In mammals, including humans, a master clock in the brain and subordinate clocks found in organs throughout the body coordinate daily, or circadian, rhythms of behavior and physiology. Now, researchers reporting in the August Cell Metabolism, published by Cell Press, have elucidated the role of clocks of the adrenal glands in keeping those physiologic and metabolic rhythms in synchrony.
The adrenal glands sit atop each kidney, where they discharge steroid hormones known as corticoids--including the stress-related hormones adrenaline and cortisol. Corticoids influence stress response, metabolism, mineral balance, and reproduction.
In a study of mice, Henrik Oster of the Wellcome Trust Centre for Human Genetics at the University of Oxford, Gregor Eichele at the Max Planck Insitute of Biophysical Chemistry, and colleagues found that the adrenal clock acts as a "gate," shaping the amount of corticosterone--the mouse equivalent of cortisol--secreted in response to other hormonal cues driven by the body's master clock.
"The adrenal clock is of particular interest since adrenal corticoids have been implicated in the synchronization of subordinated clocks and were demonstrated to control metabolic rhythms in many other organs, including liver, kidney, and brain," Oster said. "We've identified a mechanism that bridges the gap between peripheral clock gene oscillations and the control of corticoid-dependent physiological rhythms in the adrenal gland and possibly in many other organs."
Oster's team found that the majority of clock genes exhibit a circadian pattern of activity in the adrenal. The clock genes were strongly expressed specifically in outer layers of the adrenal gland that are responsible for corticoid production. The findings offered "bona fide evidence" for the presence of a peripheral circadian clock in the adrenal glands.
To find out how the adrenal clock ticks, the researchers first treated slices of adrenal tissue from normal mice and mice lacking critical clock genes at different time points. While normal adrenal tissue released varying amounts of corticosterone in response to the hormone adrenocorticotropin (ACTH) at different times of day, mutant tissue always released basal levels of hormone. The release of ACTH by the pituitary gland at the base of the brain is driven by a third hormone that is activated by the body's master clock.
The organ-culture experiments suggested that the adrenal contains a circadian clock that defines--or gates--a time window during which the gland most effectively responds to ACTH, Oster said.
"The adrenal clock doesn't appear to drive the rhythm itself but instead regulates the sensitivity of the gland to external stimuli," Oster said. "That gating mechanism provides a level of precision to stabilize circadian rhythms of physiology."
Further evidence from studies in which the researchers transplanted clock mutant adrenal glands into normal mice and normal adrenals into mutant mice reinforced the notion that the adrenal clock determines sensitivity to ACTH. Under conditions of constant darkness, however, mice with normal adrenals that lacked the master clock completely lost the rhythmic corticosterone release, they found, indicating that the adrenal alone cannot sustain the rhythm unless entrained by light.
The circadian network now revealed for the adrenal gland might serve as a "paradigm for the organization of other physiological rhythms," the researchers said.
The findings might also require scientists to do some rethinking, Oster added. Previous studies using organ cultures found that clock gene rhythms can persist for weeks in the absence of external timing signals, leading to the suggestion that peripheral clocks to a large extent operate independently. In marked contrast, the loss of corticosterone rhythm in clock mutant animals with normal adrenals after 2 days in constant darkness indicates a critical dependence of the adrenal on input from the master clock, Oster said.
The researchers include Henrik Oster, formerly of Max Planck Institute of Experimental Endocrinology in Hannover, Germany and currently at the Wellcome Trust Centre for Human Genetics, University of Oxford in Oxford, United Kingdom; Sebastian Damerow and Matthias W. Hoffmann of Hannover Medical School in Hannover, Germany; Silke Kiessling, Vladimira Jakubcakova, Diya Abraham, and Gregor Eichele of Max Planck Institute of Biophysical Chemistry in Goettingen, Germany; Jiong Tian of Hannover Medical School in Hannover, Germany and The 1st Affiliated Hospital of Zhejiang University in China.
This work was supported by the EU grant QLG3-CT-2002-01829 and the Max-Planck-Society.
Oster et al.: "The circadian rhythm of glucocorticoids is regulated by a gating mechanism residing in the adrenal cortical clock." Publishing in Cell Metabolism 4, 163–173, AUGUST 2006. DOI 10.1016/j.cmet.2006.07.002 www.cellmetabolism.org
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