OC19 (Will also be presented as a Steroids poster)

Endocrine Abstracts (2002) 4 OC19

Adrenal agouti related protein (Agrp) expression is regulated by glucocorticoids and Agrp via the MC3-R or MC4-R may have an inhibitory paracrine role on corticosterone secretion

WS Dhillo1, CJ Small1, JV Gardiner1, GA Bewick1, EJ Whitworth2, PH Jethwa1, LJ Seal1, MA Ghatei1, JP Hinson2 & SR Bloom1

1Department of Endocrinology, Imperial College Faculty of Medicine, London, UK; 2Molecular Signaling Group, Clinical Sciences Centre, Barts and the London, Queen Mary School of Medicine & Dentistry, London, UK.

(Will also be presented as a Steroids poster)

Alpha-melanocyte-stimulating-hormone (alpha-MSH) is an agonist at the melanocortin-3-receptor (MC3-R) and the MC4-R. It stimulates corticosterone release from rat adrenal glomerulosa cells. The receptor mediating this effect is unidentified since only MC2-R and MC5-R have been reported to be expressed in the adrenal and alpha-MSH is a poor agonist at these receptors. Agrp, an endogenous antagonist at the MC3-R and MC4-R is expressed in the adrenal gland. We investigated the role of adrenal Agrp. MC3-R and MC4-R expression was detected in rat adrenal glands using RT-PCR with nested primers. Using dispersed rat adrenal glomerulosa cells, Agrp's effects on alpha-MSH-induced corticosterone release was investigated. alpha-MSH caused a dose-dependant increase in corticosterone release from adrenal glomerulosa cells in agreement with previous observations (corticosterone release: basal 100plus/minus4%, alpha-MSH10-8M 142plus/minus7% (p<0.01 vs. basal), alpha-MSH10-7M 241plus/minus22% (p<0.001 vs. basal), alpha-MSH10-6M 246plus/minus12% (p<0.001 vs. basal). Agrp(83-132) administered alone did not affect corticosterone release from glomerulosa cells (corticosterone release: basal 100plus/minus4%, Agrp(83-132)10-6M 105plus/minus13% (p=non-significant vs. basal). However, co-administration of the same concentration of alpha-MSH and Agrp(83-132) attenuated alpha-MSH-induced stimulation of corticosterone release from glomerulosa cells (corticosterone release: alpha-MSH10-8MplusAgrp(83-132)10-8M 122plus/minus7% (p=non-significant vs. alpha-MSH10-8M), alpha-MSH10-7MplusAgrp(83-132)10-7M 155plus/minus8% (p=<0.001 vs. alpha-MSH10-7M), alpha-MSH10-6MplusAgrp(83-132)10-6M 160plus/minus5% (p<0.001 vs. alpha-MSH10-6M). To investigate glucocorticoid feedback, adrenal Agrp expression was measured in rats treated with dexamethasone in their drinking water (1mg/ml) for 10 days and compared to controls. Adrenal Agrp mRNA was increased to 176plus/minus8% after dexamethasone treatment compared to controls (100plus/minus9%, p<0.0001, n=10). In conclusion this is the first report of MC3-R and MC4-R expression in the rat adrenal gland. Our findings show that adrenal Agrp mRNA is regulated by glucocorticoids and that Agrp may via the MC3-R or MC4-R have a novel inhibitory paracrine role, blocking alpha-MSH-induced corticosterone secretion.