Metabolic diseases pose a significant global health challenge, with profound impact on mortality and morbidity rates. The carotid bodies (CBs), traditionally recognized as an oxygen-sensitive organ, is a metabolic sensor implicated in these diseases [1-3]. In dysmetabolic states the CB is dysfunctional and the abolishment of its activity improves metabolic function [1-3]. Contributing to CB dysfunction is hyperinsulinemia and hyperleptinemia and probably inflammatory cytokines [4], whose presence, along with their receptors, has been evidenced within the CB [1,5]. By exploring the effects of TNF-α in the cardioventilatory responses and on CB inflammation this study aims to investigate the contribution of TNF-α to CB dysfunction in metabolic diseases. Moreover, the sexual dimorphism on TNF-α action was also explored.  

Methods: Two groups of Wistar rats (male and female) were used – a control group (CTL) submitted to a standard diet and a group fed with high-fat diet (HF, 60% energy from fat) for 3 weeks. Animals were anesthetized with pentobarbital (60 mg/kg i.p.), and ventilation, blood pressure, and autonomic activity (heart rate variability) were assessed before and after the administration of TNF-α (0.5 and 5 ng/ml) in CTL and HF groups with and without resection of the carotid sinus nerve (CSN). Blood levels of TNF-α and the levels of TNF-α and its receptors in the CBs of CTL and HF animals were evaluated. For statistical analysis, ANOVA with Dunnett's comparison test and t-Student test were used. Ethical approval was obtained from the Animal Welfare  Committee, from the NMS Ethics Committee and  from The Portuguese Authorities (DGAV).

Results: In male CTL rats, TNF-α increased minute ventilation (MV) by 26.5% and 52.0% (p<0.001) in response to 0.5 and 5 ng/ml TNF-α, respectively. Resection of the CSN attenuated MV response to TNF-α. In male HF animals, ventilatory response to TNF-α was blunted, increasing only 8%. In male CTL rats 0.5 and 5 ng/ml TNF-α reduced mean arterial pressure by 8.0% and 13.7% (p<0.01), an effect not altered by CSN resection. CTL and HF females exhibit lower basal ventilation parameters, but similar responses to TNF-α. The CBs of HF rats showed a 46% increase in TNF-α compared to CTLs (p<0.01). 

Conclusion: TNF-α increases ventilation, and effect that is mediated by the CB and blunted in high-fat animals. It seems that there is no sexual dimorphism in TNF-α ventilatory responses mediated by the CB. The effect of TNF-α in the CB might contribute to its dysfunction in dysmetabolic states.