performance, via sympathetic nervous system (SNS) activation. Besides its role in the cardiorespiratory control the CB has been proposed as a metabolic sensor implicated in the control of energy homeostasis and, more recently, in the regulation of whole body insulin sensitivity. Hypercaloric diets cause CB overactivation in rats, which seems to be at the origin of the development of insulin resistance and hypertension, core features of metabolic syndrome and type 2 diabetes. Consistent with this notion, CB sensory denervation prevents metabolic and hemodynamic alterations in hypercaloric feed animal. Obstructive sleep apnea (OSA) is another chronic disorder characterized by increased CB activity and intimately related with several metabolic and cardiovascular abnormalities. In this manuscript we review in a concise manner the putative pathways linking CB chemoreceptors deregulation with the pathogenesis of insulin resistance and arterial hypertension. Also, the link between chronic intermittent hypoxia (CIH) and insulin resistance is discussed. Then, a final section is devoted to debate strategies to reduce CB activity and its use for prevention and therapeutics of metabolic diseases with an emphasis on new exciting research in the modulation of bioelectronic signals, likely to be central in the future.

The role of caffeine consumption on insulin action is still under debate. The hypothesis that chronic caffeine intake reverses aging-induced insulin resistance in the rat was tested in this work. The mechanism by which caffeine restores insulin sensitivity was also investigated. Six groups of rats were used: 3 months old (3 M), 3 months old caffeine-treated (3MCaf), 12 months old (12 M), 12 months old caffeine-treated (12MCaf), 24 months old (24 M), and 24 months old caffeine-treated (24MCaf). Caffeine was administered in drinking water (1 g/l) during 15 days. Insulin sensitivity was assessed by means of the insulin tolerance test. Blood pressure, body weight, visceral and total fat, fasting glycemia and insulinemia, plasma nonesterified fatty acids (NEFA), total antioxidant capacity (TAC), cortisol, nitric oxide, and catecholamines were monitored. Skeletal muscle Glut4 and 5'-AMP activated protein kinase (AMPK) protein expression and activity were also assessed. Aged rats exhibited diminished insulin sensitivity accompanied by hyperinsulinemia and normoglycemia, increased visceral and total fat, decreased TAC and plasma catecholamines, and also decreased skeletal muscle Glut4 and AMPK protein expression. Chronic caffeine intake restored insulin sensitivity and regularized circulating insulin and NEFA in both aging models. Caffeine neither modified skeletal muscle AMPK expression nor activity in aged rats; however, it decreased visceral and total fat in 12 M rats and it restored skeletal muscle Glut4 expression to control values in 24 M rats. We concluded that chronic caffeine intake reverses aging-induced insulin resistance in rats by decreasing NEFA production and also by increasing Glut4 expression in skeletal muscle.

Increased sympathetic activity is a well-known pathophysiological mechanism in insulin resistance (IR) and hypertension (HT). The carotid bodies (CB) are peripheral chemoreceptors that classically respond to hypoxia by increasing chemosensory activity in the carotid sinus nerve (CSN), causing hyperventilation and activation of the sympathoadrenal system. Besides its role in the control of ventilation, the CB has been proposed as a glucose sensor implicated in the control of energy homeostasis. However, to date no studies have anticipated its role in the development of IR. Herein, we propose that CB overstimulation is involved in the etiology of IR and HT, core metabolic and hemodynamic disturbances of highly prevalent diseases like the metabolic syndrome, type 2 diabetes, and obstructive sleep apnoea. We demonstrate that CB activity is increased in IR animal models and that CSN resection prevents CB overactivation and diet-induced IR and HT. Moreover, we show that insulin triggers CB, highlighting a new role for hyperinsulinemia as a stimulus for CB overactivation. We propose that CB is implicated in the pathogenesis of metabolic and hemodynamic disturbances through sympathoadrenal overactivation and may represent a novel therapeutic target in these diseases.