Ghrelin Increases Neuropeptide Y and Agouti-Related Peptide Gene Expression in the Arcuate Nucleus in Rat Hypothalamic Organotypic Cultures

Aug 5, 2006Endocrinology

Ghrelin raises hunger-related gene activity in the brain's appetite control area in rat brain tissue cultures

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Abstract

Ghrelin significantly increased NPY and AGRP mRNA expression in hypothalamic cultures in the presence of glucocorticoids.

Ghrelin stimulates the expression of two peptides, NPY and AGRP, which are associated with increased food intake.
This stimulation occurs in hypothalamic organotypic cultures only when glucocorticoids are present.
In vivo, ghrelin injection increases NPY and AGRP expression in the arcuate nucleus of sham-operated rats but not in adrenalectomized rats.
The effects of ghrelin on gene expression do not require action potentials, as shown by the lack of effect from a sodium channel blocker.
Inhibition of protein translation with cycloheximide abolishes ghrelin's stimulatory effects, indicating that new protein synthesis is necessary.

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Ghrelin, which was identified from the rat stomach, is a potent stimulant for food intake. Several lines of evidence suggest that the orexigenic action of ghrelin is mediated via the neuropeptide Y (NPY) neurons in the arcuate nucleus, although the detailed mechanisms by which ghrelin stimulates NPY neurons are not clear. In this study, we examined the gene regulation of NPY and agouti-related peptide (AGRP), another orexigenic peptide synthesized in the NPY neurons, in the arcuate nucleus by ghrelin in hypothalamic organotypic cultures. Incubation of the hypothalamic explants with ghrelin significantly increased NPY and AGRP mRNA expression in the presence, but not absence, of dexamethasone. Glucocorticoids were also necessary for ghrelin action in vivo because an intracerebroventricular injection of ghrelin significantly increased NPY and AGRP mRNA expression in the arcuate nucleus only in sham-operated, but not in adrenalectomized rats. The stimulatory effects of ghrelin on gene expression were not blocked by a sodium channel blocker tetrodotoxin in the organotypic cultures. Ghrelin also increased NPY heteronuclear (hn) RNA expression, the first transcript that has been used as an indicator for gene transcription. The stimulatory effects of ghrelin on NPY gene expression were abolished in the presence of cycloheximide, which blocks translation, suggesting that de novo protein synthesis is required for ghrelin action. These data suggest that ghrelin stimulates NPY and AGRP gene expression independently of action potentials only in the presence of glucocorticoids. Furthermore, our data demonstrate stimulatory action of ghrelin on NPY gene transcription, which requires de novo protein synthesis.

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Ghrelin Increases Neuropeptide Y and Agouti-Related Peptide Gene Expression in the Arcuate Nucleus in Rat Hypothalamic Organotypic Cultures

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