| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2000: ¥1,700,000 (Direct Cost: ¥1,700,000)
Fiscal Year 1999: ¥1,800,000 (Direct Cost: ¥1,800,000)
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| Research Abstract |
Growth hormone secretagogues (GHSs) are synthetic peptide and nonpeptide compounds that stimulate the release of GH acting on the hypothalamus and pituitary. The GHS receptor (GHS-R) has been cloned, and the existence of the endogenous ligand has been assumed. Recently, an endogenous peptide ligand for the GHS receptor, ghrelin, was purified from the rat stomach and subsequently cloned by Kangawa et.al. However, the physiological significance of ghrelin is not clear. In this study, we found several new insights concerning GHS/GHS-R axis.
1. GHRH infusion resulted in a 2.5-fold increase in GHS-R mRNA levels of the rat pituitary. GHRH does not induce GHS-R mRNA levels of primary cell cultures from normal rat pituitaries in vitro, suggests that other systemic or central factors are necessary for GHRH-initiated augmentation of GHS-R synthesis.
2. GHS infusion reduced GHS-R mRNA levels significantly. This phenomenon was reproduced by adding GHS to the rat primary pituitary cell cultures, suggesting that the action of GHS on pituitary GHS-R mRNA levels is, at least in part, due to a direct interaction with the pituitary. These studies also indicate that GHS, like GHRH, can rapidly downregulate its own receptor message.
3. We examined the effect of glucocorticoids and thyroid hormones on pituitary GHS-R mRNA levels. We found that glucocorticoids directly increase pituitary GHS-R mRNA levels by stimulating GHS-R gene transcription, whereas T3 increases GHS-R mRNA levels in vitro by increasing message stability.
4. We found that central ghrelin administration increased hypothalamic Agouli-related protein (AGRP) mRNA levels as well as increased food intakes. On the other hand, 1μg of rat ghrelin central administration did not alter the episodic GH release of freely moving adult male rats. Thus ghrelin has an alternative role in stimulating food intake via an increase of AGRP than GH release from the pituitary.
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