Abstract
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.
Highlights
Metabolic diseases such as obesity, metabolic syndrome, and type 2 diabetes are some of the most common non-communicable diseases whose prevalence continues to increase, contributing to significant morbidity and mortality worldwide and considered worldwide epidemics [1,2]
Alongside the hypothesis that Carotid bodies (CBs) dysfunction contributes to metabolic diseases, we described how hypercaloric diet animals [13] and prediabetes patients [21] exhibit increased basal ventilation and showed that prediabetic dysmetabolism correlates with increased peripheral chemosensitivity, as evaluated by the Dejours test, which measures the decrease in basal ventilation produced by 100% O2, and that this correlates with abdominal perimeter and insulin resistance [21]
Fernandez et al [103] demonstrated, through in vitro recordings of the carotid sinus nerve (CSN) activity, that TNF-α was unable to change the basal CSN chemosensory activity, it was able to reduce the hypoxia-induced enhanced frequency of chemosensory discharge in a dose-dependent manner [103]. This inhibitory effect of TNF-α observed in the cat contrasts with the findings reported by Lam et al [94,95] in rats, as the authors described in dissociated CB type I cells that TNF-α application induces a rise in [Ca2+]i in response to acute hypoxia, this increase being larger in cells from the CBs of rats exposed to chronic hypoxia [95] or chronic intermittent hypoxia [95]
Summary
Metabolic diseases such as obesity, metabolic syndrome, and type 2 diabetes are some of the most common non-communicable diseases whose prevalence continues to increase, contributing to significant morbidity and mortality worldwide and considered worldwide epidemics [1,2]. Alongside the hypothesis that CB dysfunction contributes to metabolic diseases, we described how hypercaloric diet animals [13] and prediabetes patients [21] exhibit increased basal ventilation and showed that prediabetic dysmetabolism correlates with increased peripheral chemosensitivity, as evaluated by the Dejours test, which measures the decrease in basal ventilation produced by 100% O2 (hyperoxia), and that this correlates with abdominal perimeter and insulin resistance [21]. Knowing that metabolic diseases are characterized by high glucose concentrations in blood, our group tested, in the isolated rat CB-CSN ex vivo preparation, the effect of 25mM of glucose on CSN chemosensory activity and showed that hyperglycemia did not change either basal or CSN chemosensory activity in response to hypoxia [14] This suggests that hyperglycemia acting directly on the CB cannot be one of the major factors contributing to CB dysfunction in metabolic diseases. In obesity, and in parallel with the increased secretion of leptin from adipose tissue, there is a disturbed adipose tissue secretory pattern characterized by an increased release of pro-inflammatory factors and decreased production of anti-inflammatory adipokines [42] and associated with the development of obesity-associated comorbidities, we hypothesize that inflammation can contribute to the CB dysfunction that is involved in the genesis of metabolic diseases
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