| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2002: ¥1,700,000 (Direct Cost: ¥1,700,000)
Fiscal Year 2001: ¥1,800,000 (Direct Cost: ¥1,800,000)
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| Research Abstract |
Ghrelin, an endogenous ligand for the growth hormone secretagogue receptor (GHS-R), was originally purified from the rat stomach. Consistent with the central actions of GHSs, ghrelin-immunoreactive cells were shown to be located in the hypotnalamic arcuate nucleus (ARC) as well as the stomach. In this study we found several new insights concerning the central action of ghrelin.
1. Chronic central administration of rat ghrelin significantly increased food intake and body weight. However, it did not affect plasma insulin, glucose, leptin, or GH concentrations. We also found that it increased both neuropeptide Y (NPY) mRNA levels and AGRP mRNA levels in the ARC.
2. The expression of the ghrelin gene in the pituitary is developmentally regulated and the infusion of GHRH in freely-moving adult male rats resulted in a 1.9-fold increase in ghrelin mRNA levels.
3. We have created transgenic (Tg) rats expressing an antisense GHS-R mRNA under the control of the promoter for tyrosine hydroxylase, thus selectively attenuating GHS-R protein expression in the ARC. Tg rats had lower body weight and less adipose tissue than did control rats. Daily food intake was reduced, and the stimulatory effect of GHS treatment on feeding was abolished in Tg rats. GH secretion and plasma IGF-I levels were reduced in female Tg rats.
4. Ghrelin stimulates GH secretion but not food intake in ARC ablated rats that were neonatally treated with monosodium glutamate.
5. To investigate the role of ghrelin in the hyperphagic response to uncontrolled diabetes, adult male rats were studied after administration of streptozotocin. Plasma ghrelin concentrations in diabetic rats were significantly higher than in control rats and were normalized by insulin treatment. The hyperphagia was partially reversed by the administration of a ghrelin-receptor antagonist.
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