Yonsei Med J.  2018 Dec;59(10):1174-1180. 10.3349/ymj.2018.59.10.1174.

Effect of the Orally Active Growth Hormone Secretagogue MK-677 on Somatic Growth in Rats

• Lee J
• Kwon A
• Chae HW
• Lee WJ
• Kim TH
• Kim HS

• KMID: 2426331
• DOI: http://doi.org/10.3349/ymj.2018.59.10.1174

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 secretagogue receptor (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 stimulatory effect 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.

Keyword

Growth hormone-releasing peptide; oral administration; growth; rats; somatostatin

MeSH Terms

Administration, Oral
Animals
Body Weight
Growth Hormone*
Growth Plate
Hypothalamus
Insulin-Like Growth Factor I
Pituitary Gland
Rats*
RNA, Messenger
Somatostatin
Tibia
Growth Hormone
Insulin-Like Growth Factor I
RNA, Messenger
Somatostatin

Figure

• 

  Fig. 1 Serum growth hormone (GH) levels after oral administration of MK-677. (A) Dose range study at baseline. MK-677 at 0, 2, and 4 mg/kg were administered. (B) MK-677 at 4 mg/kg was administered in rats at 6 weeks after treatment of MK-677. n=4/treatment. *p<0.001.

• 

  Fig. 2 Efficacy of oral administration of MK-677 for 6 weeks. (A) Body weight, (B) body length, and (C) width of tibia growth plate (arrows) detected by hematoxylin-eosin staining (×40). n=4/treatment.

• 

  Fig. 3 Serum insulin-like growth factor (IGF)-I levels during oral administration of MK-677 for 6 weeks. n=4/treatment.

• 

  Fig. 4 Effect of MK-677 on mRNA and protein expression of growth hormone (GH), GH-releasing hormone (GHRH), GH secretagogue receptor (GHSR), somatostatin (SST), somatostatin receptor (SSTR)-2, and SSTR-5 in the hypothalamus or pituitary gland. (A) Pituitary GH mRNA level, (B) hypothalamic GHRH mRNA level, (C) hypothalamic and pituitary GHSR mRNA level, (D) hypothalamic SST mRNA level, (E) pituitary SSTR-2 mRNA level, (F) pituitary SSTR-5 mRNA level, and (G) protein levels of GHSR and SST in the hypothalamus and SSTR-2 and SSTR-5 in the pituitary gland. n=4/treatment. *p<0.01 or †p<0.001.

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