Effect of the Orally Active Growth Hormone Secretagogue MK-677 on Somatic Growth in Rats
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Purpose: Growth hormone secretagogues (GHSs) possess the ability to release growth hormone (GH) in the body. This study aimed to investigate the effects of MK-677, an orally active GHS, on somatic growth in rats. Materials and Methods: The serum levels of GH were measured after oral administration of MK-677 to confirm GH stimulatory effects. Body weight, body length, tibia length, epiphyseal plate width, and serum levels of insulin-like growth factor (IGF)-I were measured after oral administration of 4 mg/kg of MK-677 for 6 weeks to investigate growth-promoting effects. Results: Oral administration of MK-677 at 4 mg/kg increased peak GH concentrations by 1.8-fold, compared to baseline. However,oral administration of MK-677 for 6 weeks did not increase body growth or serum levels of IGF-I. At 6 weeks after treatment, the GH response to MK-677 was abolished. Pituitary GH mRNA and hypothalamic GH-releasing hormone mRNA, and GH secretagoguereceptor (GHSR) mRNA expression in the pituitary and hypothalamus did not differ between the control and treatment group. Somatostatin (SST) mRNA expression in the hypothalamus was markedly increased in the treatment group, whereas SST receptor (SSTR)-2 mRNA expression in the pituitary gland was decreased. Protein expression of hypothalamic GHSR, SST, and pituitary SSTR-2 showed patterns similar to those for mRNA expression. Conclusion: Our results suggest that prolonged administration of MK-677 in rats does not promote growth despite the GH stimulatoryeffect of MK-677, which may be related to increased expression of SST in the hypothalamus. Further studies are needed to overcome the observed desensitization to GHS.
Abstract
Purpose: Growth hormone secretagogues (GHSs) possess the ability to release growth hormone (GH) in the body. This study aimed to investigate the effects of MK-677, an orally active GHS, on somatic growth in rats. Materials and Methods: The serum levels of GH were measured after oral administration of MK-677 to confirm GH stimulatory effects. Body weight, body length, tibia length, epiphyseal plate width, and serum levels of insulin-like growth factor (IGF)-I were measured after oral administration of 4 mg/kg of MK-677 for 6 weeks to investigate growth-promoting effects. Results: Oral administration of MK-677 at 4 mg/kg increased peak GH concentrations by 1.8-fold, compared to baseline. However,oral administration of MK-677 for 6 weeks did not increase body growth or serum levels of IGF-I. At 6 weeks after treatment, the GH response to MK-677 was abolished. Pituitary GH mRNA and hypothalamic GH-releasing hormone mRNA, and GH secretagoguereceptor (GHSR) mRNA expression in the pituitary and hypothalamus did not differ between the control and treatment group. Somatostatin (SST) mRNA expression in the hypothalamus was markedly increased in the treatment group, whereas SST receptor (SSTR)-2 mRNA expression in the pituitary gland was decreased. Protein expression of hypothalamic GHSR, SST, and pituitary SSTR-2 showed patterns similar to those for mRNA expression. Conclusion: Our results suggest that prolonged administration of MK-677 in rats does not promote growth despite the GH stimulatoryeffect of MK-677, which may be related to increased expression of SST in the hypothalamus. Further studies are needed to overcome the observed desensitization to GHS.
참고문헌 (29)
- Chen K, "A novel non-peptidyl growth hormone secretagogue", Horm Res, 40, pp.109~115 (1993)
- Ghigo E, "Biological activities of growth hormone secretagogues in humans", Endocrine, 14, pp.87~93 (2001)
- Smith RG, "Growth hormone secretagogues : prospects and potential pitfalls", Best Prac Res Clin Endocrinol Metab, 18, pp.333~347 (2004)
- Patchett AA, "Design and biological activities of L-163,191 (MK-0677): a potent, orally active growth hormone secretagogue", Proc Natl Acad Sci U S A, 92, pp.7001~7005 (1995)
- Ghigo E, "Orally active growth hormone secretagogues : state of the art and clinical perspectives", Ann Med, 30, pp.159~168 (1998)
- Jacks T, "MK0677, a potent, novel, orally active growth hormone (GH) secretagogue: GH, insulin-like growth factor I, and other hormonal responses in beagles", Endocrinology, 137, pp.5284~5289 (1996)
- Schleim KD, "Increases in circulating insulin-like growth factor I levels by the oral growth hormone secretagogue MK-0677 in the beagle are dependent upon pituitary mediation", Endocrinology, 140, pp.1552~1558 (1999)
- Chapman IM, "Stimulation of the growth hormone(GH)-insulinlike growth factor I axis by daily oral administration of a GH secretogogue(MK-677)in healthy elderly subjects", J Clin Endocrinol Metab, 81, pp.4249~4257 (1996)
- Chapman IM, "Oral administration of growth hormone(GH)releasing peptide-mimetic MK-677 stimulates GH", insulin-like growth factor-I axis in selected GH-deficient adults, 1997, pp.82, 3455~3463
- Codner E, "Effects of oral administration of ibutamorenmesylate, a nonpeptide growth hormone secretagogue, on the growth hormone-insulin-like growth factor I axis in growth hormone-deficient children", Clin Pharmacol Ther, 70, pp.91~98 (2001)
- Svensson J, "Two-month treatment of obese subjects with the oral growth hormone (GH) secretagogue MK-677 increases GH secretion, fatfree mass, and energy expenditure", J Clin Endocrinol Metab, 83, pp.362~369 (1998)
- Svensson J, "Treatment with the oral growth hormone secretagogue MK677 increases markers of bone formation and bone resorption in obese young males", J Bone Miner Res, 13, pp.1158~1166 (1998)
- Murphy MG, "Oral administration of the growth hormone secretagogue MK677 increases markers of bone turnover in healthy and functionally impaired elderly adults. The MK-677 Study Group", J Bone Miner Res, 14, pp.1182~1188 (1999)
- Weise JM, "Telomeres and telomerase. A survey about methods and recent advances in cancer diagnostic and therapy", Histol Histopathol, 21, pp.1249~1261 (2006)
- Tuggle CK, "Control of growth hormone synthrsis", Domest Anim Endocrinol, 13, pp.1~33 (1996)
- Bowers CY, "Molecular endocrinology", pp.1977, Elsevier
- Ghigo E, "Growth hormone-releasing peptides", Eur J Endocrinol, 136, pp.445~460 (1997)
- Smith RG, "Development of growth hormone secretagogues", Endocr Rev, 26, pp.346~360 (2005)
- Roh SG, "Differential regulation of GHRH-receptor and GHS-receptor expression by long-term in vitro treatment of ovine pituitary cells with GHRP-2 and GHRH", Endocrine, 30, pp.55~62 (2006)
- Nagamine J, "Pharmacological profile of a new orally active growth hormone secretagogue, SM-130686", J Endocrinol, 171, pp.481~489 (2001)
- Klinger B, "Desensitization from long-term intranasal treatment with hexarelin does not interfere with the biological effects of this growth hormonereleasing peptide in short children", Eur J Endocrinol, 134, pp.716~719 (1996)
- Debell WK, "Growth hormone(GH)secretion during continuous infusion of GH-releasing peptide : partial response attenuation", J Clin Endocrinol Metab, 72, pp.1312~1316 (1991)
- Huhn WC, "Twenty-fourhour growth hormone(GH)-releasing peptide(GHRP)infusion enhances pulsatile GH secretion and specifically attenuates the response to a subsequent GHRP bolus", J Clin Endocrinol Metab, 76, pp.1202~1208 (1993)
- Massoud AF, "The effect of repeated administration of hexarelin, a growth hormone releasing peptide, and growth hormone releasing hormone on growth hormone responsivity", Clin Endocrinol (Oxf), 44, pp.555~562 (1996)
- Arvat E, "Mechanisms underlying the negative growth hormone(GH)autofeedback on the GH-releasing effect of hexarelin in man", Metabolism, 46, pp.83~88 (1997)
- Wells T, "Skeletal growth acceleration with growth hormone secretagogues in transgenic growth retarded rats : pattern-dependent effects and mechanisms of desensitization", J Neuroendocrinol, 13, pp.496~504 (2001)
- McDowell RS, "Growth hormone secretagogues: characterization, efficacy, and minimal bioactive conformation", Proc Natl Acad Sci U S A, 92, pp.11165~11169 (1995)
- Bennett PA, "Hypothalamic growth hormone secretagogue-receptor (GHS-R) expression is regulated by growth hormone in the rat", Endocrinology, 138, pp.4552~4557 (1997)
- Bailey AR, "Chronic central infusion of growth hormone secretagogues : effects on fos expression and peptide gene expression in the rat arcuate nucleus", Neuroendocrinology, 70, pp.83~92 (1999)