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.

Immunity and the carotid body: implications for metabolic diseases

“…However, while IL-1β application did not modify the release of catecholamines from the rat CB, extracellular administration of IL-6 induced a rise in [Ca 2+ ] i and catecholamine release from in vitro-cultured CB type I cells (Fan et al 2009 ). As described for TNF-α, the administration of IL-6 in the rat femoral vein in doses of 0.5 and 5 ng/ml augmented minute ventilation, an effect that was prevented by CSN denervation, suggesting that the effect of IL-6 on ventilation is CB-mediated (Sacramento et al 2020 ).…”

“…Additionally, TNF-α intravenous systemic administration in a dose of 5 ng/ml in the rat induced an increase in basal ventilation. This effect was abolished by CSN resection, demonstrating that TNF-α-induced increase in ventilation is mediated by the CB (Sacramento et al 2020 ).…”

“…TNF-α receptor expression in human, rat and mouse CBs was observed using microarray analysis (Mkrtchian et al 2012 ) and western blot (Sacramento et al 2020 ). Also, Fernandez et al showed that the canonical LPS receptor TLR-4, and TNF-α receptors are functional (Fernández et al 2008 ; Fernández et al 2011 ).…”

“…Apart from relaying circulating immune signals to the brain in response to acute/intermediate systemic inflammatory conditions, the effect of proinflammatory cytokines on the CB has been proposed to be in the basis of CB overactivation that is associated with several diseases, such as obstructive sleep apnea and obesity that are associated with chronic systemic inflammation (Conde et al 2017 ; Oyarce and Iturriaga 2018 ; Sacramento et al 2020 ). Additionally, the role of CB on inflammation regulation blends with the autonomic reflex since CB stimulation provokes a wide array of cardiopulmonary and autonomic reflexes, as well as endocrine responses (e.g., plasma release of catecholamines and cortisol) (Fitzgerald 2014 ).…”

“…So, hyperinsulinemia, hyperleptinemia, and high pro-inflammatory cytokine levels seem to be determining factors that contribute to the CB overactivation in metabolic diseases (Fig. 2 ) (Sacramento et al 2020 ).…”