GLP‐1 AGONIST LIRAGLUTIDE ACTIVATES METABOLIC‐ AND CARDIOVASCULAR‐RELATED HYPOTHALAMIC NEURONS AND AUGMENTS REFLEX SYMPATHETIC ACTIVITY IN THE RAT
Authors: Lindsey Stacia Jayce , Mounger David Kyle , Fraley Stephanie Kate , Hillard Kynlee Jo , Zahner Matthew Ralph 
Published: April 2020

Metabolic syndrome is associated with pathologies that include type 2 diabetes, hypertension, and dyslipidemia, all increase the risks of heart disease. Glucagon‐like peptide (GLP‐1) is a hormone produced by intestinal enteroendocrine L‐cells. GLP‐1 increases insulin sensitivity, augments glucose‐dependent insulin secretion, and suppresses glucagon release. GLP‐1 also works centrally to decrease appetite and increase metabolism. Evidence suggests that this beneficial effect of GLP‐1 is mediated in part by metabolically‐related sympathetic neurons within the hypothalamus. Considering the main goal of obesity and diabetes treatments is to reduce cardiovascular comorbidities, any drug‐induced increase in blood pressure is unacceptable. Therefore, a better understanding of the central mechanism of GLP‐1 agonists on sympathetic cardiovascular and metabolic activity, and the role of the hypothalamus in GLP‐1 activity is needed. We tested the hypothesis that liraglutide activates both metabolic and cardiovascular‐related hypothalamic neurons and augments reflex cardiovascular sympathetic activity in rats. To test this hypothesis, we administered liraglutide (125 mg/kg) or vehicle to rats daily for 15 days and measured food intake and body weight. Next, we directly recorded blood pressure and renal sympathetic nerve activity (RSNA) in the anesthetized rat before and after liraglutide treatment. Finally, to determine activation of hypothalamic neurons we performed retrograde tracing studies to identify metabolically‐related (raphe‐projecting) neurons with green FluoSpheres, and cardiovascular‐related (rostroventrolateral medulla, RVLM) neurons with red FluoSpheres. After treating rats with an acute dose of liraglutide, (125 mg/kg SC) we performed immunohistochemical labeling to identify neurons expressing cFos. Daily liraglutide treatment significantly (p < 0.05) reduced food intake and body weight from the pretreatment baseline. In vehicle‐treated rats, prior to treatment, the mean food intake was 27.9 ± 0.5 g. During vehicle treatment, the mean food intake was 28.6 ± 0.8 g and body weight was 110 ± 1.5% of its baseline. In liraglutide‐treated rats, the mean baseline food intake prior to treatment was 29.9 ± 0.7 g. During liraglutide treatment, the mean food intake was 22.7 ± 1.4 g and body weight was 105 ± 1.1 % of its baseline. At the end of liraglutide treatment, food intake and body weight returned to that of the vehicle‐treated rats. In the anesthetized rat, liraglutide did not significantly affect basal blood pressure. However, liraglutide significantly (p < 0.05) increased basal RSNA and augmented baroreflex and chemoreflex activity. Lastly, preliminary data from our cFos study suggest that liraglutide activates raphe‐projecting neurons but not RVLM‐projecting neurons. These data suggest that liraglutide augments sympathetic cardiovascular reflex activity and activates hypothalamic neurons.

Support or Funding Information

NHLBI R15HL145645‐01