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

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^b), and diet-induced obesity (DIO) increases Lepr^b 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^b 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^b mRNA level in CB and abolished obesity-induced hypertension. Lepr^b 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^b in the carotid bodies abolished obesity-induced hypertension.NEW & NOTEWORTHY 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^b 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^b in the carotid body.