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

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.

Keywords: carotid body; glucose; inflammation; insulin; leptin; obesity related syndromes; sympathetic overactivation; type 2 diabetes.

Figure 1

Schematic representation of the carotid body (CB) involvement in the development of obesity, insulin resistance, and glucose intolerance through an increase in sympathetic nervous system activity. (A) Hypercaloric diets and intermittent hypoxia promote an increase in CB activity that contributes to the augmentation of sympathetic nervous system activity, leading to metabolic dysfunction. (B) Modulation of CB activity through the carotid sinus nerve (CSN) resection or via hyperbaric oxygen therapy, normalized sympathetic nervous system activity, improving dysmetabolism.

Figure 2

Mediators contributing to carotid body (CB) overactivation in metabolic diseases. Schematic representation of the several factors, such as hyperglycemia, hyperinsulinemia, hyperleptinemia, and inflammation, could induce an increase in CB that will contribute to the development of obesity, insulin resistance, and glucose tolerance through the overactivation of the sympathetic nervous system.

Figure 3

Effect of carotid sinus nerve resection (CSN) on leptin effects on ventilation in control (CTR) and high-fat (HF) animals. Leptin (90 and 270 ng/mL) was administrated intracarotidally, as a bolus in anesthetized animals with pentobarbital (60 mg/kg i.p.), as previously described by Ribeiro et al. [13,22]. CSN resection was performed acutely prior to leptin administration. HF animals were submitted to a lipid-rich diet (60% energy from fat) for 3 weeks. Data are presented as mean ± SEM of 5–8 control and 3–5 HF animals. Two-way ANOVA with Bonferroni multiple comparison tests: * p < 0.05, ** p < 0.01, leptin (ng/mL) baseline vs. diet or diet plus leptin; # p < 0.01 without CSN resection vs. with CSN resection; § p < 0.05 control vs. HF diet.

Figure 4

Effect of hypercaloric diets on the expression of pro-inflammatory cytokines receptors in CB and effect of pro-inflammatory cytokines on ventilation and catecholamine release from the carotid body (CB). (A) Effect of high-fat (HF) for 3 weeks and high-fat high-sucrose (HFHSu) diet for 25 weeks on the expression of the receptors IL-1RI, IL-6Rα, and TNF-R1 in rat CB. (B) Effect of interleukin-1 beta (IL-1β, 40 ng/mL) on the release of catecholamines from the CB in control and HF animals. (C,D) Effect of interleukin-6 (IL-6, 0.5 or 5 ng/mL) and tumor necrosis factor alpha (TNF-α, 0.5 or 5 ng/mL) on basal ventilation, respectively, measured in anesthetized animals with pentobarbital (60 mg/kg.i.p.). TNF-α and IL-6 were administrated in the femoral vein, as described previously by Cracchiolo et al. [20]. Carotid sinus nerve (CSN) resection was performed acutely prior to TNF-α and IL-6 administration. The catecholamine release protocol consisted of two incubations of CB in normoxic solutions (20% O₂ plus 5% CO₂ balanced 75% N₂, 10 min), followed by IL-1β application for 30 min in normoxia, followed by two normoxic incubations, one hypoxic incubation (5% O₂, 10 min), and two final normoxic incubations. The release of catecholamines from the CB was normalized for catecholamine content in each CB. Each bar represents a 10 min incubation and sample collection period. Protocol for catecholamines release from the CB was similar to that previously used [13,83]. Data are presented as mean ± SEM of 3 (A), 14–15 carotid bodies (B), and 3–6 animals (C,D). Two-way ANOVA with Bonferroni multicomparison test: * p < 0.05, ** p < 0.01 and *** p < 0.001 compared with 20% O₂ prior to hypoxic (5% O₂) stimulus.