In the last several years, I dove into the research exploring the intersection between circadian rhythm and the HPA axis. As most of you probably know, normal cortisol production follows a predictable circadian output, which rises sharply upon awakening (the cortisol awakening response, or CAR) and then drops quickly over the next few hours, gradually declining and reaching its nadir late at night. What many may not know is that glucocorticoid receptors (i.e., cortisol receptors), found in almost every tissue, are vital in helping to maintain peripheral circadian rhythm, which can greatly influence cellular metabolic function.1
Briefly, chronobiology usually describes two biological clocks, the peripheral clocks found in almost every cell in the body and the central clock located in the suprachiasmatic nucleus (SCN) of the hypothalamus. The peripheral clocks function using a series of “clock genes,” which are basically several feed-forward and feedback loops involving interdependent transcription factors. These include proteins such as CLOCK, BMAL, PER, CRY and several others. This allows the cell to function (semi-autonomously) on a metabolic cycle of approximately 24 hours, where roughly 30-50% of the gene expression of a given cell is governed by circadian control. However, left to themselves, these cells would slowly drift away from an exact 24-hour rhythm. Therefore, they need an external signal to help them stay on time.
The signals needed to entrain the peripheral clocks come from the central clock of the suprachiasmatic nucleus. One of the most prominent of these signals is the SCN’s control of the circadian output of cortisol from the adrenal glands. It does this by affecting the timing of the hypothalamus/pituitary release of CRH and ACTH, respectively, and by direct sympathetic innervation of the adrenal gland, affecting its circadian sensitivity to ACTH. Cortisol is a powerful metabolic hormone that signals cell function through the glucocorticoid receptor (GR). This receptor functions as a transcription factor turning on (or off) genes as part of the cortisol-response.
As it turns out, there is a back and forth interaction between cortisol signaling through the GR and clock genes and their proteins2. This includes the modulation of clock gene expression by cortisol via the GR and the post-transcriptional modification of the GR by clock proteins. On the one hand, this back and forth is thought to fine-tune the cell’s circadian rhythm, while also adjusting the sensitivity of the cell to glucocorticoids throughout the day. On the other hand, these mechanisms also explain the global metabolic disruption that occurs when cortisol output is altered (in magnitude or timing) during acute stress or with sudden changes in circadian rhythm (jet lag, shift work, etc.).3 In addition, the (mal)adaptation to chronic stress and its influence on cortisol output, timing and glucocorticoid receptor sensitivity is likely to increase cellular sensitivity to circadian-disrupted metabolic outcomes, further degrading an individual’s resilience to stress.4,5
Often lost in the discussion of cortisol’s roles in the stress and immune/inflammatory responses is its function in regulating energy, especially glucose availability (it is a glucocorticoid, after all). Therefore, it is equally important to understand that nutrient availability is also a major coordinating link between the HPA axis, cortisol and circadian metabolic functions. In fact, the gold standard method of activating the HPA axis is through laboratory-induced hypoglycemia (though this is rarely done anymore in clinical research as it is quite…well, stressful). But this makes sense, because hypoglycemia is dangerous to the brain and cortisol can quickly raise blood glucose by affecting insulin sensitivity in peripheral tissues and increasing the conversion of stored energy to glucose.
However, stepping back from this acute management of glucose, the HPA axis (and the SCN) play a much broader role in managing energy. Beyond the signals driving cortisol from the central clock mentioned above, the SCN also sends signals to control the feeding-fasting cycle, as well as signals that affect circadian changes in body temperature. These indirect signals are also very important for modulating the circadian metabolism of cells.6 These signals are meant to coordinate the circadian production of enzymes and co-factors for efficient nutrient metabolism with the timing of nutrient availability. This whole process is synchronized by the SCN’s access to light in a circadian fashion.
All these factors (and many more) are only acting to reinforce the importance of maintaining proper circadian rhythm and help explain the many metabolic dysfunctions that circadian disruption causes. It also may explain how a circadian eating pattern, especially one that shifts calories toward breakfast (shown to reinforce circadian gene expression) may be so beneficial–not surprisingly, this is essentially what most time-restricted feeding patterns reinforce.7,8 On the other hand, this also reinforces the admonition for avoiding or limiting phase-shifting events such as jet lag, sleep disruption, limited out-of-phase access to light, and—perhaps the worst—working swing-shifts (though night shift can be just as problematic in some).9 In my opinion, attempting to rebuild health without maintaining a proper diurnal rhythm (reinforced by light and meal timing) is an uphill battle, and one of the first and easiest discussions between physician and patient.
2 Moreira AC, Antonini SR, de Castro M. MECHANISMS IN ENDOCRINOLOGY: A sense of time of the glucocorticoid circadian clock: from the ontogeny to the diagnosis of Cushing's syndrome. Eur J Endocrinol. 2018 Jul;179(1):R1-R18.
3 Kino T. Circadian rhythms of glucocorticoid hormone actions in target tissues: potential clinical implications. Sci Signal. 2012 Oct 2;5(244):pt4.
4 Rao R, Androulakis IP. The physiological significance of the circadian dynamics of the HPA axis: Interplay between circadian rhythms, allostasis and stress resilience. Horm Behav. 2019 Mar 14;110:77-89.
5 Helfrich-Förster C. Interactions between psychosocial stress and the circadian endogenous clock. Psych J. 2017 Dec;6(4):277-289.
6 Gerber A, Saini C, Curie T, et al. The systemic control of circadian gene expression. Diabetes Obes Metab. 2015 Sep;17 Suppl 1:23-32.
7 Wehrens SMT, Christou S, Isherwood C, et al. Meal Timing Regulates the Human Circadian System. Curr Biol. 2017 Jun 19;27(12):1768-1775.e3.
8 Jakubowicz D, Wainstein J, Landau Z, et al. Influences of Breakfast on Clock Gene Expression and Postprandial Glycemia in Healthy Individuals and Individuals With Diabetes: A Randomized Clinical Trial. Diabetes Care. 2017 Nov;40(11):1573-1579.
9 Boivin DB, Boudreau P. Impacts of shift work on sleep and circadian rhythms. Pathol Biol (Paris). 2014 Oct;62(5):292-301.
Dr. Guilliams earned his doctorate from the Medical College of Wisconsin (Milwaukee) where he studied molecular immunology in the Microbiology Department. Since 1996, he has spent his time studying the mechanisms and actions of natural-based therapies, and is an expert in the therapeutic uses of nutritional supplements.
As the Vice President of Scientific Affairs for Ortho Molecular Products, he has developed a wide array of products and programs which allow clinicians to use nutritional supplements and lifestyle interventions as safe, evidence-based and effective tools for a variety of patients. Tom teaches at the University of Wisconsin-School of Pharmacy, where he holds an appointment as a Clinical Instructor; at the University of Minnesota School of Pharmacy and is a faculty member of the Fellowship in Anti-aging Regenerative and Functional Medicine. He lives outside of Stevens Point, Wisconsin with his wife and children.
You can learn more about this topic from Dr. Guilliams at the upcoming PLMI Spring Conference in Chicago! Reserve your spot today!
