Abstract
Leptin and TNFα can individually work in the brain to affect blood pressure; however, it remains unknown whether these two cytokines might have an interactive role in this process and, if so, how. In this work, we found that leptin stimulation led to TNFα production under both in vitro and in vivo conditions, and diurnal fluctuation of leptin concentrations in the cerebrospinal fluid predicted the circadian changes of TNFα gene expression in the hypothalamus. Signaling analysis showed that leptin stimulation led to a rapid and strong STAT3 activation followed by a second-phase moderate STAT3 activation, which was selectively abolished by anti-inflammatory chemical PS1145 or TNFα antagonist WP9QY. Physiological study in normal mice revealed that diurnal rise of blood pressure was abrogated following central administration of PS1145 or a leptin receptor antagonist. Central TNFα pretreatment was found to potentiate the effect of leptin in elevating blood pressure in normal mice. In pathophysiology, dietary obesity mimicked TNFα pretreatment in promoting leptin-induced blood pressure rise, and this effect was blocked by central treatment with either PS1145 or WP9QY. Hence, central leptin employs TNFα to mediate the diurnal blood pressure elevation in physiology while enhancement of this mechanism can contribute to hypertension development.
Highlights
In coordination with physical and physiological requirements, blood pressure (BP)2 levels are tightly regulated to rise and fall in circadian manners, while alterations in these regulatory processes can chronically lead to the development of hypertension
In this background and hinted by evidence showing that leptin can influence immune response [22], we carried out the current study to investigate if there exists an interactive action between leptin and TNF␣ in the central control of BP in normal physiology and whether this potential mechanism is important for the development of obesity-related hypertension
We investigated the molecular relationship between leptin and TNF␣, examined their role through the central nervous system (CNS) in the physiological control of diurnal BP rise, and studied the potential contribution of central leptin-TNF␣ connection, when augmented, to obesity-related hypertension (Fig. 7)
Summary
In coordination with physical and physiological requirements, blood pressure (BP)2 levels are tightly regulated to rise and fall in circadian manners, while alterations in these regulatory processes can chronically lead to the development of hypertension. In this background and hinted by evidence showing that leptin can influence immune response [22], we carried out the current study to investigate if there exists an interactive action between leptin and TNF␣ in the central control of BP in normal physiology and whether this potential mechanism is important for the development of obesity-related hypertension.
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