What and how much we eat might change our internal clocks and hormone responses
November 8, 2019
Science Daily/Helmholtz Zentrum München - German Research Center for Environmental Health
For the first time, a study shows how glucocorticoid hormones, such as cortisol, control sugar and fat levels differently during day and night, feeding and fasting, rest and activity, over the course of 24 hours.
The research conducted in mice found that the time-of-day dependent metabolic cycle is altered by high caloric diet. Since glucocorticoids are widely used drugs for the treatment of inflammatory diseases, these findings published in Molecular Cell suggest that lean and obese patients might respond differently to steroid therapy. Finally, it reveals the biological function of daily rhythms of hormone secretion (high before awakening and feeding, low when sleeping and fasting) as well as daily cycles of sugar and fat storage or release by the liver.
Each cell in the human body is driven by an internal clock which follows the circadian rhythm of 24 hours. It is synchronized with the natural cycle of day and night mainly by sunlight, but also through social habits. In a healthy system, glucocorticoid stress hormones, are produced every morning by the adrenal gland. The secretion of glucocorticoidpeaks before awakening, prompting the body to use fatty acids and sugar as sources of energy, and enabling us to start our daily activities. When the circadian rhythm is disrupted (e.g. through shift work or jetlag) and/or when the glucocorticoid level alters (e.g. through Cushing syndrome or long-term clinical application), profound metabolic dysregulation can be caused -- like obesity, type 2 diabetes, and fatty liver disease. The researcher's goal therefore was to understand the relevance of these daily peaks of stress hormone secretion, the impact of these hormones on our "internal clock" and their role for daily cycles of metabolism.
Glucocorticoids' metabolic actions in the liver
To study glucocorticoids' metabolic actions in the liver, the researchers characterized the activity of their receptor, called the glucocorticoid receptor, using novel high throughput techniques. They analyzed mouse livers every 4 hours during day and night. The mice were either in normal condition or fed with high-fat diet. They then used cutting-edge technologies in genomics, proteomics, and bioinformatics to picture when and where the glucocorticoid receptor exerts its metabolic effects. The researchers dissected the impact of daily surges of glucocorticoid release in the 24-hour-cycle of liver metabolism. They could illustrate how glucocorticoids regulate metabolism differently during fasting (when the mice sleep) and during feeding (when they are active), by time-dependent binding to the genome. Furthermore, they showed how the majority of rhythmic gene activity is controlled by these hormones. When this control is lost (in so-called knockout mice), blood levels of sugar and fat are affected. This explains how the liver controls blood levels of sugar and fat differently during day and night.
In a next step, as the glucocorticoid receptor is a widely-used drug target in immune therapies, they investigated its genomics effects after the injection of the drug dexamethasone, a synthetic glucocorticoid that also activates this receptor. "With this experiment," explains Dr. Fabiana Quagliarini, "we found that the drug response was different in obese mice compared to lean mice. It is the first time to show that diet can change hormonal and drug responses of metabolic tissues."
New insights for Chronomedicine and metabolic disease therapy
Glucocorticoids are a group of natural and synthetic steroid hormones such as cortisol. They have potent anti-inflammatory and immunosuppressive properties which can control the activity of the immune system. This is why they are widely exploited in medicine. The major drawback is that glucocorticoids also cause severe side effects by virtue of their ability to modulate sugar and fat metabolism: Patients may develop obesity, hypertriglyceridemia, fatty liver, hypertension or type 2 diabetes.
"Understanding how glucocorticoids control 24-hour-cycles of gene activity in the liver and consequently blood levels of sugar and fat, provides new insights into 'Chronomedicine' and the development of metabolic disease. We could describe a new link between lifestyle, hormones and physiology at the molecular level, suggesting that obese people may respond differently to daily hormone secretion or to glucocorticoid drugs. These mechanisms are the basis for the design of future therapeutic approaches," highlights Prof. Henriette Uhlenhaut.
https://www.sciencedaily.com/releases/2019/11/191108171637.htm
Stress hormone helps control the circadian rhythm of brain cells
November 8, 2019
Science Daily/University of Copenhagen The Faculty of Health and Medical Sciences
Researchers have shown how the brain's circadian rhythm in rats is, among other things, controlled by the stress hormone corticosterone -- in humans called cortisol. This has been shown by means of a completely new method in the form of implanted micropumps.
As day turns into night, and night turns into day, the vast majority of living organisms follow a fixed circadian rhythm that controls everything from sleep needs to body temperature.
This internal clock is found in everything from bacteria to humans and is controlled by some very distinct hereditary genes, known as clock genes.
In the brain, clock genes are particularly active in the so-called suprachiasmatic nucleus. It sits just above the point where the optic nerves cross and sends signals to the brain about the surrounding light level. From here, the suprachiasmatic nucleus regulates the rhythm of a number of other areas of the body, including the cerebellum and the cerebral cortex.
However, these three areas of the brain are not directly linked by neurons, and this made researchers at the University of Copenhagen curious. Using test rats, they have now demonstrated that the circadian rhythm is controlled by means of signalling agents in the blood, such as the stress hormone corticosterone.
'In humans, the hormone is known as cortisol, and although the sleep rhythm in rats is the opposite of ours, we basically have the same hormonal system', says Associate Professor Martin Fredensborg Rath of the Department of Neuroscience.
He explains that recent years have seen an increasing, scientific focus on research on clock genes, one reason being that previous research on clock genes have found a correlation between depression and irregularities in the body's circadian rhythms.
New Method with Medical Micropumps
In the study with the stress hormone corticosterone, the researchers removed the suprachiasmatic nucleus in a number of rats. As expected, this removed the circadian rhythm of the animals.
Among other things, the body temperature and activity level of the rats went from circadian oscillations to a more constant state. The same was true of the otherwise rhythmic hormone production.
However, the circadian rhythm of the cerebellum was restored when the rats were subsequently implanted with a special programmable micropump, normally used to dose medication in specific quantities.
In this case, however, the researchers used the pump to emit carefully metered doses of corticosterone at different times of the day and night, similar to the animals' natural rhythm.
'Nobody has used these pumps for anything like this before. So technically, we were onto something completely new', says Martin Fredensborg Rath.
For that reason, the researchers spent the best part of a year carrying out a large number of control tests to ensure that the new method was valid.
Interaction Between Neurons and Hormones
As mentioned, the new method paid off. With the artificial corticosterone supplement, researchers were again able to read a rhythmic activity of clock genes in the cerebellum of the rats, even though their suprachiasmatic nucleus had been removed.
'This is hugely interesting from a scientific point of view, because it means that we have two systems -- the nervous system and the hormonal system -- that communicate perfectly and influence one another. All in the course of a reasonably tight 24-hour programme', says Martin Fredensborg Rath.
With the test results and the new method in the toolbox, the researchers' next step is to study other rhythmic hormones in a similar manner, including hormones from the thyroid gland.
https://www.sciencedaily.com/releases/2019/11/191108102850.htm