Leptin receptor downregulation in the carotid body treats obesity-induced hypertension

Authors

Mi-Kyung Shin, Department of Anesthesiology and Critical Care Medicine, George Washington University School of Medicine and Health Sciences, Washington, District of Columbia, United States.
Lenise J. Kim, Department of Anesthesiology and Critical Care Medicine, George Washington University School of Medicine and Health Sciences, Washington, District of Columbia, United States.
Dashdulam Davaanyam, Department of Anesthesiology and Critical Care Medicine, George Washington University School of Medicine and Health Sciences, Washington, District of Columbia, United States.
Mateus R. Amorim, Department of Anesthesiology and Critical Care Medicine, George Washington University School of Medicine and Health Sciences, Washington, District of Columbia, United States.
Sean M. Lee, Office of Clinical Research, George Washington University, Washington, District of Columbia, United States.
Wan-Yee Tang, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania, United States.
Vsevolod Y. Polotsky, Department of Anesthesiology and Critical Care Medicine, George Washington University School of Medicine and Health Sciences, Washington, District of Columbia, United States.

Document Type

Journal Article

Publication Date

3-1-2025

Journal

Journal of neurophysiology

Volume

133

Issue

3

DOI

10.1152/jn.00133.2024

Keywords

carotid body; hypertension; leptin; leptin receptor b; obesity

Abstract

Obesity and comorbid sleep disordered breathing (SDB) lead to high cardiovascular morbidity and mortality via multiple mechanisms including hypertension. Obesity also leads to high levels of leptin, which is produced in adipocytes. Increased leptin levels have also been implicated in increased sympathetic activity and the pathogenesis of hypertension in obesity. However, mechanisms for the effects of leptin on blood pressure are unclear. The carotid bodies (CB) express leptin receptor (Lepr), and diet-induced obesity (DIO) increases Lepr expression levels, but the mechanisms and consequences of leptin action in CB are poorly understood. We hypothesize that leptin signaling in CB in obesity leads to hypertension, which can be treated by Lepr knockdown specifically in CB. DIO male and female mice and lean male C57BL/6J mice were implanted with telemetry in the left femoral artery for continuous blood pressure monitoring. The adenoviral vectors carrying antisense RNA, Ad-LepR shRNA or Ad-scrambled control shRNA, were administered locally to the CB region. Blood pressure measurements were performed at baseline and 9-11 days after CB infection with the adenoviral vector. DIO male mice showed increased blood pressure compared with lean males and DIO females. Ad-LepR shRNA induced a twofold decrease in Lepr mRNA level in CB and abolished obesity-induced hypertension. Lepr knockdown was particularly effective during the light phase, when animals were predominantly asleep, decreasing mean arterial pressure by 8.5 mmHg. Control shRNA had no effect on DIO-induced hypertension. We conclude that inhibition of Lepr in the carotid bodies abolished obesity-induced hypertension. Obesity and comorbid sleep apnea are key predisposing factors to hypertension. Obesity increases circulating leptin levels and hyperleptinemia may contribute to hypertension but mechanisms are not clear. Here, we have shown that knockdown of the leptin receptor LepR in the carotid body decreased blood pressure and treated hypertension in diet-induced obese mice. Thus, we identified a novel mechanism of obesity hypertension and a novel drug target, LepR in the carotid body.

APA Citation

Shin, Mi-Kyung; Kim, Lenise J.; Davaanyam, Dashdulam; Amorim, Mateus R.; Lee, Sean M.; Tang, Wan-Yee; and Polotsky, Vsevolod Y., "Leptin receptor downregulation in the carotid body treats obesity-induced hypertension" (2025). GW Authored Works. Paper 6511.
https://hsrc.himmelfarb.gwu.edu/gwhpubs/6511

Department

Anesthesiology and Critical Care Medicine