Effects of Ghrelin Administration After Total Gastrectomy: A Prospective, Randomized, Placebo-Controlled Phase II Study

Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Osaka, Japan.
Gastroenterology (Impact Factor: 16.72). 04/2010; 138(4):1312-20. DOI: 10.1053/j.gastro.2009.12.058
Source: PubMed


Body weight (BW) loss and reduction of blood ghrelin level are commonly observed after total gastrectomy (TG). A prospective study was designed to elucidate whether exogenous ghrelin administration prevents postoperative BW loss by improving appetite and oral food intake in patients with gastric cancer after undergoing TG.
In this randomized phase II study, 21 patients undergoing TG were assigned to a ghrelin (11 patients) or placebo group (10 patients). They received intravenous infusion of synthetic human ghrelin (3 microg/kg) or saline twice daily for 10 days after starting oral food intake following surgery. Changes in BW, appetite visual analog scale score, food intake calories, body composition, basal metabolic rate, and various blood test results were evaluated.
Excluding one patient who developed profound diaphoresis during ghrelin infusion, 20 patients completed the study. Food intake and appetite were significantly higher with ghrelin compared with placebo (average, 13.8 vs 10.4 kcal/kg/day [P = .030] and 5.7 vs 3.9 cm [P = .032], respectively). BW loss was significantly lower in the ghrelin than in the placebo group (-1.4% vs -3.7%; P = .044). Fat mass, lean body mass, and basal metabolic rate decreased significantly in the placebo group; however, the reductions in lean body mass and basal metabolic rate were not significant in the ghrelin group, although that of fat mass was significant.
Short-term administration of synthetic ghrelin was safe and successfully lessened postoperative BW loss and improved appetite and food intake after TG.

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    • "Ghrelin, an orexigenic hormone secreted primarily from the stomach, is an endogenous ligand for the growth hormone secretagogue receptor (GHS-R1a; also called 'ghrelin receptor') (Kojima et al., 1999). Ghrelin stimulates food intake and body weight gain in both humans and rodents (Wren et al., 2001; Druce et al., 2005; Adachi et al., 2010), by up-regulating neuropeptide Y (NPY) and agouti-related peptide (AgRP) expressions (Nakazato et al., 2001), activating NPY/ AgRP neurons (Cowley et al., 2003), and inhibiting proopiomelanocortin (POMC) neurons (Cowley et al., 2003) in the arcuate nucleus (Arc) of the hypothalamus, where GHS-R1a is highly expressed (Guan et al., 1997; Zigman et al., 2006; Harrold et al., 2008). "
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    ABSTRACT: Excessive weight gain is a major metabolic side effect of second-generation antipsychotics (SGAs) in the treatment of schizophrenia. Ghrelin is an orexigenic hormone secreted mainly from the stomach, which can induce weight gain and hyperphagia through regulating neuropeptides at the hypothalamus. Accumulating evidence implicates a relationship between ghrelin signalling and SGA-induced hyperphagia and weight gain. We report that olanzapine (a SGA with high weight gain liability) potently and time-dependently up-regulate ghrelin and ghrelin signalling, leading to hyperphagia and weight gain in female Sprague-Dawley rats, an action reversed by i.c.v. injection of a ghrelin receptor (GHS-R1a) antagonist. These findings indicate a crucial role of ghrelin signalling in hyperphagia induced by olanzapine, supporting the notion that GHS-R1a antagonist may be useful for pharmacological treatment of SGA-induced weight gain resulted from hyperphagia.
    The International Journal of Neuropsychopharmacology 01/2014; 17(05):1-12. DOI:10.1017/S1461145713001697 · 4.01 Impact Factor
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    • "This study thus emphasizes that ghrelin's effects on body mass may be mediated without increased food intake or increases in IGF-1. Finally, treatment with ghrelin following removal of gastric cancer decreased the loss of body weight, though this may have been partly due to replacement of normal endogenous ghrelin secretion (Adachi et al. 2010). "
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    ABSTRACT: Cachexia is a syndrome of wasting and anorexia that worsens the prognosis of many chronic diseases including cancer, chronic kidney disease, chronic heart disease and chronic obstructive pulmonary disease. Properties of the orexigenic hormone ghrelin-including appetite-stimulation, weight-gain production and increased cardiac output make it a logical treatment for cachexia. While endogenous ghrelin levels are increased in the setting of cachexia, treatment with ghrelin and other GHSR-1a agonists in animal models of cachexia and in humans with cachexia has demonstrated consistent effects of increased appetite and improved weight gain. These positive effects occur in multiple underlying diseases associated with cachexia and appear to be sustained over treatment duration of up to 12 weeks. The mechanism of action in producing these effects is likely related to stimulation of central appetite centers such as the central melanocortin system and to increased growth hormone release, though ghrelin's effects may also relate to decreased systemic inflammation and other direct and indirect actions. Questions regarding the long-term safety of ghrelin treatment are still unanswered, as is the important question of whether successful treatment of cachexia will improve the prognosis of the underlying disease itself.
    Molecular and Cellular Endocrinology 02/2011; 340(1):97-105. DOI:10.1016/j.mce.2011.02.012 · 4.41 Impact Factor
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    • "Ghrelin treatment has also been applied to other causes of anorexia, sarcopenia, and emaciation, including anorexia nervosa [87], functional dyspepsia [88], aging [21], post-gastrectomy anorexia [22], esophagectomy [23], chemotherapy [89, 90], and thermal injury [91]. In addition, the effects of ghrelin mimetics were examined in age-dependent sarcopenia [21, 32]. "
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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.
    12/2010; 1(2):169-176. DOI:10.1007/s13539-010-0011-5
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