Glucocorticoid Regulation of Hypothalamic Proopiomelanocortin

Abstract

Although glucocorticoids clearly inhibit proopiomelanocortin (POMC) gene transcription and peptide synthesis in the anterior pituitary, the effects of glucocorticoids on POMC in the hypothalamus are still unclear, even though most POMC neurons in the arcuate nucleus are known to have glucocorticoid receptors. In this study, we have therefore examined the effect of adrenalectomy (ADX) and glucocorticoid replacement on POMC mRNA and peptide (β-EP and α-MSH) levels in the medial basal hypothalamus (MBH) of the rat. POMC mRNA was measured by a sensitive solution hybridization S1 nuclease protection assay, and β-EP and α-MSH were measured by radioimmunoassay. In a first experiment, animals were studied 7 days after ADX or sham surgery. The mean POMC mRNA concentration was 1.01 ± 0.14 pg/µg RNA (means ± SE) in the intact animals and decreased to 0.55 ± 0.07 pg/µg RNA in the MBH of the ADX animals (p < 0.005). β-EP levels decreased in parallel from 4.30 ± 0.18 to 3.36 ± 0.11 ng/mg protein (p < 0.001); α-MSH levels decreased from 3.25 ± 0.21 to 2.41 ± 0.16 ng/mg protein (p < 0.005). In a second experiment, animals were studied 2 weeks after ADX. POMC mRNA levels again fell significantly from 1.15 ± 0.19 pg/µg RNA in the intact animals to 0.51 ± 0.06 pg/µg in the ADX animals (p < 0.01). β-EP levels fell also, but this was not significant. In a third experiment, all animals underwent ADX, and half of them received daily subcutaneous injections of dexamethasone (20 µg). Nine days after ADX, the mean POMC mRNA level was 0.66 ± 0.04 pg/µg RNA in the saline-treated animals and increased to 0.98 ± 0.08 pg/µg RNA in the dexamethasone-treated animals (p < 0.005). A parallel increase in β-EP levels from 5.03 ± 0.41 to 6.01 ± 0.53 ng/mg protein was also noted, but this was not statistically significant. We conclude that POMC gene expression is significantly inhibited in the MBH at 1 and 2 weeks after ADX. This effect was reversed by glucocorticoid replacement with doses close to the physiological range. The parallel changes in POMC mRNA and peptide levels strongly suggest that, in contrast to the anterior pituitary, low doses of glucocorticoids stimulate the biosynthesis of POMC in the MBH of ADX rats.