Central leptin and tumor necrosis factor-α (TNFα) in diurnal control of blood pressure and hypertension

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.