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GLP1 acts on the carotid body to modulate glucose homeostasis and cardiorespiratory responses
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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.
Descrição
Palavras-chave
glucose homeostasis carotid body