Central Leptin and Tumor Necrosis Factor-α (TNFα) in Diurnal Control of Blood Pressure and Hypertension

Abstract

Leptin and TNF␣ 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 TNF␣ production under both in vitro and in vivo conditions, and diurnal fluctuation of leptin concentrations in the cerebrospinal fluid predicted the circadian changes of TNF␣ 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 TNF␣ 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 TNF␣ pretreatment was found to potentiate the effect of leptin in elevating blood pressure in normal mice. In pathophysiology, dietary obesity mimicked TNF␣ 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 TNF␣ to mediate the diurnal blood pressure elevation in physiology while enhancement of this mechanism can contribute to hypertension development.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. From both physiological and pathological perspectives, BP changes involve peripheral contributions as well as neural inputs. Recently, there was an increasing amount of research in addressing the molecular and neuronal types in the central nervous system (CNS) mechanisms of hypertension (1-5). Leptin, an adipose tissue-derived cytokine which is overproduced in obesity, has been shown to increase BP when chronically administrated centrally (4, 6 -9), and the underlying physiological basis involves up-regulation in the sympathetic outflow from the brain to the peripheral tissues (6, 10). Interestingly, the central effects of leptin on BP versus feeding do not necessarily follow the same line (8,11,12), for example, while leptin's regulation on feeding is compromised (namely "leptin resistance") in obesity, its action in raising BP is well reserved, leading to a notion that leptin resistance is physiologically selective (8, 9, 13). Taken together, the action of leptin on BP is probably mediated by certain mechanisms which are less clear compared with the mechanisms in mediating metabolic regulation. Also, an acute excess of leptin, e.g. via a single injection, has a prominent effect on feeding but little influences on the BP in normal animals (14, 15), leaving it unsolved regarding if leptin is involved in BP control under normal physiology and if so, how.In addition to leptin, inflammatory cytokines were recently found to play cruc...

Physiological and pathophysiological roles of hypothalamic astrocytes in metabolism

“…Hypothalamic inflammation is key in the development of obesity‐induced hypertension because proinflammatory cytokines also regulate sympathetic activity . Central effects of leptin are mediated via TNF‐α with a differential regulation in physiological and obesity conditions . Increases in cerebrospinal fluid leptin levels over a 24‐hour circadian period correlate with a moderate increase in hypothalamic TNF‐α expression and a transient physiological BP rise.…”

“…Increases in cerebrospinal fluid leptin levels over a 24‐hour circadian period correlate with a moderate increase in hypothalamic TNF‐α expression and a transient physiological BP rise. However, the excess of both leptin and TNF‐α in obesity chronically elevate BP, mediating its pathological increase . TNF‐α is an activator of nuclear factor‐kappa B (NF‐κB) in astrocytes .…”

“…125,126 Central effects of leptin are mediated via TNF-α with a differential regulation in physiological and obesity conditions. 127 Increases in cerebrospinal fluid leptin levels over a 24-hour circadian period correlate with a moderate increase in hypothalamic TNF-α expression and a transient physiological BP rise. However, the excess of both leptin and TNF-α in obesity chronically elevate BP, mediating its pathological increase.…”

“…However, the excess of both leptin and TNF-α in obesity chronically elevate BP, mediating its pathological increase. 127 TNF-α is an activator of nuclear factorkappa B (NF-κB) in astrocytes. 128 Acute activation of pro-inflammatory NF-κB in the mouse mediobasal hypothalamus induces a rapid elevation in BP independently of obesity.…”

Hypothalamic mechanisms underlying the cardiovascular and metabolic actions of leptin

“…In addition to this interaction with the RAS, the leptin-induced increase in blood pressure requires activation of inflammatory pathways via IKKβ/NF-κB in POMC neurons [45,46]. Central administration of TNFα has been shown to potentiate the blood pressure response to leptin, while inhibition of TNFα or IKKβ prevents the hypertensive effect of leptin during diet-induced obesity [47,48]. These interactions are not surprising given that hypertension and obesity are both associated with RAS dysregulation and elevated levels of inflammatory cytokines, and may explain why leptin alone is not always sufficient to drive hypertension in humans and animal models with normal inflammatory and RAS activity.…”