Ghrelin Modulates Sympathetic Nervous System Activity and Stress Response in Lean and Overweight Men

Lambert, Elisabeth; Lambert, Gavin W.; Ika-Sari, Caroline; Dawood, Tye; Lee, Katie; Chopra, Reena; Straznicky, Nora E.; Eikelis, Nina; Drew, Sara; Tilbrook, Alan John; Dixon, John; Esler, Murray; Schlaich, Markus P.

doi:10.1161/hypertensionaha.111.171025

Cited by 75 publications

(65 citation statements)

References 43 publications

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“…Ghrelin has also been reported to increase muscle sympathetic activity in both lean and obese men. 28 In the current study, offspring from mothers fed an NFD showed no change in RSNA, whereas m-HFD rabbits had elevated RSNA in response to ghrelin. This elevation occurred at the low dose of ghrelin that produced little change in MAP or HR; hence, renal sympathetic outflow is not likely to be the primary mechanism by which ghrelin at higher doses reduces MAP and HR.…”

Section: Hypertensionmentioning

confidence: 45%

Exposure to a High-Fat Diet During Development Alters Leptin and Ghrelin Sensitivity and Elevates Renal Sympathetic Nerve Activity and Arterial Pressure in Rabbits

et al. 2014

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With the rising prevalence of obesity, particularly among women of reproductive age, it is important to understand the consequences of maternal obesity and nutrient excess on processes underlying development because they may lead to adverse outcomes in offspring. Animal models of maternal fat-rich diets that reflect the dietary intakes of humans in affluent societies have demonstrated the programming of offspring hyperphagia, adiposity, insulin resistance, and hypertension.1,2 Various factors, including elevated blood pressure (BP), insulin resistance, hyperglycemia, elevated plasma glucocorticoids, and leptin, associated with obesity during gestation can affect the development of a fetus.3 These factors can all contribute to a suboptimal intrauterine environment and predispose offspring to an increased risk of obesity and hypertension. There is evidence that the sympathetic nervous system (SNS) may be activated in offspring of fat-fed dams that develop hypertension, 1 but to date no study has shown direct evidence for increased sympathetic vasomotor activity. The adipokine hormone leptin and the gut hormone ghrelin act on neural circuitry of the hypothalamus important for energy homeostasis and the regulation of the SNS. 4,5 We have recently shown that the renal sympathetic nerve activity (RSNA) and BP increases in the first few days of consuming a high-fat diet (HFD) in rabbits can be largely reversed by a leptin antagonist given intracerebroventricularly (ICV). [6][7][8][9] In contrast, ghrelin secreted by the stomach activates arcuate neurons containing neuropeptide Y and agouti-related protein and has been shown to suppress sympathetic activity, decrease BP, and stimulate appetite.10,11 Thus, both leptin and ghrelin may play a key role in the association between obesity and hypertension and may also be involved in the hypertension programmed by a maternal HFD (m-HFD).The purpose of this study was to examine the effect of an m-HFD during development on arterial pressure and RSNA and the central sympathetic effects of leptin and ghrelin in offspring. We used a rabbit model in which an HFD induces elevated BP and RSNA. [6][7][8][9] We hypothesized that offspring exposed to an HFD during development would retain greater deposits of fat and show a selective leptin-resistant phenotype Abstract-Exposure to maternal obesity or a maternal diet rich in fat during development may have adverse outcomes in offspring, such as the development of obesity and hypertension. The present study examined the effect of a maternal high-fat diet (m-HFD) on offspring blood pressure and renal sympathetic nerve activity, responses to stress, and sensitivity to central administration of leptin and ghrelin. Offspring of New Zealand white rabbits fed a 13% HFD were slightly heavier than offspring from mothers fed a 4% maternal normal fat diet (P<0.05) but had 64% greater fat pad mass (P=0.015). Mean arterial pressure, heart rate, and renal sympathetic nerve activity at 4 months of age were 7%, 7%, and 24% greater, respectively (P<0.001),...

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Section: Hypertensionmentioning

confidence: 45%

Exposure to a High-Fat Diet During Development Alters Leptin and Ghrelin Sensitivity and Elevates Renal Sympathetic Nerve Activity and Arterial Pressure in Rabbits

et al. 2014

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“…Another limitation refers to the fact that in our patients we did not assess plasma ghrelin levels, which have been shown to exert sympathoexcitatory effects and to be reduced by sleeve gastrectomy. 46,47 Finally, although the MSNA data were calculated by an investigator unaware of the experimental design, our study has the intrinsic limitations of a study with an unblinded study design. The clinical implication refers to the fact that removal of the sympathetic activation by sleeve gastrectomy may eliminate a factor that is involved in the high prevalence of hypertension, congestive heart failure, ischemic heart disease, and sudden death typical of the severe obese state.…”

Section: Perspectivesmentioning

confidence: 99%

Long-Term Sympathoinhibitory Effects of Surgically Induced Weight Loss in Severe Obese Patients

Seravalle

Colombo

et al. 2014

Hypertension

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L ong-term prospective studies have recently shown that bariatric surgery significantly reduces the risk of death in severely obese patients.1 This has been confirmed by retrospective analyses of a large cohort of obese individuals in whom surgery-related reductions in body weight were associated with a significant reduction in death rate compared with obese individuals followed under dietary and medical treatment. [2][3][4] It is a widespread belief that the protective effect of bariatric surgery in obese patients may perhaps be related to a reduction of body weight per se but that the concomitant improvement of the array of risk factors commonly associated with obesity, for example, alterations in lipid and glucose metabolism, is likely to play a major role. [5][6][7] In this context, however, little attention has to date been given to whether bariatric surgery is also associated with the improvement of another adverse phenomenon of obesity (ie, sympathetic activation). 8,9 The only information available comes from 3 studies that assessed sympathetic tone by making use of spectral analysis of heart rate signal or 24-hour norepinephrine urinary excretion [10][11][12] (ie, approaches that display major intrinsic limitations not allowing to provide any direct insight on the effects of the intervention on central sympathetic outflow, as the microneurographic technique only allows to achieve 13 .) The issue has pathophysiological and clinical relevance because sympathetic activation has been shown to be an adverse prognostic factor in several clinical conditions.14-17 Furthermore, evidence has been obtained that sympathetic overdrive may cause or worsen insulin resistance, 18,19 thus contributing to a common metabolic alteration in obesity.Abstract-Weight loss improves insulin sensitivity and exerts sympathomodulatory effects. No data, however, are available on the effects of the weight loss induced by vertical sleeve gastrectomy on sympathetic neural drive, insulin sensitivity, and their reciprocal cross talks. In 10 severe obese hypertensives (age, 54.0±2.3 years [mean±SEM]), we measured sphygmomanometric blood pressure, heart rate, body mass index, homeostatic model assessment index, plasma leptin, muscle sympathetic nerve traffic (microneurography), and baroreflex sensitivity (vasoactive drug technique). Measurements were performed 2 to 3 days before surgery and repeated 6 and 12 months after the procedure. Ten matched hypertensive obeses not undergoing gastrectomy served as controls. Six months after bariatric surgery, a significant (P<0.05) reduction in body mass index (−9.1±1.4 kg/m 2 ), sphygmomanometric systolic blood pressure (−10.2±4.5 mm Hg), heart rate (−11.0±2.4 bpm), homeostatic model assessment index (−3-3±1.3 AU), plasma leptin (−53.6±8.8 μg/L), and muscle sympathetic nerve traffic (−15.0±3.4 bursts/100 heart beats) was observed. The weight loss, the plasma leptin reduction, and the sympathetic inhibition were maintained after 12 months, whereas homeostatic model assessment index showed a tendency ...

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“…A notable exception to the sympathoinhibitory effect of ghrelin is the finding of Lambert et al (43) that intravenous infusion of ghrelin resulted in elevation of muscle sympathetic nerve activity in both healthy lean and overweight individuals. The exact mechanism for the seemingly opposite effects of ghrelin on muscle sympathetic nerve activity compared with other organs, such as kidney, is unknown.…”

Section: Ghrelin-mediated Sympathoinhibition and Anti-inflammatory Efmentioning

confidence: 99%

Ghrelin-mediated sympathoinhibition and suppression of inflammation in sepsis

Cheyuo

Jacob

Wang

2012

American Journal of Physiology-Endocrinology and Metabolism

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Cheyuo C, Jacob A, Wang P. Ghrelin-mediated sympathoinhibition and suppression of inflammation in sepsis. Am J Physiol Endocrinol Metab 302: E265-E272, 2012. First published November 8, 2011 doi:10.1152/ajpendo.00508.2011.-Sepsis, a systemic inflammatory response to infection, continues to carry a high mortality despite advances in critical care medicine. Elevated sympathetic nerve activity in sepsis has been shown to contribute to early hepatocellular dysfunction and subsequently multiple organ failure, resulting in a poor prognosis, especially in the elderly. Thus, suppression of sympathetic nerve activity represents a novel therapeutic option for sepsis. Ghrelin is a 28-amino acid peptide shown to inhibit sympathetic nerve activity and inflammation in animal models of tissue injury. Age-related ghrelin hyporesponsiveness has also been shown to exacerbate sepsis. However, the mechanistic relationship between ghrelin-mediated sympathoinhibition and suppression of inflammation remains poorly understood. This review assesses the therapeutic potential of ghrelin in sepsis in the context of the neuroanatomical and molecular basis of ghrelin-mediated suppression of inflammation through inhibition of central sympathetic outflow. sympathoexcitation; ventrolateral medulla; ␣ 2A-adrenergic receptor; norepinephrine DESPITE STRIDES IN CRITICAL CARE, the 751,000 annual cases of sepsis in the United States continue to be costly, causing 215,000 deaths, with an estimated economic burden of 16.7 billion dollars on the United States annually. Multiple organ failure, resulting in part from the deleterious effects of proinflammatory cytokines, is responsible for most deaths in sepsis (5,70). We discovered that norepinephrine released from the gut causes early hepatocellular dysfunction in sepsis by stimulating ␣ 2A -adrenoceptors on Kupffer cells, potentiating lipopolysaccharide (LPS)-stimulated NF-B-mediated cytokine release (56). The proinflammatory cytokines released by Kupffer cells contribute to multiple organ failure. Thus, suppression of sympathetic nerve activity and norepinephrine release represents a promising novel therapeutic approach to sepsis.Ghrelin is a stomach-derived 28-amino acid peptide that exerts anti-inflammatory effects in sepsis. Serum ghrelin levels are reduced during sepsis, and administration of exogenous ghrelin improves survival in sepsis (69,85,86). Ghrelin can act centrally to inhibit peripheral sympathetic nerve activity following tissue injury (67,73,87). However, the mechanisms of central ghrelin-mediated sympathoinhibition and how this translates into suppression of systemic inflammation in sepsis remain poorly understood. This review assesses the therapeutic potential of ghrelin in sepsis by discussing the neuroanatomical and molecular bases of ghrelin-mediated inhibition of central sympathetic outflow and the relation to suppression of inflammation and attenuation of tissue injury in sepsis. Guided by the current recommendations of the surviving sepsis campaign (19), we make suggestions for...

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Ghrelin Modulates Sympathetic Nervous System Activity and Stress Response in Lean and Overweight Men

Cited by 75 publications

References 43 publications

Exposure to a High-Fat Diet During Development Alters Leptin and Ghrelin Sensitivity and Elevates Renal Sympathetic Nerve Activity and Arterial Pressure in Rabbits

Exposure to a High-Fat Diet During Development Alters Leptin and Ghrelin Sensitivity and Elevates Renal Sympathetic Nerve Activity and Arterial Pressure in Rabbits

Long-Term Sympathoinhibitory Effects of Surgically Induced Weight Loss in Severe Obese Patients

Ghrelin-mediated sympathoinhibition and suppression of inflammation in sepsis

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