GLP1R Attenuates Sympathetic Response to High Glucose via Carotid Body Inhibition

Abstract

Background: Aberrant sympathetic nerve activity exacerbates cardiovascular risk in hypertension and diabetes, which are common comorbidities, yet clinically sympathetic nerve activity remains poorly controlled. The hypertensive diabetic state is associated with increased reflex sensitivity and tonic drive from the peripheral chemoreceptors, the cause of which is unknown. We have previously shown hypertension to be critically dependent on the carotid body (CB) input in spontaneously hypertensive rat, a model that also exhibits a number of diabetic traits. CB overstimulation by insulin and leptin has been similarly implicated in the development of increased sympathetic nerve activity in metabolic syndrome and obesity. Thus, we hypothesized that in hypertensive diabetic state (spontaneously hypertensive rat), the CB is sensitized by altered metabolic signaling causing excessive sympathetic activity levels and dysfunctional reflex regulation. Methods: Using a hypothesis-free RNA-seq approach, we investigated potential molecular targets implicated in energy metabolism mediating CB sensitization and its regulation of sympathetic outflow in experimental hypertension. Identified targets were characterized using molecular and functional techniques assessing peripheral chemoreflex sensitivity in situ and in vivo. Results: We discovered GLP1R (glucagon-like peptide-1 receptor) expression in the CBs of rat and human and showed that its decreased expression is linked to sympathetic hyperactivity in rats with cardiometabolic disease. We demonstrate GLP1R to be localized to CB chemosensory cells, while targeted administration of GLP1R agonist to the CB lowered its basal discharge and attenuated chemoreflex-evoked blood pressure and sympathetic responses. Importantly, hyperglycemia-induced peripheral chemoreflex sensitization and associated basal sympathetic overactivity were abolished by GLP1R activation in the CB suggesting a role in a homeostatic response to high blood glucose. Conclusions: We show GLP1 (glucagon-like peptide-1) to modulate the peripheral chemoreflex acting on the CB, supporting this organ as a multimodal receptor. Our findings pinpoint CBs as potential targets for ameliorating excessive sympathetic activity using GLP1R agonists in the hypertensive-diabetic condition.

Long-Term Hypercaloric Diet Consumption Exacerbates Age-Induced Dysmetabolism and Carotid Body Dysfunction: Beneficial Effects of CSN Denervation

“…Figure 6B presents the immunoreactivity of GLP-1R in young and adult animals and the impact of HFHSu on these levels. It should be noted that GLP-1R (red fluorescence) is detected in type I cells and demonstrated here by the colocalization with TH (green fluorescence), in accordance with Pauza et al (2022) . Short-term HFHSu intake or CSN resection in young animals did not modify the percentage of cells immunoreactive to GLP-1R.…”

“…The CB has been described as a metabolic sensor, and its dysfunction has been associated with metabolic diseases, such as prediabetes and type 2 diabetes ( Ribeiro et al, 2013 ; Conde et al, 2017 ; Conde et al, 2018 ; Sacramento et al, 2020 ). Knowing that insulin ( Ribeiro et al, 2013 ) and GLP-1 ( Pauza et al, 2022 ) are metabolic mediators that activate the CBs, we evaluated the effect of HFHSu consumption, ageing, and CSN resection on the immunoreactivity of insulin receptors and GLP-1R in the CBs ( Figure 6 ). The presence of insulin receptors in the CBs was already described by our group ( Ribeiro et al, 2013 ), but herein, we showed that the insulin receptors are detected in the TH-positive glomus cells (red fluorescence – IR, green fluorescence – TH, Figure 6A ).…”

“…In an attempt to correlate the effects of short-term and long-term hypercaloric diet intake, ageing, and of CSN resection on whole-body metabolic parameters with CB function, we analyzed, by immunohistochemistry, markers of type I and type II cells of the CBs, the TH, and GFAP, as well as a marker for hypoxia, HIF-1α, and receptors for metabolic mediators that are known to act on the CBs, the insulin receptor ( Ribeiro et al, 2013 ) and GLP-1R ( Pauza et al, 2022 ). As expected, as previously described by our group and others, adult/old CBs exhibited less positive staining for TH, this corresponding to a lower number of type I cells per CB area ( Di Giulio et al, 2003 ; Conde et al, 2006 ; Sacramento et al, 2019 ), thus agreeing with the lower baseline ventilatory parameters found in adult animals.…”

“…The CBs apart from participating in cardiorespiratory control are also involved in the homeostatic regulation of carbohydrates, lipid metabolism, and inflammation ( Ribeiro et al, 2013 ; Conde et al, 2017 ; Conde et al, 2020 ; Sacramento et al, 2020 ; Iturriaga et al, 2021 ). In fact, in the last decade it has become consensual that the CBs are involved in the genesis of metabolic diseases since 1) CB activity is increased in prediabetes and T2D animal models ( Ribeiro et al, 2013 ; Ribeiro et al, 2018 ) and prediabetic patients ( Cunha-Guimaraes et al, 2020 ); 2) insulin, leptin, and glucagon-like peptide-1 (GLP-1) mediators that contribute to metabolic homeostasis are known to act on the CBs ( Ribeiro et al, 2013 ; Ribeiro et al, 2018 ; Caballero-Eraso et al, 2019 ; Cracchiolo et al, 2019 ; Pauza et al, 2022 ); and 3) the abolishment of the CB activity, via CSN resection or its neuromodulation, prevents and reverses pathological features of dysmetabolism in animal models of dysmetabolism ( Ribeiro et al, 2013 ; Sacramento et al, 2017 ; Sacramento et al, 2018 ).…”

Dysmetabolism and Neurodegeneration: Trick or Treat?

“…They are surrounded by a dense net of capillaries and penetrated by the sensory nerve ending of the carotid sinus nerve (CSN) a tiny branch of the glossopharyngeal nerve which does the connection from the CBs to the brainstem where their information is integrated [ 298 , 300 ]. In recent years, the CBs have been shown to have a key role in the control of peripheral glucose metabolism and insulin action, since it was shown that: (1) in animal models of dysmetabolism and in prediabetic patients, the CBs were overactivated, this being correlated with a state of insulin resistance and glucose intolerance [ 295 , 301 , 302 ]; (2) insulin, leptin, and GLP-1, known metabolic mediators involved in metabolic regulation, are capable of activating the CBs [ 295 , 296 , 303 , 304 ]; and (3) the resection or neuromodulation of the CSN prevents and reverses the pathological features associated with dysmetabolic states [ 295 , 297 , 301 ]. Considering the close association between metabolic and neurodegenerative disorders, and that the therapeutics that provide metabolic control have a huge impact on neurodegenerative processes, we anticipate that the modulation of the CBs might be a useful therapeutic strategy to improve metabolism, and therefore prevent and/or delay the progression of neurodegenerative disorders.…”