And yet, today, “discovery-driven research,” as these expeditions have now been relabeled, is acceptable. By applying discovery-driven methods, Dr. Chrousos and his colleagues have begun to uncover additional properties of GR signaling. He highlighted one such “expedition” begun 15 years ago, when he and his team decided to use pieces of the GR as “bait” to see what kinds of proteins would interact within the cell.
One of the most interesting things they found was that one component of the GR bound to the CLOCK transcription factor, an important molecule that regulates day and night activity of an organism. They also discovered that glucocorticoid actions are coupled to the body’s circadian rhythms. For example, the CLOCK transcription factor produces part of the 24-hour oscillations of the genome through altering the activity of the glucocorticoid receptor. Cortisol secretion is typically high at around 8 a.m., peaks again at lunchtime, and then decreases each evening. Examining 24-hour oscillations in the sensitivity of circulating white cells to glucocorticoids, Dr. Chrousos observed that their response to cortisol is an inverse one: In the morning, when cortisol levels are high, the body’s tissues are resistant to its effects. In the evening, when cortisol levels are low, tissues are hypersensitive.
There are many examples of pathology due to the aberrant coupling of the CLOCK and the HPA axis, such as chronic stress, when the body is subjected to chronically high levels of endogenous cortisol, and in such diseases as Cushing’s disease. Likewise, in people who do night-shift work or travel across time zones frequently, the decoupling of CLOCK and the HPA axis can lead to functional hypercortisolism and serious health consequences, such as developing metabolic syndrome (possibly leading to diabetes mellitus type 2), atherosclerosis, and cardiovascular disease. These are just some of the ways by which glucocorticoids, when hypersecreted or hyperfunctional because of uncoupling with tissue sensitivity, can cause premature aging, collection of visceral fat, and loss of muscle.
Earlier, Dr. Chrousos used Hooke’s Law of Physics to illustrate the parallels between GR signaling and pressure exerted on metal. Just as with a metal rod, the body can withstand and bend with the “pressure” of dealing with stress hormones. For the most part, he noted, “we are resilient to perturbations.” But if the tipping point is crossed, returning to homeostasis will not be possible. Cacostasis ensues.5 We now know that glucocorticoid over- or under-secretion or, respectively, tissue hypersensitivity or resistance play significant roles in the genesis of many disorders, including metabolic syndrome, diabetes type II, inflammatory and allergic disorders, depression, and insomnia. Humans, according to Dr. Chrousos, consist of multiple systems self-organized into a whole. “And in complex systems, too much or too little is associated with poor performance; everything in moderation is very important.”
Future Implications
At the conclusion of the lecture, moderator Steven R. Goldring, MD, of the Hospital for Special Surgery in New York City, said that given the different functions of the glucocorticoid receptors in different tissues, these might present an ideal system for developing selective glucocorticoid receptor modulators.