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      Ghrelin for cachexia

      review-article
      1 , , 2
      Journal of Cachexia, Sarcopenia and Muscle
      Springer-Verlag
      Anorexia, Sarcopenia, Catabolism, Anabolism, Growth hormone, GHS

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          Abstract

          Ghrelin, a natural ligand for the growth hormone (GH)-secretagogue receptor, is primarily produced in the stomach. Administration of ghrelin stimulates food intake and GH secretion in both animals and humans. Ghrelin is the only circulating hormone known to stimulate appetite in humans. As GH is an anabolic hormone, protein stores are spared at the expense of fat during conditions of caloric restriction. Ghrelin also inhibits the production of anorectic proinflammatory cytokines. Thus, ghrelin exhibits anti-cachectic actions via both GH-dependent and -independent mechanisms. Several studies are evaluating the efficacy of ghrelin in the treatment of cachexia caused by a variety of diseases, including congestive heart failure, chronic obstructive pulmonary disease, cancer, and end-stage renal disease. These studies will hopefully lead to the development of novel clinical applications for ghrelin in the future. These studies have also facilitated a better understanding of the molecular basis of the anti-catabolic effects of ghrelin. This review summarizes the recent advances in this area of research.

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          Most cited references68

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          Regulation of muscle mass by growth hormone and IGF-I.

          Growth hormone (GH) is widely used as a performance-enhancing drug. One of its best-characterized effects is increasing levels of circulating insulin-like growth factor I (IGF-I), which is primarily of hepatic origin. It also induces synthesis of IGF-I in most non-hepatic tissues. The effects of GH in promoting postnatal body growth are IGF-I dependent, but IGF-I-independent functions are beginning to be elucidated. Although benefits of GH administration have been reported for those who suffer from GH deficiency, there is currently very little evidence to support an anabolic role for supraphysiological levels of systemic GH or IGF-I in skeletal muscle of healthy individuals. There may be other performance-enhancing effects of GH. In contrast, the hypertrophic effects of muscle-specific IGF-I infusion are well documented in animal models and muscle cell culture systems. Studies examining the molecular responses to hypertrophic stimuli in animals and humans frequently cite upregulation of IGF-I messenger RNA or immunoreactivity. The circulatory/systemic (endocrine) and local (autocrine/paracrine) effects of GH and IGF-I may have distinct effects on muscle mass regulation.
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            Ghrelin inhibits leptin- and activation-induced proinflammatory cytokine expression by human monocytes and T cells.

            Ghrelin, a recently described endogenous ligand for the growth hormone secretagogue receptor (GHS-R), is produced by stomach cells and is a potent circulating orexigen, controlling energy expenditure, adiposity, and growth hormone secretion. However, the functional role of ghrelin in regulation of immune responses remains undefined. Here we report that GHS-R and ghrelin are expressed in human T lymphocytes and monocytes, where ghrelin acts via GHS-R to specifically inhibit the expression of proinflammatory anorectic cytokines such as IL-1beta, IL-6, and TNF-alpha. Ghrelin led to a dose-dependent inhibition of leptin-induced cytokine expression, while leptin upregulated GHS-R expression on human T lymphocytes. These data suggest the existence of a reciprocal regulatory network by which ghrelin and leptin control immune cell activation and inflammation. Moreover, ghrelin also exerts potent anti-inflammatory effects and attenuates endotoxin-induced anorexia in a murine endotoxemia model. We believe this to be the first report demonstrating that ghrelin functions as a key signal, coupling the metabolic axis to the immune system, and supporting the potential use of ghrelin and GHS-R agonists in the management of disease-associated cachexia.
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              The role of the gastric afferent vagal nerve in ghrelin-induced feeding and growth hormone secretion in rats.

              Visceral sensory information is transmitted to the brain through the afferent vagus nerve. Ghrelin, a peptide primarily produced in the stomach, stimulates both feeding and growth hormone (GH) secretion. How stomach-derived ghrelin exerts these central actions is still unknown. Here we determined the role of the gastric afferent vagal nerve in ghrelin's functions. Food intake and GH secretion were examined after an administration of ghrelin intravenously (IV) to rats with vagotomy or perivagal application of capsaicin, a specific afferent neurotoxin. We investigated Fos expression in neuropeptide Y (NPY)-producing and growth hormone-releasing hormone (GHRH)-producing neurons by immunohistochemistry after administration IV of ghrelin to these rats. The presence of the ghrelin receptor in vagal afferent neurons was assessed by using reverse-transcription polymerase chain reaction and in situ hybridization histochemistry. A binding study on the vagus nerve by (125)I-ghrelin was performed to determine the transport of the ghrelin receptor from vagus afferent neurons to the periphery. We recorded the electric discharge of gastric vagal afferent induced by ghrelin and compared it with that by cholecystokinin (CCK), an anorectic gut peptide. Blockade of the gastric vagal afferent abolished ghrelin-induced feeding, GH secretion, and activation of NPY-producing and GHRH-producing neurons. Ghrelin receptors were synthesized in vagal afferent neurons and transported to the afferent terminals. Ghrelin suppressed firing of the vagal afferent, whereas CCK stimulated it. This study indicated that the gastric vagal afferent is the major pathway conveying ghrelin's signals for starvation and GH secretion to the brain.
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                Author and article information

                Contributors
                +81-75-7514720 , +81-75-7514731 , akamizu@kuhp.kyoto-u.ac.jp
                Journal
                J Cachexia Sarcopenia Muscle
                Journal of Cachexia, Sarcopenia and Muscle
                Springer-Verlag (Berlin/Heidelberg )
                2190-5991
                2190-6009
                17 December 2010
                17 December 2010
                December 2010
                : 1
                : 2
                : 169-176
                Affiliations
                [1 ]Ghrelin Research Project, Department of Experimental Therapeutics, Translational Research Center, Faculty of Medicine, Kyoto University, 54 Shogoin-Kawaharacho, Sakyo-ku, Kyoto, 606-8507 Japan
                [2 ]National Cerebral and Cardiovascular Center Research Institute, Osaka, 565-8565 Japan
                Article
                11
                10.1007/s13539-010-0011-5
                3060649
                21475698
                0e028362-e32b-4019-85f3-47eea4a67548
                © The Author(s) 2010
                History
                : 30 April 2010
                : 2 November 2010
                Categories
                Review
                Custom metadata
                © Springer-Verlag 2010

                Orthopedics
                anabolism,ghs,sarcopenia,growth hormone,anorexia,catabolism
                Orthopedics
                anabolism, ghs, sarcopenia, growth hormone, anorexia, catabolism

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