A Circadian Clock Entrained by Melatonin Is Ticking in the Rat Fetal Adrenal

Mar 3, 2011Endocrinology

A daily biological clock controlled by melatonin is active in the rat fetal adrenal gland

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Abstract

The rat fetal adrenal gland exhibits circadian rhythms in gene expression and hormone levels.

Circadian expression of Bmal-1 and Per-2 in the rat fetal adrenal gland occurs in antiphase, with peaks at 2200 and 1300 hours, respectively.
Corticosterone levels and StAR expression also show a circadian rhythm, peaking at 0600 hours.
In culture, the oscillatory expression of key genes persisted for 48 hours, although the antiphase relationship between Per-2 and Bmal-1 was disrupted.
A melatonin pulse shifted the timing of gene expression peaks and restored the antiphase relationship between Per-2 and Bmal-1.
These findings suggest that the fetal adrenal gland functions as a peripheral clock that may be regulated by maternal melatonin.

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The adrenal gland in the adult is a peripheral circadian clock involved in the coordination of energy intake and expenditure, required for adaptation to the external environment. During fetal life, a peripheral circadian clock is present in the nonhuman primate adrenal gland. Whether this extends to the fetal adrenal gland like the rat is unknown. Here we explored in vivo and in vitro whether the rat fetal adrenal is a peripheral circadian clock entrained by melatonin. We measured the 24-h changes in adrenal content of corticosterone and in the expression of clock genes Per-2 and Bmal-1 and of steroidogenic acute regulatory protein (StAR), Mt1 melatonin receptor, and early growth response protein 1 (Egr-1) expression. In culture, we explored whether oscillatory expression of these genes persisted during 48 h and the effect of a 4-h melatonin pulse on their expression. In vivo, the rat fetal adrenal gland showed circadian expression of Bmal-1 and Per-2 in antiphase (acrophases at 2200 and 1300 h, respectively) as well as of Mt1 and Egr-1. This was accompanied by circadian rhythms of corticosterone content and of StAR expression both peaking at 0600 h. The 24-h oscillatory expression of Bmal-1, Per-2, StAR, Mt1, and Egr-1 persisted during 48 h in culture; however, the antiphase between Per-2 and Bmal-1 was lost. The pulse of melatonin shifted the acrophases of all the genes studied and restored the antiphase between Per-2 and Bmal-1. Thus, in the rat, the fetal adrenal is a strong peripheral clock potentially amenable to regulation by maternal melatonin.

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A Circadian Clock Entrained by Melatonin Is Ticking in the Rat Fetal Adrenal

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