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Biological, physiological, pathophysiological, and pharmacological aspects of ghrelin
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van der Lely AJ, Tschop M, Heiman ML, et al. Biological, physiological, pathophysiological, and pharmacological aspects of ghrelin. Endocr Rev 2004; 25:426-457. This is the most encyclopedic published review on ghrelin, written by some of the most prolific authors in the field. It covers the full breadth of known and hypothesized biologic roles for ghrelin. Beyond describing well-documented aspects of ghrelin's regulation and actions, the authors also tackle controversial issues, such as the possibilities of alternate receptors for ghrelin, alternate ligands for the ghrelin receptor, physiologic roles for des-acyl ghrelin, and the biologic importance of centrally produced ghrelin.
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Endocr Rev
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Ghrelin, a novel growth hormone-releasing acylated peptide, is synthesized in a distinct endocrine cell type in the gastrointestinal tracts of rats and humans
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Date Y, Kojima M, Hosoda H, et al. Ghrelin, a novel growth hormone-releasing acylated peptide, is synthesized in a distinct endocrine cell type in the gastrointestinal tracts of rats and humans. Endocrinology 2000; 141:4255-4261.
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Korbonits M, Bustin SA, Kojima M, et al. The expression of the growth hormone secretagogue receptor ligand ghrelin in normal and abnormal human pituitary and other neuroendocrine tumors. J Clin Endocrinol Metab 2001; 86:881-887.
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Ghrelin and des-octanoyl ghrelin promote adipogenesis directly in vivo by a mechanism independent of the type 1a growth hormone secretagogue receptor
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Thompson NM, Gill DA, Davies R, et al. Ghrelin and des-octanoyl ghrelin promote adipogenesis directly in vivo by a mechanism independent of the type 1a growth hormone secretagogue receptor. Endocrinology 2004; 145:234-242.
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Thompson, N.M.1
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Ghrelin and des-acyl ghrelin both inhibit isoproterenol-induced lipolysis in rat adipocytes via a non-type 1a growth hormone secretagogue receptor
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Muccioli G, Pons N, Ghe C, et al. Ghrelin and des-acyl ghrelin both inhibit isoproterenol-induced lipolysis in rat adipocytes via a non-type 1a growth hormone secretagogue receptor. Eur J Pharmacol 2004; 498:27-35.
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Administration of acylated ghrelin reduces insulin sensitivity, whereas the combination of acylated plus unacylated ghrelin strongly improves insulin sensitivity
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Gauna C, Meyler FM, Janssen JA, et al. Administration of acylated ghrelin reduces insulin sensitivity, whereas the combination of acylated plus unacylated ghrelin strongly improves insulin sensitivity. J Clin Endocrinol Metab 2004; 89:5035-5042. Among the handful of studies that claim biologic roles for des-acyl ghrelin, this is one of the few performed in humans. The authors report that administration of acylated ghrelin increased blood glucose and insulin levels - effects that were prevented by concomitant injection of des-acyl ghrelin.
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J Clin Endocrinol Metab
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Gauna, C.1
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Expression of ghrelin and biological activity of specific receptors for ghrelin and des-acyl ghrelin in human prostate neoplasms and related cell lines
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Cassoni P, Ghe C, Marrocco T, et al. Expression of ghrelin and biological activity of specific receptors for ghrelin and des-acyl ghrelin in human prostate neoplasms and related cell lines. Eur J Endocrinol 2004; 150:173-184.
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Ghrelin and des-acyl ghrelin inhibit cell death in cardiomyocytes and endothelial cells through ERK1/2 and PI 3-kinase/AKT
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Baldanzi G, Filigheddu N, Cutrupi S, et al. Ghrelin and des-acyl ghrelin inhibit cell death in cardiomyocytes and endothelial cells through ERK1/2 and PI 3-kinase/AKT. J Cell Biol 2002; 159:1029-1037.
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Halem HA, Taylor JE, Dong JZ, et al. Novel analogs of ghrelin: physiological and clinical implications. Eur J Endocrinol 2004; 151(suppl 1):S71-S75.
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Halem, H.A.1
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Transgenic mice overexpressing desacyl ghrelin show small phenotype
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Epub ahead of print
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Ariyasu H, Takaya K, Iwakura H, et al. Transgenic mice overexpressing desacyl ghrelin show small phenotype. Endocrinology 2004 [Epub ahead of print]. Transgenic mice overexpressing des-acyl ghrelin ubiquitously, with circulating levels increased 10- to 44-fold, showed reductions in body weight, axial length, insulin-like growth factor-1 levels, and the GH response to ghrelin, suggesting that very high levels of des-acyl ghrelin may block some of the actions of acylated ghrelin.
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(2004)
Endocrinology
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Ariyasu, H.1
Takaya, K.2
Iwakura, H.3
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16
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Non-acylated ghrelin counteracts the metabolic but not the neuroendocrine response to acylated ghrelin in humans
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Broglio F, Gottero C, Prodam F, et al. Non-acylated ghrelin counteracts the metabolic but not the neuroendocrine response to acylated ghrelin in humans. J Clin Endocrinol Metab 2004; 89:3062-3065. In humans, coinjection of des-acyl ghrelin blocked the effect of exogenous acylated ghrelin to increase glucose and decrease insulin levels, but had no effect on acylated ghrelin's stimulation of GH, ACTH, cortisol, or prolactin.
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J Clin Endocrinol Metab
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Broglio, F.1
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Ghrelin stimulation of growth hormone release and appetite is mediated through the growth hormone secretagogue receptor
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Sun Y, Wang P, Zheng H, et al. Ghrelin stimulation of growth hormone release and appetite is mediated through the growth hormone secretagogue receptor. Proc Natl Acad Sci U S A 2004; 101:4679-4684. Using GHS-R knockout mice, the authors prove that this receptor mediates the effects of ghrelin on food intake and GH. The mice display modest decreases in insulin-like growth factor-1 levels and body weight.
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(2004)
Proc Natl Acad Sci U S A
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Sun, Y.1
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Orexigenic action of peripheral ghrelin is mediated by neuropeptide Y and agouti-related protein
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Chen HY, Trumbauer ME, Chen AS, et al. Orexigenic action of peripheral ghrelin is mediated by neuropeptide Y and agouti-related protein. Endocrinology 2004; 145:2607-2612. This paper proves that NPY and Agrp mediate the orexigenic effects of ghrelin and GH secretagogues, demonstrating that these effects are absent in mice lacking both genes. The paper does not settle the question of whether hypothalamic NPY/Agrp neurons are primarily first-order targets of circulating ghrelin (acting as a hormone), targets of hypothalamic ghrelin (acting as a neuropeptide), or required components of an indirect pathway relaying ghrelin signaling from the vagus and/or hindbrain.
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Chen, H.Y.1
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Holst B, Cygankiewicz A, Jensen TH, et al. High constitutive signaling of the ghrelin receptor: identification of a potent inverse agonist. Mol Endocrinol 2003; 17:2201-2210. This paper shows that ghrelin can signal not only through the canonical Gq/phospholipase C pathway, but also via Gs/protein kinase A, and that the ghrelin receptor exhibits substantial ligand-independent constitutive activity.
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Mol Endocrinol
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Holst, B.1
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Holst B, Holliday ND, Bach A, et al. Common structural basis for constitutive activity of the ghrelin receptor family. J Biol Chem 2004 [Epub ahead of print]. The high constitutive activity of the ghrelin receptor is shown to exist in other members of this receptor family and to be determined by an aromatic cluster on the inner face of the extracellular ends of transmembrane segments VI and VII.
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J Biol Chem
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Holst, B.1
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Bednarek MA, Feighner SD, Pong SS, et al. Structure-function studies on the new growth hormone-releasing peptide, ghrelin: minimal sequence of ghrelin necessary for activation of growth hormone secretagogue receptor 1a. J Med Chem 2000; 43:4370-4376,
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Bednarek, M.A.1
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Ariyasu H, Takaya K, Tagami T, et al. Stomach is a major source of circulating ghrelin, and feeding state determines plasma ghrelin-like immunoreactivity levels in humans. J Clin Endocrinol Metab 2001; 86:4753-4758.
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Gnanapavan S, Kola B, Bustin SA, et al. The tissue distribution of the mRNA of ghrelin and subtypes of its receptor, GHS-R, in humans. J Clin Endocrinol Metab 2002; 87:2988-2991.
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Prado CL, Pugh-Bernard AE, Elghazi L, et al. Ghrelin cells replace insulin-producing beta cells in two mouse models of pancreas development. Proc Natl Acad Sci U S A 2004; 101:2924-2929. A novel, ghrelin-producing ε-cell type is identified in pancreatic islets and is shown to replace β cells when development of the latter is ablated by deleting key transcription factor genes.
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Proc Natl Acad Sci U S A
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Prado, C.L.1
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Cowley MA, Smith RG, Diano S, et al. The distribution and mechanism of action of ghrelin in the CNS demonstrates a novel hypothalamic circuit regulating energy homeostasis. Neuron 2003; 37:649-661. The authors provide a detailed description of immunoreactive ghrelin neurons, with cell bodies positioned between traditional hypothalamic nuclei, projecting to NPY/Agrp neurons as well as other cells involved in energy homeostasis. They also report that ghrelin mRNA can be detected in the brain using RT-PCR.
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Neuron
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Wortley KE, Anderson KD, Garcia K, et al. Genetic deletion of ghrelin does not decrease food intake but influences metabolic fuel preference. Proc Natl Acad Sci U S A 2004; 101:8227-8232. Ghrelin knockout mice show a very subtle phenotype, with no detectable GH abnormalities, but increased fat catabolism and a modest lean phenotype revealed on a high-fat diet.
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Proc Natl Acad Sci U S A
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Deletion of ghrelin impairs neither growth nor appetite
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Sun Y, Ahmed S, Smith RG: Deletion of ghrelin impairs neither growth nor appetite. Mol Cell Biol 2003; 23:7973-7981. These authors detect no apparent defects in energy homeostasis among ghrelin-deficient mice.
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Williams DL, Cummings DE, Grill HJ, Kaplan JM: Meal-related ghrelin suppression requires postgastric feedback. Endocrinology 2003; 144:2765-2767. Using rats fitted with pyloric cuffs, the authors show that nutrients constrained within the stomach do not affect ghrelin levels.
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Endocrinology
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J Clin Endocrinol Metab
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Ghrelin enhances appetite and increases food intake in humans
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Cummings DE, Frayo RS, Marmonier C, et al. Plasma ghrelin levels and hunger scores in humans initiating meals voluntarily without time- and food-related cues. Am J Physiol Endocrinol Metab 2004; 287:E297-E304. This work shows that preprandial surges of plasma ghrelin levels occur in people initiating meals spontaneously, in the absence of time- and food-related cues. Moreover, the temporal profile of ghrelin levels overlaps tightly with that of subjective hunger scores in this setting.
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Am J Physiol Endocrinol Metab
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Endocrinology
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