Project Title

GLP-1 agonist liraglutide increases metabolic- and cardiovascular-related sympathetic activity of the central nervous system.

Authors' Affiliations

Department of Health Science, College of Public Health, East Tennessee State University, Johnson City, TN.

Location

White Top Mtn

Start Date

4-12-2019 9:00 AM

End Date

4-12-2019 2:30 PM

Poster Number

123

Faculty Sponsor’s Department

Health Sciences

Name of Project's Faculty Sponsor

Dr. Matthew Zahner

Type

Poster: Competitive

Classification of First Author

Undergraduate Student

Project's Category

Cardiovascular System, Nervous System, Physiological Controls and Systems

Project's Category

Arts and Humanities

Abstract Text

Metabolic syndrome is associated with pathologies that include type 2 diabetes, hypertension, and dyslipidemia, all of which 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 the beneficial effect is mediated by metabolically related sympathetic neurons within the hypothalamus. Although the hypothalamus contains neurons that control metabolism, there are also neurons that control cardiovascular activity. Considering that one main goal of obesity and diabetes treatments is to reduce cardiovascular-related comorbidities, any drug‑induced increase in blood pressure is unacceptable. Therefore, a better understanding of GLP-1 agonists on sympathetic activity and the role of the hypothalamus in central GLP‑1 activity is essential. In this study, we tested the hypothesis that the long‑acting FDA approved GLP-1 receptor agonist 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, SC, n=10) or vehicle (saline, n=10) to rats for 15 days and measured food intake and body weight. Next, we recorded blood pressure and renal sympathetic nerve activity (RSNA) in the anesthetized rat before and after liraglutide treatment. Finally, to determine the activation of hypothalamic neurons we performed neuroanatomical tracing studies and turned metabolically-related (raphe‑projecting) neurons green, and cardiovascular-related (rostroventrolateral medulla, RVLM) neurons red. After treating rats with liraglutide, (75 mg/kg IV) we performed immunohistochemical (IHC) labeling to identify neurons expressing cFos, a marker of neuronal activation. Daily liraglutide significantly (p < 0.05) reduced both food intake and body weight from the pretreatment baseline. In vehicle-treated rats, the mean baseline food intake was 27.9 ± 0.5g. 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 was 29.9 ± 0.7g. During liraglutide treatment, the mean food intake was 22.7 ± 1.4g 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 significantly (p < 0.05) increased basal RSNA and augmented baroreflex and chemoreflex activity. Lastly, our cFos data show that liraglutide activates metabolic, but not cardiovascular hypothalamic neurons. Collectively, these data suggest that although liraglutide elevates sympathetic activity, it is not by activation of pre-sympathetic hypothalamic neurons.

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Apr 12th, 9:00 AM Apr 12th, 2:30 PM

GLP-1 agonist liraglutide increases metabolic- and cardiovascular-related sympathetic activity of the central nervous system.

White Top Mtn

Metabolic syndrome is associated with pathologies that include type 2 diabetes, hypertension, and dyslipidemia, all of which 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 the beneficial effect is mediated by metabolically related sympathetic neurons within the hypothalamus. Although the hypothalamus contains neurons that control metabolism, there are also neurons that control cardiovascular activity. Considering that one main goal of obesity and diabetes treatments is to reduce cardiovascular-related comorbidities, any drug‑induced increase in blood pressure is unacceptable. Therefore, a better understanding of GLP-1 agonists on sympathetic activity and the role of the hypothalamus in central GLP‑1 activity is essential. In this study, we tested the hypothesis that the long‑acting FDA approved GLP-1 receptor agonist 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, SC, n=10) or vehicle (saline, n=10) to rats for 15 days and measured food intake and body weight. Next, we recorded blood pressure and renal sympathetic nerve activity (RSNA) in the anesthetized rat before and after liraglutide treatment. Finally, to determine the activation of hypothalamic neurons we performed neuroanatomical tracing studies and turned metabolically-related (raphe‑projecting) neurons green, and cardiovascular-related (rostroventrolateral medulla, RVLM) neurons red. After treating rats with liraglutide, (75 mg/kg IV) we performed immunohistochemical (IHC) labeling to identify neurons expressing cFos, a marker of neuronal activation. Daily liraglutide significantly (p < 0.05) reduced both food intake and body weight from the pretreatment baseline. In vehicle-treated rats, the mean baseline food intake was 27.9 ± 0.5g. 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 was 29.9 ± 0.7g. During liraglutide treatment, the mean food intake was 22.7 ± 1.4g 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 significantly (p < 0.05) increased basal RSNA and augmented baroreflex and chemoreflex activity. Lastly, our cFos data show that liraglutide activates metabolic, but not cardiovascular hypothalamic neurons. Collectively, these data suggest that although liraglutide elevates sympathetic activity, it is not by activation of pre-sympathetic hypothalamic neurons.