Dissertação de Mestrado Investigação Biomédica 2022 Faculdade de Ciências Médicas, Universidade NOVA de Lisboa

GLP-1 is an incretin released by the gut in response to oral food intake. Its binding to GLP-1 receptor (GLP-1R) increases insulin and decreases glucagon secretion by the pancreas and promotes nutrient storage and usage. As such, GLP-1R agonists are used in type 2 diabetes (T2D) treatment for their effects on glycemic control with benefits on weight loss but also in diabetes comorbidities such as hyperlipidemia, hypertension, and fatty liver. The carotid bodies (CBs), peripheral chemoreceptors defined as O2 sensors, are also metabolic sensors involved in insulin action and glucose homeostasis and whose dysfunction has been associated with metabolic diseases. Recently, GLP-1 has been described to act on the CB to modulate sympathetic activity. Therefore, herein we investigated the role of the CBs in GLP1-mediated cardiometabolic effects. For that, we have used a rat model of dysmetabolism, the high fat (HF) diet fed animal model with corresponding age-matched controls. The groups were tested for the effect of intracarotid administration of liraglutide (a GLP-1R agonist) and of the abolishment of CBs activity, through the resection of the carotid sinus nerve (CSN), on whole-body glucose metabolism, ventilation and cardiovascular parameters – blood pressure, heart rate and autonomic balance. Moreover, the presence and the effects of hypercaloric diets on GLP-1R expression in the CBs was evaluated. We observed that GLP-1R are expressed in the CB and co-localize with tyrosine hydroxylase, a marker for CB type 1 cells. As expected, HF diet intake promoted a decrease in insulin sensitivity and glucose tolerance, as well as an increase in cardiac autonomic balance and the development of hypertension. CSN resection as expected decreased ventilation while completely reverting heightened autonomic balance and high mean blood pressure, effects reverted with CSN resection. Additionally, we observed that liraglutide increases basal ventilation and decreases mean blood pressure in CTL and HF animals, effects mediated by the CB, since they were abolished by CSN resection. Furthermore, liraglutide decreased ventilatory response and exacerbated the decrease in mean blood pressure promoted by ischemic hypoxia, an effect mediated by the CB. As expected, liraglutide decreases blood glucose levels in both CTL and HF animals, but HF diet increased the latency of GLP-1 action on glycemia and impaired the physiological counterregulatory responses to hypoglycemia, effects abolished by CSN resection. Finally, liraglutide was observed to decreased cardiac autonomic balance in all conditions. In conclusion, this project demonstrates that GLP-1 is an important modulator of CB activity with effects on glucose metabolism, ventilation, and cardiovascular activity. Targeting GLP-1 actions on the CB can be important in managing cardiometabolic homeostasis in metabolic disorders.