Endocrine Abstracts (2002) 3 OC42

A possible role for the melanocortin 3 receptor in the control of the hypothalamo-pituitary gonadal axis

S Stanley1, S Davies1, C Small1, J Gardiner1, MA Ghatei1, D Smith2 & S R Bloom1

1Endocrine Unit, Division of Medicine, ICSMT, Hammersmith Campus, Du Cane Road, London, UK; 2AstraZeneca, CVGI, Alderley Park, Macclesfield, Cheshire, UK.

The hypothalamic melanocortin 4 receptor, its endogenous agonist, alpha melanocyte stimulating hormone and the endogenous antagonist, Agouti related peptide (Agrp) regulate energy homeostasis. However, the physiological role of the hypothalamic melanocortin receptor, MC3-R and its agonist, gamma MSH are currently unknown. We have previously shown that the MC3/4 agonist, a-MSH has no effect on GnRH release from hypothalamic explants and does not influence plasma gonadotrophins following third ventricle injection. In this study we demonstrate that activation of MC3-R modulates the hypothalamo-pituitary gonadal axis.

Gamma MSH stimulated intracellular cAMP accumulation and GnRH secretion in a dose-dependent manner, in the immortalised GnRH clonal cell lines, GT1-7 and NLT. Agrp blocked this action. RT-PCR demonstrated the presence of MC3-R mRNA in GT1-7 cells. Gamma MSH stimulated GnRH release from medial basal hypothalamic explants in a dose dependent manner. Injection of the MC3/4 agonist, a-MSH, into the medial preoptic area significantly increased 1 hour food intake but was without significant effect on plasma gonadotrophins. However, following injection of g-MSH into the medial preoptic area, at a dose that did not influence food intake, there was a significant increase in plasma gonadotrophins.

We have demonstrated MC3-R activation to significantly increase GnRH release from clonal cell lines and hypothalamic explants and to stimulate plasma LH in vivo. This suggests that MC3-R may play a role in the control of the hypothalamo-pituitary gonadal axis

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