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      Effects of Combined Long-Term Treatment with a Growth Hormone-Releasing Hormone Analogue and a Growth Hormone Secretagogue in the Growth Hormone-Releasing Hormone Knock Out Mouse

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          GH secretagogues (GHS) are synthetic ghrelin receptor agonists that stimulate GH secretion. It is not clear whether they act predominantly by stimulating the secretion of hypothalamic growth hormone-releasing hormone (GHRH), or directly on the somatotrope cells. In addition, it is not known whether combined treatment with GHRH and GHS has synergistic effects on growth. To address these questions, we used the GH-deficient GHRH knock out (GHRHKO) mouse model, which has severe somatotrope cell hypoplasia. We treated GHRHKO mice for 5 weeks (from week 1 to week 6 of age) with the GHRH analogue JI-38 alone, or in combination with a GHS (GHRP-2), and at the end of the treatment we examined their response to an acute stimulus with GHRP-2 or GHRP-2 plus JI-38. We used placebo-treated GHRHKO mice and animals heterozygous for the GHRHKO allele as controls. Animals treated with JI-38+GHRP-2 reached higher body length and weight than animals treated with JI-38 alone. All the animals receiving JI-38 (with or without GHRP-2) showed similar correction of somatotrope cell hypoplasia. None of the GHRHKO animals showed a serum GH response to the acute stimulation with GHRP-2 alone, while both treated groups responded to the combined test with JI-38 + GHRP-2. These data demonstrate that in GHRHKO mice, GHRP-2 has a growth-stimulating effect that augments the response induced by JI-38. In addition, the presence of GHRH seems necessary for the stimulation of GH secretion by GHRP-2.

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          Most cited references 21

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          A receptor in pituitary and hypothalamus that functions in growth hormone release.

          Small synthetic molecules termed growth hormone secretagogues (GHSs) act on the pituitary gland and the hypothalamus to stimulate and amplify pulsatile growth hormone (GH) release. A heterotrimeric GTP-binding protein (G protein)-coupled receptor (GPC-R) of the pituitary and arcuate ventro-medial and infundibular hypothalamus of swine and humans was cloned and was shown to be the target of the GHSs. On the basis of its pharmacological and molecular characterization, this GPC-R defines a neuroendocrine pathway for the control of pulsatile GH release and supports the notion that the GHSs mimic an undiscovered hormone.
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            Normal growth and development in the absence of hepatic insulin-like growth factor I.

            The somatomedin hypothesis proposed that insulin-like growth factor I (IGF-I) was a hepatically derived circulating mediator of growth hormone and is a crucial factor for postnatal growth and development. To reassess this hypothesis, we have used the Cre/loxP recombination system to delete the igf1 gene exclusively in the liver. igf1 gene deletion in the liver abrogated expression of igf1 mRNA and caused a dramatic reduction in circulating IGF-I levels. However, growth as determined by body weight, body length, and femoral length did not differ from wild-type littermates. Although our model proves that hepatic IGF-I is indeed the major contributor to circulating IGF-I levels in mice it challenges the concept that circulating IGF-I is crucial for normal postnatal growth. Rather, our model provides direct evidence for the importance of the autocrine/paracrine role of IGF-I.
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              Deletion of ghrelin impairs neither growth nor appetite.

              Pharmacological studies show that ghrelin stimulates growth hormone release, appetite, and fat deposition, but ghrelin's physiological role in energy homeostasis has not been established. Ghrelin was also proposed to regulate leptin and insulin release and to be important for the normal function of stomach, heart, kidney, lung, testis, and placenta. To help determine a definable physiological role for ghrelin, we generated ghrelin-null mice. In contrast to predictions made from the pharmacology of ghrelin, ghrelin-null mice are not anorexic dwarfs; their size, growth rate, food intake, body composition, reproduction, gross behavior, and tissue pathology are indistinguishable from wild-type littermates. Fasting produces identical decreases in serum leptin and insulin in null and wild-type mice. Ghrelin-null mice display normal responses to starvation and diet-induced obesity. As in wild-type mice, the administration of exogenous ghrelin stimulates appetite in null mice. Our data show that ghrelin is not critically required for viability, fertility, growth, appetite, bone density, and fat deposition and not likely to be a direct regulator of leptin and insulin. Therefore, antagonists of ghrelin are unlikely to have broad utility as antiobesity agents.

                Author and article information

                S. Karger AG
                May 2006
                08 May 2006
                : 82
                : 3-4
                : 198-207
                aDepartment of Medicine, Division of Endocrinology, and the Ilyssa Center for Molecular and Cellular Endocrinology, Johns Hopkins University School of Medicine, Baltimore, Md.; bEndocrine, Polypeptide and Cancer Institute, Veterans Affairs Medical Centers of New Orleans, La. and Miami, Fla., and Tulane University, New Orleans, La.; cDivision of Endocrinology and Metabolism, Department of Internal Medicine, Tulane University Medical Center, New Orleans, La., and dNational Hormone and Peptide Program Harbor UCLA Medical Center, Torrance, Calif., USA
                92520 Neuroendocrinology 2005;82:198–207
                © 2005 S. Karger AG, Basel

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                Page count
                Figures: 7, References: 31, Pages: 10
                Original Paper


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