Endocrinologia

0013-7227/08/$15.00/0 Printed in U.S.A.

Endocrinology 149(4):1451–1453 Copyright © 2008 by The Endocrine Society doi: 10.1210/en.2008-0166

Circadian Clocks: Showtime for the Adrenal Cortex
HE LAST 10 yr have seen remarkable advances in understanding the control and interrelationships of circadian rhythms in the brain and peripheral organ systems of mammals and of their critical importanceto human health. Disturbances in circadian timekeeping have been linked to cardiovascular disease, hypertension, metabolic syndrome, gastrointestinal disorders, affective disorders, and cancer (1). The adrenal gland, and the adrenal cortex in particular, has increasingly been seen as a critical source of signals to coordinate and temporally program metabolic activities throughout the body. Formany years the prominent circadian oscillations in steroidogenesis and glucocorticoid secretion of the adrenal cortex were thought to be a consequence of similar circadian rhythms in ACTH secretion. However, evidence of functional neural innervation of the adrenal cortex (2, 3) and findings of nycthemeral rhythms in adrenal responsiveness to ACTH that could be altered extremely rapidly (4, 5) led tothe recent demonstration of direct neural control of adrenal rhythms (6, 7). In this issue of Endocrinology, a study by Valenzuela and Torres-Farfan and colleagues (8) takes another step in advancing understanding of the regulation of adrenocortical rhythms by demonstrating the presence of an intrinsic circadian oscillator in the adrenal cortex of the capuchin monkey (Cebus apella) and by showingthat expression of its clock genes are influenced by melatonin, another major role-player in the circadian rhythm story (9). Circadian rhythms are generated and synchronized by endogenous oscillators that maintain a rhythm with an approximate 24-h period in the absence of any time cues. This rhythm can be entrained or kept “on schedule” by a time signal or Zeitgeber, the most potent of which isthe day/night cycle. Over 35 yr ago, the first evidence was obtained for the existence of a “master clock” responsible for generating and synchronizing mammalian circadian rhythms residing in the paired suprachiasmatic nuclei (SCN) of the anterior hypothalamus, just above the optic chiasm (10, 11). However, it has only been recently that the mechanisms by which the SCN generates a circadian rhythmhave been elucidated. Light is signaled to the SCN by direct input from the retina via the retinohypothalamic tract. The basis of the timekeeping mechanism is in interacting positive and negative feedback loops in gene expression that include both transcriptional and posttranslational regulatory mechanisms (1). Members of the Period (Per1, Per2, and Per3) and Cryptochrome (Cry1 and Cry2) genefamilies are major components of the clock. Transcription of these genes at the onset
See article p. 1454. Abbreviation: SCN, Suprachiasmatic nuclei. Endocrinology is published monthly by The Endocrine Society (http:// www.endo-society.org), the foremost professional society serving the endocrine community.

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of daylight is activated by the positive arm of the system, heterodimeric proteinproducts of Clock and Bmal1 genes acting through the E-box regulatory sequences of the Per and Cry genes. CRY and PER proteins, which increase until reaching a peak at the end of daytime, inhibit Clock and Bmal1 transcription, thus eventually inhibiting their own activation until their mRNA levels reach a nadir near daybreak. Redundancy of control is achieved by additional negative feedback loopsoperating through the Reverb- protein to inhibit Bmal1 transcription during the day and through inhibition of Rev-erb- transcription by CRY and PER with a resultant nighttime increase in Bmal1 transcription as daylight approaches again. Translational expression of Bmal1 and Clock is in antiphase with the expression of Cry and Per genes. In addition to the master clock in the SCN, independent...