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Ghrelin and its potential in the treatment of eating/wasting disorders and cachexia.
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PMID:  21475701     Owner:  NLM     Status:  Publisher    
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The gastrointestinal "hunger" hormone ghrelin is the only known circulating peripheral molecule with the ability to decrease body fat utilization and to increase body weight gain. Accordingly, due to ghrelin's effects to promote food intake while decreasing energy expenditure ghrelin may offer potential as a drug for treatment of eating/wasting disorders and cachexia. Therapeutic potential of ghrelin and ghrelin analogues to promote food intake and body weight gain was recently indicated in several clinical studies. The recent discovery of the ghrelin O-acyltransferase as the key enzyme responsible for ghrelin acylation has further deepened our understanding of ghrelin activation, thereby paving the way for more efficient targeting of the ghrelin pathway. Here, we summarize the current knowledge pertaining to the potential of the endogenous ghrelin system as a drug target for the treatment of eating/wasting disorders and cachexia.
Authors:
Timo D Müller; Diego Perez-Tilve; Jenny Tong; Paul T Pfluger; Matthias H Tschöp
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Type:  JOURNAL ARTICLE     Date:  2010-12-17
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Title:  Journal of cachexia, sarcopenia and muscle     Volume:  1     ISSN:  2190-6009     ISO Abbreviation:  -     Publication Date:  2010 Dec 
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Created Date:  2011-4-8     Completed Date:  -     Revised Date:  -    
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Nlm Unique ID:  101552883     Medline TA:  J Cachex Sarcopenia Muscle     Country:  -    
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Languages:  ENG     Pagination:  159-167     Citation Subset:  -    
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Division of Endocrinology, Department of Medicine, University of Cincinnati, Metabolic Diseases Institute, Cincinnati, OH USA.
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Journal ID (nlm-ta): J Cachex Sarcopenia Muscle
ISSN: 2190-5991
ISSN: 2190-6009
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© The Author(s) 2010
Received Day: 23 Month: 4 Year: 2010
Accepted Day: 2 Month: 11 Year: 2010
Electronic publication date: Day: 17 Month: 12 Year: 2010
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PubMed Id: 21475701
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DOI: 10.1007/s13539-010-0012-4

Ghrelin and its potential in the treatment of eating/wasting disorders and cachexia
Timo D. MüllerAff1
Diego Perez-TilveAff1
Jenny TongAff1
Paul T. PflugerAff1
Matthias H. TschöpAff1 Address: tschoemh@ucmail.uc.edu
Division of Endocrinology, Department of Medicine, University of Cincinnati, Metabolic Diseases Institute, Cincinnati, OH USA

Introduction

Cachexia (Greek: kakós—bad; hexis—condition) is a multifactorial syndrome characterized by substantial loss of body weight due to an involuntarily wasting of skeletal muscle and adipose tissue mass as a result of an imbalance between catabolic and anabolic processes (Fig. 1) [1, 2]. Cachexia frequently develops in advanced stages of various chronic diseases such as chronic heart failure (CHF), chronic obstructive pulmonary disease (COPD), end-stage renal disease (ESRD), sepsis, acquired immune deficiency syndrome and various kinds of cancer [1, 3]. Dependent on the type of tumor, cancer-cachexia is observed in 30–80% of cancer patients with patients suffering from pancreatic or gastric cancer having the highest frequency of weight loss while patients with breast cancer, non-lymphocytic leukemia, and sarcomas having the lowest [4]. Irrespective of the underlying disease, however, cachexia is associated with a low response to drug treatment, a poor quality of life, a poor prognosis, and an increased mortality rate compared to non-cachexia patients [1, 5]. Accordingly, cachexia is believed to be the immediate cause of 10–20% of all deaths in cancer patients [5].

Cachexia is frequently, but not necessarily, accompanied by anorexia, defined as the loss of the desire to eat [4, 6]. Decreased energy intake due to anorexia contributes to increased weight loss but, however, cannot solely explain the typical metabolic changes associated with cachexia, such as an excess release of pro-inflammatory cytokines and an increased activity of the sympathetic nervous system [1, 3, 4].

Cachexia is typically associated with an increased release of pro-inflammatory cytokines, such as tumor necrosis factor-α (TNFα), Interleukin-1ß (IL-1ß), IL-6, and IL-8 [5]. Pro-inflammatory cytokines, especially TNFα and IL6, act as catabolic factors in the pathogenesis of cachexia by stimulating proteolytic pathways leading to muscle atrophy and increased adipose tissue breakdown (Fig. 1) [5]. In particular, TNFα stimulates muscle protein breakdown, causes contractile dysfunction and inhibits myogenesis and myogenic differentiation through activation of the nuclear factor-kappa B pathway [5, 7, 8]. TNFα further promotes wasting of adipose tissue through stimulation of lipolysis, inhibition of adipocyte differentiation and by increasing apoptosis in adipocytes [3, 5, 9].

Increased activity of the sympathetic nervous system is frequently described in patients with cachexia [4, 10, 11]. In particular, increased plasma concentrations of catecholamines as a result of sympathetic overactivity contribute to body weight loss and tissue wasting by increasing energy expenditure, stimulation of lipolysis, and stimulation of apoptosis in skeletal muscle [3, 12].

Various previous studies have, with only limited success, focused on the evaluation of potential drug targets for the treatment of eating/wasting disorders and cachexia. One of the endogenous peptides that, due to its beneficial effects on e.g. food intake, energy expenditure, and inflammation has recently reached scientific interest is the gastrointestinal “hunger” hormone ghrelin. The ability of ghrelin and ghrelin analogues to promote food intake and body weight gain in patients with eating disorders and cachexia was recently demonstrated in several clinical studies. The importance of the ghrelin system in the neuroendocrine control of energy balance has recently been highlighted in several excellent review articles [13, 14]. The aim of this review is to summarize the current knowledge pertaining to the endogenous ghrelin system as a potential target for the treatment of pathological reduced body mass, the key clinical feature of cachexia.

Ghrelin synthesis and activation

The gastrointestinal peptide hormone ghrelin was discovered in 1999 as an endogenous ligand for the growth hormone secretagogue 1a receptor (GHS-R1a) [15]. Ghrelin is synthesized as a 117 amino acid pre-prohormone, which is post-translational cleaved into a 28 amino acid peptide [16]. Ghrelin is predominantly synthesized and secreted by X/A-like cells in the oxyntic glands of the mucosa of the gastric fundus [17]. However, lower levels of ghrelin expression can also be found in, e.g., the intestine, pancreas, kidney, lung, ovaries and the brain [14]. Since its discovery in 1999, a tremendous amount of research efforts have focused on revealing ghrelin’s mechanisms of action. To promote its biological action, ghrelin is acylated on its serine 3 residue by the recently discovered membrane-bound O-acyltransferase 4 (MBOAT4), which was later accordingly renamed to ghrelin O-acyl-transferase (GOAT; Fig. 2) [18, 19]. The observation that acyl-ghrelin is absent in mice lacking Goat indicates that Goat is the only enzyme capable to activate ghrelin in vivo [18].

Ghrelin-mediated regulation food intake and energy balance

Ghrelin is secreted from the stomach into the bloodstream under conditions of fasting, thus serving as a “hunger” hormone that signals the gastrointestinal fuel status from the periphery to the central nervous system in order to stimulate food intake and to adjust energy balance through a decrease in energy expenditure. Plasma levels of ghrelin typically follow a circadian rhythm with a preprandial rise which peaks directly at meal initiation followed by a postprandial decrease to baseline levels within the first hour after a meal [2022]. In accordance to its role as a meal initiation hormone, ghrelin stimulates food intake and adiposity through stimulation of hypothalamic orexigenic neuropeptides [23]. In the arcuate nucleus (ARC), a hypothalamic key center in the control of energy metabolism, GHS-R1a is co-expressed with the agouti-related peptide (AgRP) and the neuropeptide Y (NPY), both prototypic anabolic neuropeptides that promote a positive energy balance through stimulation of food intake and by decreasing energy expenditure [2325]. Accordingly, ghrelin-mediated activation of hypothalamic GHS-R1a entails an increased expression and release of NPY and AgRP in the ARC, thus entailing an activation of anabolic downstream pathways that lead to a stimulation of food intake and a decrease of energy expenditure [2628]. Recent evidence further indicates that the ability of GOAT-mediated ghrelin acylation depends on specific dietary medium chain triglycerides as acylation sustrates [29]. These findings indicate that ghrelin, in contrast to its commonly accepted role as a hunger hormone, might rather serve as a nutrient sensor that signals the gastrointestinal nutrient availability to the central nervous system.

Ghrelin further stimulates the expression and release of growth hormone (GH) from the anterior pituitary gland and thus indirectly triggers expression and secretion of hepatic insulin-like growth factor-1 (IGF-1) [15, 30, 31]. Both, GH and IGF-1 are anabolic hormones known to increase lean body mass by stimulation of skeletal muscle growth and inhibition of skeletal muscle protein breakdown [3234]. During catabolic states, such as cachexia, GH further stimulates lipolysis through increased release and oxidation of free fatty acids which leads to decreased glucose and protein oxidation and preservation of lean body mass [33]. The fundamental importance of the endogenous GOAT/ghrelin system was very recently demonstrated by Zhao and colleagues, who showed in Goat−/− mice that ghrelin-mediated regulation of GH release prevents death by preserving blood glucose levels under conditions of severe caloric restriction [35]. Other beneficial effects of ghrelin include a decrease of body fat utilization [36] and a decrease of sympathetic nerve activity [3739]. In white adipocytes, ghrelin further stimulates the expression of fat-storage promoting enzymes, such as lipoprotein lipase, acetyl-CoA carboxylase α, fatty acid synthase, and steaoryl-CoA desaturase-1 [40]. In brown adipocytes, ghrelin dose-dependently lowers the expression of the thermogenesis-related mitochondrial uncoupling proteins 1 and 3, presumably through ghrelin’s ability to decrease sympathetic nerve activity [40]. Ghrelin further has been reported to attenuate skeletal muscle and adipose tissue wasting by decreasing the release of pro-inflammatory cytokines, such as TNFα, IL-1ß, IL-6 and IL-8 [3943] while increasing the release of anti-inflammatory cytokines, such as IL-10 [43]. In summary, these data indicate that the endogenous GOAT/ghrelin system plays a fundamental role in the neuroendocrine adaptation to starvation and that modulation of the ghrelin system might be an interesting target for the treatment of pathological reduced body weight and tissue wasting.


Ghrelin levels in patients with eating disorders and cachexia
Anorexia nervosa

Anorexia nervosa (AN) is an eating disorder of unknown etiology, typically characterized by an abnormal eating behavior with disturbances of attitudes towards body weight and shape [44, 45].

Several forms of ghrelin (octanoyl-, desacyl, (non-octanoyl) acyl-ghrelin) can be found in circulation. However, for most available immunoassays it is either not well known or not sufficiently disclosed which of those ghrelin analogues they are binding and to which extent they are cross reacting with other related peptides such as motilin. Most assays reported in the literature likely measure total ghrelin-like immunoreactivity including large amounts of presumably inactive ghrelin peptide. Nevertheless, several studies have shown a negative correlation between the body mass index (BMI) and plasma levels of ghrelin in AN [4648]. Accordingly, plasma levels of ghrelin are elevated in the acute phase of AN [4852] and decline to normal values upon weight restoration [49, 53, 54]. Compared to normal weight healthy controls, also plasma levels of acyl-ghrelin are elevated in patients with AN, even during all phases of an oral glucose tolerance test [46, 48]. Some studies further report higher plasma levels of acyl-ghrelin when compared to BMI-matched lean women [47, 5156] thus indicating that impaired ghrelin sensitivity due to persistent hyperghrelinemia might play a role in the pathogenesis of AN, comparable to leptin resistance in persistently hyperleptinemic obese individuals. Persistent hyperghrelinemia might further contribute to the frequently described impairment of the GH/IGF-1 axis in AN, as plasma levels of GH are typically elevated while IGF-1 levels are paradoxically decreased in patients with AN [5760].

The orexigenic effects of ghrelin and ghrelin analogues have been assessed in several human studies revealing that ghrelin promotes food intake in both healthy individuals [6163] and patients with AN [64]. Ghrelin treatment of anorectic individuals for 14 days (3 μg/kg twice daily) increased energy intake by 12–36% compared to baseline values in one study [64], although in another study, where ghrelin was continuously infused for 300 min at rates of 5 pmol/kg/min, ghrelin failed to detect an effect on appetite, as assessed by a visual analog scale [65]. Potential pitfalls of these studies are, however, the limited amount of study samples and the short duration of ghrelin treatment. Notably, however, both studies report no adverse side effects of ghrelin treatment [64, 65]. A further beneficial effect of ghrelin treatment in AN include an increase of blood glucose levels [66] which is in accordance with recent findings indicating that ghrelin prevents death by preservation of normoglycemia in Goat−/− mice under conditions of starvation [35].


Cancer-cachexia

Several animal studies have recently assessed the potential of ghrelin in the treatment of cancer-cachexia [6770]. Plasma concentrations of ghrelin rise with the progression of cachexia in mice inoculated with human melanoma cells [68] and ghrelin treatment of these mice attenuates cachexia by stimulation of food intake and suppression of body weight loss [67]. Similar improvements on food intake and body weight gain were reported in tumor-implanted rats treated with either ghrelin or the ghrelin analog BIM-28131 [70]. In the latter study, ghrelin increased the hypothalamic expression of AgRP and NPY whereas, interestingly, plasma levels of GH were unchanged [70]. However, not all studies were able to replicate this finding [68]. It is further noteworthy that no differences in tumor size have been observed between ghrelin and saline treated animals [67, 70].

In accordance to the animal studies, plasma concentrations of ghrelin are elevated in patients with cancer-cachexia when compared to those without cachexia [71, 72]. Continuous infusion of ghrelin (5 pmol/kg/min for 180 min) in patients with breast and colon cancer increased energy intake by 31% compared to saline treated controls [73]. However, in a 2-week randomized, double blind, placebo-controlled trial, where ghrelin was given intravenously at two time points at doses of 2 or 8 μg/kg, ghrelin failed to affect nutritional intake despite elevated plasma levels of GH indicated an increased ghrelin activity [74]. Notably, however, both studies report no adverse side effects of ghrelin treatment [73, 74].

Noteworthy is that not all studies report elevated levels of ghrelin in patients with advanced cancer and weight loss. In one study, where ghrelin was measured in 30 patients with different malignancies and 27 healthy controls, ghrelin levels were reported to be lower in patients with advanced cancer as compared to the healthy controls [75]. Further studies in other study samples are required to clarify this observation but the reduction of ghrelin levels might be attributed to the severity and progression of the disease.

Even though substantial evidence indicates the safety and tolerability of ghrelin at doses up to 10 μg/kg [62, 73, 74, 76], no long-term studies are available pertaining to the potential implication of the ghrelin/GH/IGF-1 axis on tumor growth and carcinogenesis. Both, ghrelin and/or the ghrelin receptor are expressed in various tumorous tissues, especially in tumors of the gastrointestinal tract, such as in gastric endocrine tumors [77, 78], intestinal endocrine tumors [77, 78], pancreatic endocrine tumors [79, 80] but also in, e.g., pituitary tumors [81, 82], bronchial endocrine tumors [83] and testicular tumors [84]. It remains unknown as and to what extend ghrelin secretion from these tumors affects tumor growth and/or energy balance. Increased ghrelin secretion from tumorous tissues might be implicated in either promoting or inhibiting tumor growth via autocrine/paracrine pathways [13]. On the other hand, ghrelin released from tumors might counteract skeletal muscle and fat mass wasting by stimulation of food intake and activation of anabolic pathways. Tumor-related alterations of ghrelin secretion might thus contribute to the different rates of weight loss, which are typically observed in different kinds of cancers.


Chronic obstructive pulmonary disease

Cachexia is frequently described in patients with advanced stages of COPD [11, 8587] and is considered as an independent risk factor for mortality in these patients [87, 88]. Plasma levels of ghrelin are negatively correlated with BMI in COPD patients [89] and 3-week treatment of COPD patients with ghrelin (2 μg/kg twice a day) significantly increased food intake, body weight, lean body mass, and muscle strength [11]. Intriguingly, ghrelin further increased plasma levels of GH while epinephrine levels are decreased, thus indicating a decrease of sympathetic nerve activity due to ghrelin treatment [11]. Ghrelin-mediated modulation of the GH/IGF-1 axis might be important for pulmonary cachexia as GH treatment has previously been shown to increase muscle mass in patients with COPD [90]. Together, these data support the potential of ghrelin to promote food intake and body weight gain in patients with pulmonary cachexia.


Chronic heart failure

Chronic heart failure is a major public health problem affecting approximately 5 million Americans with nearly 500,000 new cases every year [91]. Cardiac cachexia is observed in 10–15% of patients with CHF [85] and cachexia in these patients is associated with a poor prognosis and an increased mortality rate compared to non-cachexia patients [92]. Accordingly, mortality rates in patients with CHF are as high as 50% in patients with cachexia compared to 17% in patients without cachexia [1, 92].

Left ventricular dysfunction and left ventricular remodeling (dilatation and wall thinning) are frequently observed in patients with advanced stages of CHF [86, 93]. Growth hormone and IGF-1 are important physiological regulators of myocardial growth and performance [94, 95] and patients with CHF show typically elevated serum levels of GH and normal to decreased levels of IGF-1 [96, 97], thus indicating that alterations of the GH/IGF-1 axis might be implicated in the myocardial dysfunction and cachexia in these patients. Several studies have assessed the therapeutic potential of GH supplementation in the treatment of CHF, revealing that GH treatment improves left ventricular dysfunction and cardiac performance in both CHF rats [98100] and patients with CHF [101]. Due to ghrelins beneficial effects on energy metabolism and GH/IGF-1 secretion it is suggested that ghrelin might improve cardiac performance and cachexia in CHF patients through GH-dependent and -independent mechanisms [91, 102]. Accordingly, 3-week treatment of CHF rats with ghrelin (100 μg/kg/day) increased serum GH and IGF-1 levels and promoted body weight gain and improved cardiac performance by increasing the diastolic thickness of the non-infarcted posterior wall and by inhibition of left ventricular enlargement [102]. In line with these observations, twice-daily treatment of CHF patients with ghrelin at doses of 2 μg/kg for 3 weeks improved cardiac performance and attenuated cachexia by increasing muscle strength and lean body mass [10]. Ghrelin further inhibits apoptosis of cardiomyocytes and endothelial cells in vitro [103] and decreases arterial pressure while increasing cardiac output in CHF rats [102] and healthy humans [104]. Together, these data indicate that ghrelin has beneficial effects on cardiovascular performance and cachexia through GH-dependent and independent mechanisms and that modulation of the ghrelin system is an interesting target for the treatment of myocardial dysfunction and cachexia in patients with CHF.


Renal failure

Anorexia and cachexia are frequently observed in patients with chronically decreased renal function, such as in patients with ESRD or chronic kidney disease [105, 106]. Renal insufficiency in these patients is often accompanied by increased serum levels of pro-inflammatory cytokines, such as TNFα and IL-6 [105, 106], which promote tissue wasting and cachexia by, e.g., inhibition of myogenesis and stimulation of skeletal muscle protein breakdown [5, 7].

Plasma levels of desacyl- and total ghrelin are elevated in patients with renal failure [107110] and decline upon dialysis treatment [109, 110]. As the kidney is the primary site of ghrelin clearance [111] it is likely that ghrelin accumulates in these patients as a result of renal insufficiency [13, 112]. Several studies have assessed the therapeutic potential of ghrelin in the treatment of anorexia and cachexia in patients with renal failure [112114]. Continuous infusion of nephrectomized rats for 14 days with either ghrelin or ghrelin analogues (BIM-28125 and BIM-28131, 150 nmol/kg/day) significantly increased food intake and lean body mass and tended to decrease overall pro-inflammatory cytokines compared to saline treated controls [112]. Accordingly, in a randomized, double blind, placebo-controlled crossover design, in which patients with peritoneal dialysis where treated with a single subcutaneous injection of ghrelin (3.6 nmol/kg), ghrelin increased immediate food intake by 57% compared to saline treated controls [113]. A similar effect on food intake was found in a double-blinded randomized crossover study where malnourished dialysis patients were treated for 1 week with 12 μg/kg/day of ghrelin [114].


Conclusion

Total ghrelin-like immunoreactivity in plasma is typically elevated in patients with anorexia nervosa as well as in cachexia associated with chronic heart failure [115, 116], renal failure [107, 117], chronic obstructive pulmonary disease [85, 89], and various forms of cancer [71, 118, 119]. Hyperghrelinemia in these patients may reflect a compensatory response to counteract the weight loss associated with skeletal muscle and fat mass wasting.

Several animal studies support the potential of ghrelin and ghrelin analogues to promote food intake and body weight gain in cachexia associated with heart failure [91, 102, 120, 121], chronic kidney disease [112] and cancer [67, 68, 70]. Accordingly, several human trials report improvements of appetite and body mass upon ghrelin treatment in patients with anorexia nervosa [64] and cachexia associated with renal failure [113, 114], chronic heart failure [10], chronic obstructive pulmonary disease [11], and cancer [73]. Notably, as yet all studies support the safety and tolerability of ghrelin treatment and no serious adverse side effects have so far been reported [73, 74]. Together, these data indicate that the endogenous ghrelin system represents an attractive target for the treatment of pathologically reduced body weight and tissue wasting, the key clinical feature of cachexia. However, further studies in larger populations are necessary to clarify the long-term effects of ghrelin treatment and to assess the possible impact of ghrelin and ghrelin induced growth factor release on tumor growth and carcinogenesis.


The authors of this manuscript certify that they comply with the ethical guidelines for authorship and publishing in the Journal of Cachexia, Sarcopenia and Muscle [122].

Sources of funding This work was supported by grants from the Hilda and Preston Davis Foundation—Davis Foundation Postdoctoral Fellowship Program in Eating Disorders.

Disclosures The authors confirm that there is no conflict of interest.

Open Access This article is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.


References
1.. Haehling S,Lainscak M,Springer J,Anker SD. Cardiac cachexia: a systematic overviewPharmacol TherYear: 200912122725219061914
2.. Ashby D,Choi P,Bloom S. Gut hormones and the treatment of disease cachexiaProc Nutr SocYear: 20086726326918452642
3.. Ashitani J,Matsumoto N,Nakazato M. Ghrelin and its therapeutic potential for cachectic patientsPeptidesYear: 2009301951195619595727
4.. Tisdale MJ. Mechanisms of cancer cachexiaPhysiol RevYear: 20098938141019342610
5.. Langhans W. Peripheral mechanisms involved with catabolismCurr Opin Clin Nutr Metab CareYear: 2002541942612107378
6.. Bosaeus I,Daneryd P,Svanberg E,Lundholm K. Dietary intake and resting energy expenditure in relation to weight loss in unselected cancer patientsInt J CancerYear: 20019338038311433403
7.. Karin M,Ben Neriah Y. Phosphorylation meets ubiquitination: the control of NF-kappa B activityAnn Rev ImmunolYear: 20001862166310837071
8.. Li YP,Reid MB. Effect of tumor necrosis factor-alpha on skeletal muscle metabolismCurr Opin RheumatolYear: 20011348348711698724
9.. Sethi JK,Hotamisligil GS. The role of TNF alpha in adipocyte metabolismSemin Cell Dev BiolYear: 199910192910355025
10.. Nagaya N,Moriya J,Yasumura Y,Uematsu M,Ono F,Shimizu W,et al. Effects of ghrelin administration on left ventricular function, exercise capacity, and muscle wasting in patients with chronic heart failureCirculationYear: 20041103674367915569841
11.. Nagaya N,Itoh T,Murakami S,Oya H,Uematsu M,Miyatake K,et al. Treatment of cachexia with ghrelin in patients with COPDChestYear: 20051281187119316162705
12.. Dünser MW,Hasibeder WR. Sympathetic overstimulation during critical illness: adverse effects of adrenergic stressJ Intensive Care MedYear: 20092429331619703817
13.. Chen CY,Asakawa A,Fujimiya M,Lee SD,Inui A. Ghrelin gene products and the regulation of food intake and gut motilityPharmacol RevYear: 20096143048120038570
14.. Castañeda TR,Tong J,Datta R,Culler M,Tschöp MH. Ghrelin in the regulation of body weight and metabolismFront NeuroendocrinolYear: 201031446019896496
15.. Kojima M,Hosoda H,Date Y,Nakazato M,Matsuo H,Kangawa K. Ghrelin is a growth-hormone-releasing acylated peptide from stomachNatureYear: 199940265666010604470
16.. Hosoda H,Kojima M,Mizushima T,Shimizu S,Kangawa K. Structural divergence of human ghrelin. Identification of multiple ghrelin-derived molecules produced by post-translational processingJ Biol ChemYear: 2003278647012414809
17.. Sakata I,Nakamura K,Yamazaki M,Matsubara M,Hayashi Y,Kangawa K,et al. Ghrelin-producing cells exist as two types of cells, closed- and opened-type cells, in the rat gastrointestinal tractPeptidesYear: 20022353153611836003
18.. Yang J,Zhao TJ,Goldstein JL,Brown MS. Inhibition of ghrelin O-acyltransferase (GOAT) by octanoylated pentapeptidesProc Natl Acad Sci USAYear: 2008105107501075518669668
19.. Gutierrez JA,Solenberg PJ,Perkins DR,Willency JA,Knierman MD,Jin Z,et al. Ghrelin octanoylation mediated by an orphan lipid transferaseProc Natl Acad Sci USAYear: 20081056320632518443287
20.. Williams DL,Cummings DE. Regulation of ghrelin in physiologic and pathophysiologic statesJ NutrYear: 20051351320132515867333
21.. Tschöp M,Wawarta R,Riepl RL,Friedrich S,Bidlingmaier M,Landgraf R,et al. Post-prandial decrease of circulating human ghrelin levelsJ Endocrinol InvestYear: 200124RC19RC2111434675
22.. Cummings DE,Purnell JQ,Frayo RS,Schmidova K,Wisse BE,Weigle DS. A preprandial rise in plasma ghrelin levels suggests a role in meal initiation in humansDiabetesYear: 2001501714171911473029
23.. Barsh GS,Schwartz MW. Genetic approaches to studying energy balance: perception and integrationNat Rev GenetYear: 2002358960012154382
24.. Willesen MG,Kristensen P,Rømer J. Co-localization of growth hormone secretagogue receptor and NPY mRNA in the arcuate nucleus of the ratNeuroendocrinologyYear: 19997030631610567856
25.. Mondal MS,Date Y,Yamaguchi H,Toshinai K,Tsuruta T,Kangawa K,et al. Identification of ghrelin and its receptor in neurons of the rat arcuate nucleusRegul PeptYear: 2005126555915620414
26.. Kamegai J,Tamura H,Shimizu T,Ishii S,Sugihara H,Wakabayashi I. Central effect of ghrelin, an endogenous growth hormone secretagogue, on hypothalamic peptide gene expressionEndocrinologyYear: 20001414797480011108296
27.. Kamegai J,Tamura H,Shimizu T,Ishii S,Sugihara H,Wakabayashi I. Chronic central infusion of ghrelin increases hypothalamic neuropeptide Y and Agouti-related protein mRNA levels and body weight in ratsDiabetesYear: 2001502438244311679419
28.. Morton GJ,Cummings DE,Baskin DG,Barsh GS,Schwartz MW. Central nervous system control of food intake and body weightNatureYear: 200644328929516988703
29.. Kirchner H,Gutierrez JA,Solenberg PJ,Pfluger PT,Czyzyk TA,Willency JA,et al. GOAT links dietary lipids with the endocrine control of energy balanceNat MedYear: 20091574174519503064
30.. Arvat E,Maccario M,Vito L,Broglio F,Benso A,Gottero C,et al. Endocrine activities of ghrelin, a natural growth hormone secretagogue (GHS), in humans: comparison and interactions with hexarelin, a nonnatural peptidyl GHS, and GH-releasing hormoneJ Clin Endocrinol MetabYear: 2001861169117411238504
31.. Peino R,Baldelli R,Rodriguez-Garcia J,Rodriguez-Segade S,Kojima M,Kangawa K,et al. Ghrelin-induced growth hormone secretion in humansEur J EndocrinolYear: 2000143R11R1411124868
32.. Amato G,Carella C,Fazio S,Montagna G,Cittadini A,Sabatini D,et al. Body composition, bone metabolism, and heart structure and function in growth hormone (GH)-deficient adults before and after GH replacement therapy at low dosesJ Clin Endocrinol MetabYear: 199377167116768263158
33.. Fuller J,Mynett JR,Sugden PH. Stimulation of cardiac protein synthesis by insulin-like growth factorsBiochem JYear: 199228285901540148
34.. Moller N,Vendelbo MH,Kampmann U,Christensen B,Madsen M,Norrelund H,et al. Growth hormone and protein metabolismClin NutrYear: 20092859760319773097
35.. Zhao TJ, Liang G, Li RL, Xie X, Sleeman MW, Murphy AJ, Valenzuela DM, Yancopoulos GD, Goldstein JL, Brown MS. Ghrelin O-acyltransferase (GOAT) is essential for growth hormone-mediated survival of calorie-restricted mice. Proc Natl Acad Sci USA. 2010. In press [Epub ahead of print].
36.. Tschöp M,Smiley DL,Heiman ML. Ghrelin induces adiposity in rodentsNatureYear: 200040790891311057670
37.. Matsumura K,Tsuchihashi T,Fujii K,Abe I,Iida M. Central ghrelin modulates sympathetic activity in conscious rabbitsHypertensionYear: 20024069469912411464
38.. Lin Y,Matsumura K,Fukuhara M,Kagiyama S,Fujii K,Iida M. Ghrelin acts at the nucleus of the solitary tract to decrease arterial pressure in ratsHypertensionYear: 20044397798214993197
39.. Wu R,Zhou M,Das P,Dong W,Ji Y,Yang D,et al. Ghrelin inhibits sympathetic nervous activity in sepsisAm J Physiol Endocrinol MetabYear: 2007293E1697E170217911350
40.. Theander-Carrillo C,Wiedmer P,Cettour-Rose P,Nogueiras R,Perez-Tilve D,Pfluger P,et al. Ghrelin action in the brain controls adipocyte metabolismJ Clin InvestYear: 20061161983199316767221
41.. Dixit VD,Schaffer EM,Pyle RS,Collins GD,Sakthivel SK,Palaniappan R,et al. Ghrelin inhibits leptin- and activation-induced proinflammatory cytokine expression by human monocytes and T cellsJ Clin InvestYear: 2004114576615232612
42.. Kodama T,Ashitani J,Matsumoto N,Kangawa K,Nakazato M. Ghrelin treatment suppresses neutrophil-dominant inflammation in airways of patients with chronic respiratory infectionPulm Pharmacol TherYear: 20082177477918571961
43.. Delgado M,Ganea D. Anti-inflammatory neuropeptides: a new class of endogenous immunoregulatory agentsBrain Behav ImmunYear: 2008221146115118598752
44.. Hebebrand J,Muller TD,Holtkamp K,Herpertz-Dahlmann B. The role of leptin in anorexia nervosa: clinical implicationsMol PsychiatryYear: 200712233517060920
45.. Müller TD,Reichwald K,Brönner G,Kirschner J,Nguyen TT,Scherag A,et al. Lack of association of genetic variants in genes of the endocannabinoid system with anorexia nervosaChild Adolesc Psychiatry Ment HealthYear: 200823319014633
46.. Nakai Y,Hosoda H,Nin K,Ooya C,Hayashi H,Akamizu T,et al. Short-term secretory regulation of the active form of ghrelin and total ghrelin during an oral glucose tolerance test in patients with anorexia nervosaEur J EndocrinolYear: 200415091391415191363
47.. Tolle V,Kadem M,Bluet-Pajot MT,Frere D,Foulon C,Bossu C,et al. Balance in ghrelin and leptin plasma levels in anorexia nervosa patients and constitutionally thin womenJ Clin Endocrinol MetabYear: 20038810911612519838
48.. Harada T,Nakahara T,Yasuhara D,Kojima S,Sagiyama K,Amitani H,et al. Obestatin, acyl ghrelin, and des-acyl ghrelin responses to an oral glucose tolerance test in the restricting type of anorexia nervosaBiol PsychiatryYear: 20086324524717706613
49.. Otto B,Cuntz U,Fruehauf E,Wawarta R,Folwaczny C,Riepl RL,et al. Weight gain decreases elevated plasma ghrelin concentrations of patients with anorexia nervosaEur J EndocrinolYear: 200114566967311720888
50.. Nakahara T,Harada T,Yasuhara D,Shimada N,Amitani H,Sakoguchi T,et al. Plasma obestatin concentrations are negatively correlated with body mass index, insulin resistance index, and plasma leptin concentrations in obesity and anorexia nervosaBiol PsychiatryYear: 20086425225517919459
51.. Germain N,Galusca B,Grouselle D,Frere D,Tolle V,Zizzari P,et al. Ghrelin/obestatin ratio in two populations with low bodyweight: constitutional thinness and anorexia nervosaPsychoneuroendocrinologyYear: 20093441341918995969
52.. Prince AC,Brooks SJ,Stahl D,Treasure J. Systematic review and meta-analysis of the baseline concentrations and physiologic responses of gut hormones to food in eating disordersAm J Clin NutrYear: 20098975576519176730
53.. Otto B,Tschöp M,Frühauf E,Heldwein W,Fichter M,Otto C,et al. Postprandial ghrelin release in anorectic patients before and after weight gainPsychoneuroendocrinologyYear: 20053057758115808927
54.. Haas V,Onur S,Paul T,Nutzinger DO,Bosy-Westphal A,Hauer M,et al. Leptin and body weight regulation in patients with anorexia nervosa before and during weight recoveryAm J Clin NutrYear: 20058188989615817868
55.. Monteleone P,Serritella C,Martiadis V,Scognamiglio P,Maj M. Plasma obestatin, ghrelin, and ghrelin/obestatin ratio are increased in underweight patients with anorexia nervosa but not in symptomatic patients with bulimia nervosaJ Clin Endocrinol MetabYear: 2008934418442118728162
56.. Germain N,Galusca B,Roux CW,Bossu C,Ghatei MA,Lang F,et al. Constitutional thinness and lean anorexia nervosa display opposite concentrations of peptide YY, glucagon-like peptide 1, ghrelin, and leptinAm J Clin NutrYear: 20078596797117413094
57.. Golden NH,Kreitzer P,Jacobson MS,Chasalow FI,Schebendach J,Freedman SM,et al. Disturbances in growth hormone secretion and action in adolescents with anorexia nervosaJ PediatrYear: 19941256556607523649
58.. Argente J,Caballo N,Barrios V,Muñoz MT,Pozo J,Chowen JA,et al. Multiple endocrine abnormalities of the growth hormone and insulin-like growth factor axis in patients with anorexia nervosa: effect of short- and long-term weight recuperationJ Clin Endocrinol MetabYear: 199782208420929215276
59.. Støving RK,Flyvbjerg A,Frystyk J,Fisker S,Hangaard J,Hansen-Nord M,et al. Low serum levels of free and total insulin-like growth factor I (IGF-I) in patients with anorexia nervosa are not associated with increased IGF-binding protein-3 proteolysisJ Clin Endocrinol MetabYear: 1999841346135010199777
60.. Misra M,Miller KK,Bjornson J,Hackman A,Aggarwal A,Chung J,et al. Alterations in growth hormone secretory dynamics in adolescent girls with anorexia nervosa and effects on bone metabolismJ Clin Endocrinol MetabYear: 2003885615562314671143
61.. Druce MR,Wren AM,Park AJ,Milton JE,Patterson M,Frost G,et al. Ghrelin increases food intake in obese as well as lean subjectsInt J Obes LondYear: 2005291130113615917842
62.. Wren AM,Seal LJ,Cohen MA,Brynes AE,Frost GS,Murphy KG,et al. Ghrelin enhances appetite and increases food intake in humansJ Clin Endocrinol MetabYear: 200186599211739476
63.. Garcia JM,Polvino WJ. Effect on body weight and safety of RC-1291, a novel, orally available ghrelin mimetic and growth hormone secretagogue: results of a phase I, randomized, placebo-controlled, multiple-dose study in healthy volunteersOncologistYear: 20071259460017522248
64.. Hotta M,Ohwada R,Akamizu T,Shibasaki T,Takano K,Kangawa K. Ghrelin increases hunger and food intake in patients with restricting-type anorexia nervosa: a pilot studyEndocr JYear: 2009561119112819755753
65.. Miljic D,Pekic S,Djurovic M,Doknic M,Milic N,Casanueva FF,et al. Ghrelin has partial or no effect on appetite, growth hormone, prolactin, and cortisol release in patients with anorexia nervosaJ Clin Endocrinol MetabYear: 2006911491149516449333
66.. Miljic D,Djurovic M,Pekic S,Doknic M,Stojanovic M,Milic N,et al. Glucose metabolism during ghrelin infusion in patients with anorexia nervosaJ Endocrinol InvestYear: 20073077177517993770
67.. Hanada T,Toshinai K,Kajimura N,Nara-Ashizawa N,Tsukada T,Hayashi Y,et al. Anti-cachectic effect of ghrelin in nude mice bearing human melanoma cellsBiochem Biophys Res CommunYear: 200330127527912565855
68.. Hanada T,Toshinai K,Date Y,Kajimura N,Tsukada T,Hayashi Y,et al. Upregulation of ghrelin expression in cachectic nude mice bearing human melanoma cellsMetabolismYear: 200453848814681847
69.. Chance WT,Dayal R,Friend LA,Thomas I,Sheriff S. Continuous intravenous infusion of ghrelin does not stimulate feeding in tumor-bearing ratsNutr CancerYear: 200860759018444139
70.. DeBoer MD,Zhu XX,Levasseur P,Meguid MM,Suzuki S,Inui A,et al. Ghrelin treatment causes increased food intake and retention of lean body mass in a rat model of cancer cachexiaEndocrinologyYear: 20071483004301217347304
71.. Shimizu Y,Nagaya N,Isobe T,Imazu M,Okumura H,Hosoda H,et al. Increased plasma ghrelin level in lung cancer cachexiaClin Cancer ResYear: 2003977477812576449
72.. Karapanagiotou EM,Polyzos A,Dilana KD,Gratsias I,Boura P,Gkiozos I,et al. Increased serum levels of ghrelin at diagnosis mediate body weight loss in non-small cell lung cancer (NSCLC) patientsLung CancerYear: 20096639339819282046
73.. Neary NM,Small CJ,Wren AM,Lee JL,Druce MR,Palmieri C,et al. Ghrelin increases energy intake in cancer patients with impaired appetite: acute, randomized, placebo-controlled trialJ Clin Endocrinol MetabYear: 2004892832283615181065
74.. Strasser F,Lutz TA,Maeder MT,Thuerlimann B,Bueche D,Tschöp M,et al. Safety, tolerability and pharmacokinetics of intravenous ghrelin for cancer-related anorexia/cachexia: a randomised, placebo-controlled, double-blind, double-crossover studyBr J CancerYear: 20089830030818182992
75.. Legakis I,Stathopoulos J,Matzouridis T,Stathopoulos GP. Decreased plasma ghrelin levels in patients with advanced cancer and weight loss in comparison to healthy individualsAnticancer ResYear: 2009293949395219846934
76.. Akamizu T,Takaya K,Irako T,Hosoda H,Teramukai S,Matsuyama A,et al. Pharmacokinetics, safety, and endocrine and appetite effects of ghrelin administration in young healthy subjectsEur J EndocrinolYear: 200415044745515080773
77.. Papotti M,Cassoni P,Volante M,Deghenghi R,Muccioli G,Ghigo E. Ghrelin-producing endocrine tumors of the stomach and intestineJ Clin Endocrinol MetabYear: 2001865052505911600584
78.. Rayhan N,Sano T,Qian ZR,Obari AK,Hirokawa M. Histological and immunohistochemical study of composite neuroendocrine-exocrine carcinomas of the stomachJ Med InvestYear: 20055219120216167538
79.. Iwakura H,Hosoda K,Doi R,Komoto I,Nishimura H,Son C,et al. Ghrelin expression in islet cell tumors: augmented expression of ghrelin in a case of glucagonoma with multiple endocrine neoplasm type IJ Clin Endocrinol MetabYear: 2002874885488812414844
80.. Volante M,Allìa E,Gugliotta P,Funaro A,Broglio F,Deghenghi R,et al. Expression of ghrelin and of the GH secretagogue receptor by pancreatic islet cells and related endocrine tumorsJ Clin Endocrinol MetabYear: 2002871300130811889202
81.. Kim K,Arai K,Sanno N,Osamura RY,Teramoto A,Shibasaki T. Ghrelin and growth hormone (GH) secretagogue receptor (GHSR) mRNA expression in human pituitary adenomasClin Endocrinol OxfYear: 20015475976811422110
82.. Korbonits M,Bustin SA,Kojima M,Jordan S,Adams EF,Lowe DG,et al. The expression of the growth hormone secretagogue receptor ligand ghrelin in normal and abnormal human pituitary and other neuroendocrine tumorsJ Clin Endocrinol MetabYear: 20018688188711158061
83.. Arnaldi G,Mancini T,Kola B,Appolloni G,Freddi S,Concettoni C,et al. Cyclical Cushing’s syndrome in a patient with a bronchial neuroendocrine tumor (typical carcinoid) expressing ghrelin and growth hormone secretagogue receptorsJ Clin Endocrinol MetabYear: 2003885834584014671177
84.. Gaytan F,Barreiro ML,Caminos JE,Chopin LK,Herington AC,Morales C,et al. Expression of ghrelin and its functional receptor, the type 1a growth hormone secretagogue receptor, in normal human testis and testicular tumorsJ Clin Endocrinol MetabYear: 20048940040914715878
85.. Lainscak M,Andreas S,Scanlon PD,Somers VK,Anker SD. Ghrelin and neurohumoral antagonists in the treatment of cachexia associated with cardiopulmonary diseaseIntern MedYear: 20064583716880713
86.. Nagaya N,Kojima M,Kangawa K. Ghrelin, a novel growth hormone-releasing peptide, in the treatment of cardiopulmonary-associated cachexiaIntern MedYear: 20064512713416508225
87.. Landbo C,Prescott E,Lange P,Vestbo J,Almdal TP. Prognostic value of nutritional status in chronic obstructive pulmonary diseaseAm J Respir Crit Care MedYear: 19991601856186110588597
88.. Gray-Donald K,Gibbons L,Shapiro SH,Macklem PT,Martin JG. Nutritional status and mortality in chronic obstructive pulmonary diseaseAm J Respir Crit Care MedYear: 19961539619668630580
89.. Itoh T,Nagaya N,Yoshikawa M,Fukuoka A,Takenaka H,Shimizu Y,et al. Elevated plasma ghrelin level in underweight patients with chronic obstructive pulmonary diseaseAm J Respir Crit Care MedYear: 200417087988215271696
90.. Burdet L,Muralt B,Schutz Y,Pichard C,Fitting JW. Administration of growth hormone to underweight patients with chronic obstructive pulmonary disease. A prospective, randomized, controlled studyAm J Respir Crit Care MedYear: 1997156180018069412558
91.. Nagaya N,Kangawa K. Ghrelin, a novel growth hormone-releasing peptide, in the treatment of chronic heart failureRegul PeptYear: 2003114717712832093
92.. Anker SD,Ponikowski P,Varney S,Chua TP,Clark AL,Webb-Peploe KM,et al. Wasting as independent risk factor for mortality in chronic heart failureLancetYear: 1997349105010539107242
93.. Dec GW,Fuster V. Idiopathic dilated cardiomyopathyN Engl J MedYear: 1994331156415757969328
94.. Saccà L,Cittadini A,Fazio S. Growth hormone and the heartEndocr RevYear: 1994155555737843068
95.. Saccà L,Fazio S. Cardiac performance: growth hormone enters the raceNat MedYear: 1996229318564831
96.. Anker SD,Chua TP,Ponikowski P,Harrington D,Swan JW,Kox WJ,et al. Hormonal changes and catabolic/anabolic imbalance in chronic heart failure and their importance for cardiac cachexiaCirculationYear: 1997965265349244221
97.. Niebauer J,Pflaum CD,Clark AL,Strasburger CJ,Hooper J,Poole-Wilson PA,et al. Deficient insulin-like growth factor I in chronic heart failure predicts altered body composition, anabolic deficiency, cytokine and neurohormonal activationJ Am Coll CardiolYear: 1998323933979708466
98.. Yang R,Bunting S,Gillett N,Clark R,Jin H. Growth hormone improves cardiac performance in experimental heart failureCirculationYear: 1995922622677600659
99.. Yang R,Bunting S,Gillett N,Clark RG,Jin H. Effects of growth hormone in rats with postinfarction left ventricular dysfunctionCardiovasc Drugs TherYear: 199591251317786832
100.. Cittadini A,Stromer H,Katz SE,et al. Differential cardiac effects of growth hormone and insulin-like growth factor-1 in the rat: a combined in vivo and in vitro evaluationCirculationYear: 1996938008098641010
101.. Fazio S,Sabatini D,Capaldo B,et al. A preliminary study of growth hormone in the treatment of dilated cardiomyopathyN Engl J MedYear: 19963348098148596546
102.. Nagaya N,Uematsu M,Kojima M,Ikeda Y,Yoshihara F,Shimizu W,et al. Chronic administration of ghrelin improves left ventricular dysfunction and attenuates development of cardiac cachexia in rats with heart failureCirculationYear: 20011041430143511560861
103.. Baldanzi G,Filigheddu N,Cutrupi S,Catapano F,Bonissoni S,Fubini A,et al. Ghrelin and des-acyl ghrelin inhibit cell death in cardiomyocytes and endothelial cells through ERK1/2 and PI 3-kinase/AKTJ Cell BiolYear: 20021591029103712486113
104.. Nagaya N,Kojima M,Uematsu M,Yamagishi M,Hosoda H,Oya H,et al. Hemodynamic and hormonal effects of human ghrelin in healthy volunteersAm J Physiol Regul Integr Comp PhysiolYear: 2001280R1483R148711294772
105.. Cheung WW,Paik KH,Mak RH. Inflammation and cachexia in chronic kidney diseasePediatr NephrolYear: 20102571172420111974
106.. Mak RH,Cheung W. Adipokines and gut hormones in end-stage renal diseasePerit Dial IntYear: 200727Suppl 2S298S30217556323
107.. Yoshimoto A,Mori K,Sugawara A,Mukoyama M,Yahata K,Suganami T,et al. Plasma ghrelin and desacyl ghrelin concentrations in renal failureJ Am Soc NephrolYear: 2002132748275212397045
108.. Jarkovská Z,Rosická M,Krsek M,Sulková S,Haluzík M,Justová V,et al. Plasma ghrelin levels in patients with end-stage renal diseasePhysiol ResYear: 20055440340815588149
109.. Jarkovská Z,Hodková M,Sazamová M,Rosická M,Dusilová-Sulková S,Marek J,et al. Plasma levels of active and total ghrelin in renal failure: a relationship with GH/IGF-I axisGrowth Horm IGF ResYear: 20051536937616198134
110.. Rodriguez Ayala E,Pecoits-Filho R,Heimbürger O,Lindholm B,Nordfors L,Stenvinkel P. Associations between plasma ghrelin levels and body composition in end-stage renal disease: a longitudinal studyNephrol Dial TransplantYear: 20041942142614736968
111.. Wu R,Zhou M,Cui X,Simms HH,Wang P. Ghrelin clearance is reduced at the late stage of polymicrobial sepsisInt J Mol MedYear: 20031277778114533009
112.. Deboer MD,Zhu X,Levasseur PR,Inui A,Hu Z,Han G,et al. Ghrelin treatment of chronic kidney disease: improvements in lean body mass and cytokine profileEndocrinologyYear: 200814982783518039782
113.. Wynne K,Giannitsopoulou K,Small CJ,Patterson M,Frost G,Ghatei MA,et al. Subcutaneous ghrelin enhances acute food intake in malnourished patients who receive maintenance peritoneal dialysis: a randomized, placebo-controlled trialJ Am Soc NephrolYear: 2005162111211815888560
114.. Ashby DR,Ford HE,Wynne KJ,Wren AM,Murphy KG,Busbridge M,et al. Sustained appetite improvement in malnourished dialysis patients by daily ghrelin treatmentKidney IntYear: 20097619920619387475
115.. Nagaya N,Uematsu M,Kojima M,Date Y,Nakazato M,Okumura H,et al. Elevated circulating level of ghrelin in cachexia associated with chronic heart failure: relationships between ghrelin and anabolic/catabolic factorsCirculationYear: 20011042034203811673342
116.. Xin X,Ren AJ,Zheng X,Qin YW,Zhao XX,Yuan WJ,et al. Disturbance of circulating ghrelin and obestatin in chronic heart failure patients especially in those with cachexiaPeptidesYear: 2009302281228519666068
117.. Aygen B,Dogukan A,Dursun FE,Aydin S,Kilic N,Sahpaz F,et al. Ghrelin and obestatin levels in end-stage renal diseaseJ Int Med ResYear: 20093775776519589259
118.. Garcia JM,Garcia-Touza M,Hijazi RA,Taffet G,Epner D,Mann D,et al. Active ghrelin levels and active to total ghrelin ratio in cancer-induced cachexiaJ Clin Endocrinol MetabYear: 2005902920292615713718
119.. Wolf I,Sadetzki S,Kanety H,Kundel Y,Pariente C,Epstein N,et al. Adiponectin, ghrelin, and leptin in cancer cachexia in breast and colon cancer patientsCancerYear: 200610696697316411208
120.. Nagaya N,Kangawa K. Ghrelin improves left ventricular dysfunction and cardiac cachexia in heart failureCurr Opin PharmacolYear: 2003314615112681236
121.. Xu XB,Pang JJ,Cao JM,Ni C,Xu RK,Peng XZ,et al. GH-releasing peptides improve cardiac dysfunction and cachexia and suppress stress-related hormones and cardiomyocyte apoptosis in rats with heart failureAm J Physiol Heart Circ PhysiolYear: 2005289H1643H165115951341
122.. von Haehling S, Morley JE, Coats AJ, Anker SD. Ethical guidelines for authorship and publishing in the Journal of Cachexia, Sarcopenia and Muscle. J Cachexia Sarcopenia Muscle. 2010;1:7–8.

Figures

[Figure ID: Fig1]
Fig. 1 

Molecular mechanisms of cachexia. Typical metabolic changes associated with the development of cachexia are an increased release of pro-inflammatory cytokines as well as an overactivity of the sympathetic nervous system, as indicated by increased plasma concentrations of catecholamines. Both, pro-inflammatory cytokines and catecholamines promote catabolic processes leading to skeletal muscle and fat mass wasting, such as stimulation of lipid utilization and skeletal muscle protein breakdown while decreasing energy intake and increasing energy expenditure. ESRD end-stage renal disease, CKD chronic kidney disease, CHF chronic heart failure, COPD chronic obstructive pulmonary disease, IL6 Interleukin 6, IL8 Interleukin 8, IL1β Interleukin 1 beta, TNFα tumor necrosis factor alpha



[Figure ID: Fig2]
Fig. 2 

Ghrelin-mediated neuroendocrine alterations of energy metabolism. Ghrelin is secreted from the stomach and is acylated at its serine 3 residues by the ghrelin O-acyltransferase (GOAT). Central-mediated effects of ghrelin include (besides others) the stimulation of food intake and the decrease of energy expenditure through stimulation of hypothalamic neurons expressing neuropeptide Y (NPY) and agouti-related peptide (AgRP). In the anterior pituitary ghrelin stimulates the release of growth hormone (GH), which in turn stimulates the release of hepatic insulin-like growth factor-1 (IGF-1). Both, GH and IGF-1 increase lean body mass by inhibition of skeletal muscle protein breakdown. In adipose tissue, ghrelin stimulates the expression of genes coding for fat-storage promoting enzymes, such as lipoprotein lipase (LPL), fatty acid synthase (FAS), acetyl-CoA carboxylase α, and steaoryl-CoA desaturase-1 (SCD1). Either through central or peripheral mechanisms ghrelin further inhibits the release of pro-inflammatory cytokines, such as Interleukin (IL) 6, IL 8, IL1β and the tumor necrosis factor α. Dashed lines indicate potential signal pathways. ARC arcuate nucleus



Article Categories:
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Keywords: Keywords Anorexia, Cachexia, Wasting, Ghrelin.

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