A recent animal model shows that the adrenal clock may help stabilize the circadian glucocorticoid rhythm in response to chronic exposure to aberrant light cycles, according to a study recently published in Endocrinology.
Researchers led by William C. Engeland, PhD, of the Department of Neuroscience at the University of Minnesota in Minneapolis, point out that the misalignment of circadian rhythms that occurs chronically in shift work and jet lag contributes to adverse health effects and that the superchiasmatic nucleus (SCN) had been shown in previous work to be sufficient to maintain these rhythms.
However, the SCN clock may only help to maintain circadian rhythms during a normal 24-hour light cycle. “Whether the adrenal clock is important for maintaining GC rhythmicity during chronic exposure to an aberrant LD cycle is unknown,” the authors write. “To address this possibility, we have generated a novel adrenal cortex-specific Bmal1 knockout (KO) mouse and examined the hypothesis that the adrenal clock is required to maintain the circadian GC rhythm during aberrant light exposure produced by an ultradian 3.5:3.5h (T7) LD cycle.” Endocrine News caught up with Engeland and his team to talk about this new study and what it could mean for people who work shifts or suffer from chronic insomnia or jetlag.
Endocrine News: First off, what was the impetus of this study? What made you want to look at the adrenal clock’s role in maintaining circadian rhythms?
William C. Engeland: The circadian glucocorticoid (GC) rhythm is thought to be dependent on a molecular clock in the suprachiasmatic nucleus (SCN) and a peripheral clock in the adrenal cortex that is synchronized by SCN-dependent signals. However, adrenal cortex-selective clock disruption does not alter circadian GC rhythms, suggesting that the central SCN clock is solely responsible for light entrainment of glucocorticoid rhythms under normal environmental day-night cycles. We were interested in determining if the adrenal clock was important for maintaining the circadian GC rhythm during chronic exposure to aberrant light cycles.
EN: It seems the adrenal clock is not necessary to maintain normal circadian rhythm during a normal light-dark cycle, but according to your results, it may be necessary during chronic exposure to aberrant light. Can you speak more to that?
WCE: Based on the premise that the SCN clock and the adrenal clock require synchronization to maintain timing of GC rhythms, we exposed mice to aberrant light produced by an ultradian T7 light cycle (alternating 3.5 hour periods of light and dark) in an attempt to desynchronize the SCN and adrenal clock. Our results showed that circadian (~24 hour) GC rhythms were still maintained under T7 LD, suggesting that the SCN and adrenal clock remain synchronized under aberrant light exposure. In contrast, circadian GC rhythms were lost in mice in which the core clock gene, Bmal1, was selectively deleted in the adrenal cortex. These findings led to our conclusion that the adrenal clock is necessary to prevent desynchronization of the circadian GC rhythm under aberrant light exposure.
EN: Can you tell us about the process of producing these Bmal1 knock-out mice, and what these new animal models could mean for future studies of the circadian clock?
WCE: We generated a novel adrenal cortex-selective Bmal1 null mouse using a Cre-LoxP strategy in collaboration with David Breault and colleagues at Harvard Medical School. By intercrossing mice expressing aldosterone synthase-Cre recombinase (ASCre/+) with floxed Bmal1 mice, we obtained adrenal cortex-selective Bmal1 deletion in adulthood by taking advantage of the capability of the rodent adrenal to undergo postnatal transdifferentiation. Future work using these mice can examine whether a functioning adrenal clock is required for rhythms in adrenocortical responses to stress and to ACTH.
EN: It appears the adrenal clock acts to maintain normal circadian rhythms and protect against increases in corticosterone responses. What implications do these findings have in the clinical setting?
WCE: Our work highlights the importance of the adrenal clock in rodents to maintain the circadian GC rhythm during aberrant light exposure. A functioning adrenal clock may be required to maintain GC rhythms in humans, reducing alterations in metabolic, hemodynamic and cognitive function observed under conditions linked to irregular light exposure including shift work, jet lag and light at night. Additionally, our study indicates that Bmal1 may act in part by repressing GC responses to ACTH. We have identified dysregulated adrenals genes in Bmal1 null mice exposed to aberrant light that may be responsible for increasing steroidogenesis. Additional work is required to determine whether dysregulation of adrenal Bmal1 contributes to forms of hyperadrenocorticoidism observed clinically.