Leptin antagonist reverses hypertension caused by leptin overexpression, but fails to normalize obesity-related hypertension

Tümer, Nihal; Erdös, Benedek; Matheny, Michael; Cudykier, Idan; Scarpace, Philip J.

doi:10.1097/hjh.0b013e3282e9a9fd

Cited by 33 publications

(28 citation statements)

References 29 publications

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“…Leptin has been shown to affect central BP regulatory mechanisms increasing SNS activity and BP (5,8), and leptin-induced sympathoexcitation has been implicated in the pathomechanism of obesity-related hypertension (1). However, even though exogenously infused leptin increases SNS activity and BP, we demonstrated in a previous study that HF diet-induced elevation of BP cannot be reversed with central infusion of a leptin antagonist (38). Results from our current study further prove that serum leptin level alone cannot be responsible for elevated BP, since BP in old animals failed to increase in response to HF diet despite the extremely high serum leptin levels.…”

Section: Age-related Changes In the Metabolic Effects Of Hf Feedingsupporting

confidence: 44%

Effect of age on high-fat diet-induced hypertension

Erdös

Kirichenko

Whidden

et al. 2011

American Journal of Physiology-Heart and Circulatory Physiology

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Aging and obesity both have a significant impact on central blood pressure (BP) regulation, and previous studies indicated that changes in central redox signaling with age may affect high-fat (HF) diet-induced cardiovascular responses. Therefore, we investigated the effects of 60% HF feeding on BP regulation in young adult (5 mo) and old (26 mo) Fischer-344 × Brown-Norway rats. Radiotelemetric transmitters were implanted to measure BP, heart rate (HR), locomotor activity, and spontaneous baroreflex sensitivity. Expression and activity of NADPH oxidase and ANG II type 1 receptor were assessed in the hypothalamus and in the nucleus tractus solitarii. Old animals gained more weight on HF diet compared with young, whereas central NADPH oxidase expression and activity elevated similarly in the two age groups. After an initial hypotensive and tachycardic response during the first week of HF feeding, BP in young animals increased and became significantly elevated after 6 wk of HF feeding. In contrast, BP in old animals remained depressed. Nighttime HR and locomotor activity decreased in both young and old rats fed with HF diet, but these changes were more significant in young rats. As a result, amplitudes of circadian variation of BP, HR, and activity that were originally higher in young rats declined significantly and became similar in the two age groups. In conclusion, our experiments led to the surprising finding that HF diet has a more serious impact on cardiovascular regulation in young animals compared with old.

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Section: Age-related Changes In the Metabolic Effects Of Hf Feedingsupporting

confidence: 44%

Effect of age on high-fat diet-induced hypertension

Erdös

Kirichenko

Whidden

et al. 2011

American Journal of Physiology-Heart and Circulatory Physiology

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“…As it has been raised in the research that the mechanisms for the hypertensive effect exerted by leptin under obesity and lean conditions are different (55,56), our study indicates that cytokines such as TNF␣ could be a key point for appreciating the role of leptin in mediating pathological BP increase. This concept is also supported by our result showing that treatment with anti-inflammatory chemical PS1145 and TNF␣ antagonist WP9QY were both effective in reducing the hypertensive effect of leptin in obesity.…”

Section: Discussionmentioning

confidence: 99%

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

Han

Alé

et al. 2016

Journal of Biological Chemistry

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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...

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“…A recent experimental study in obese animals concluded that the inhibition of central leptin signaling was insufficient to reverse obesity-induced hypertension and that the peripheral effects of leptin may be more important in mediating hypertension than stimulation of the sympathetic nervous system centrally. 35 Although there is evidence supporting the idea that leptin does not have a direct effect on resistance vessels in vivo, 9 the interplay between BP levels and free leptin may share a reciprocal modulation with sympathetic activation, systemic subclinical inflammation, and endothelial dysfunction, anticipating adverse BP clinical phenotypes, including masked hypertension, with possible adverse repercussion on cardio-metabolic outcomes. 36,37 Indeed, a previous study among hypertensive insulin-resistant subjects found increased leptin levels associated with left ventricle hypertrophy, whereas our findings extended the A reference category for the dependent variable was considered the normotensive BP phenotype.…”

Section: Discussionmentioning

confidence: 99%

Free Leptin Is Associated With Masked Hypertension in Nonobese Subjects

et al. 2009

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Abstract-The aim of the study was to investigate whether diverse clinical blood pressure phenotypes are associated with free leptin surrogates, as reflected by plasma leptin, human soluble leptin receptor, and their ratio (ie, free leptin index) in nonobese normoglycemic subjects. Three separate clinic blood pressure measurements and ambulatory blood pressure monitoring were implemented to divide 494 subjects (aged 44Ϯ5 years; 272 men; body mass index: Ͻ30 kg/m 2 ) into hypertensives (nϭ166), white-coat hypertensives (nϭ82), masked hypertensives (nϭ66), and normotensives (nϭ180). Participants underwent echocardiography, while, from fasting venous blood samples, metabolic profile, plasma leptin, and its receptor levels were assessed. Hypertensives and masked hypertensives demonstrated higher levels of log (10)(leptin) and log (10)(free leptin index), as well as lower levels of log (10)(human soluble leptin receptor) with respect to normotensives. White-coat hypertensives had similar free leptin surrogates compared with normotensives. Younger age, 24-hour systolic and diastolic blood pressures, 24-hour heart rate, and left ventricle mass index were common correlates of free leptin surrogates. After adjustment for confounders, masked hypertensive and hypertensive with respect to normotensive phenotype were associated with log (10)(leptin) with odds ratios (95% CIs) of 1.31 (1.12 to 3.80) and 1.26 (1.09 to 2.24), respectively, log (10)(human soluble leptin receptor) with 0.65 (0.53 to 0.78) and 0.69 (0.57 to 0.84), respectively, and log (10)(free leptin index) with 2.46 (1.32 to 7.23) and 1.84 (1.26 to 3.73), respectively (PϽ0.05 for all of the cases). Free leptin surrogates are associated with masked hypertension in nonobese normoglycemic subjects. Free leptin is almost equally increased in masked and sustained hypertension, suggesting a similar leptin-related vascular impairment. ncreased leptin levels have been independently associated with cardiovascular diseases 1 and risk factors such as obesity, insulin resistance, type 2 diabetes mellitus, 2 as well as with blood pressure (BP) levels even below the clinically defined hypertensive cutoff value. 3,4 Leptin may be implicated on the perpetuation of systemic inflammation given its modulator effect on C-reactive protein 5 and its structural and functional resemblance to proinflammatory cytokines like interleukin 6. 6 Because between hypertension and systemic inflammation there is an established reciprocal pathophysiological link, 7 hyperleptinemia might be implicated on the adverse hemodynamic regulation beyond the centrally obesity-mediated mechanisms of leptin resistance. 8 Although in vivo studies supported the notion that chronic hemodynamic actions of leptin are likely attributable to widespread sympathoactivation of metabolically active tissues and not to the vasculature to increase vasomotor tone, 9 in vitro evidence suggested that leptin at concentrations higher than the physiologically relevant level may exert adverse effects on the vasculature by periphe...

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Leptin antagonist reverses hypertension caused by leptin overexpression, but fails to normalize obesity-related hypertension

Cited by 33 publications

References 29 publications

Effect of age on high-fat diet-induced hypertension

Effect of age on high-fat diet-induced hypertension

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

Free Leptin Is Associated With Masked Hypertension in Nonobese Subjects

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