For the first time, a study led by Helmholtz Zentrum München and the German Center for Diabetes Research (DZD) shows how glucocorticoid hormones, such as cortisol, control sugar and fat levels.
Different reactions to steroid therapies in lean and obese patients?
For the first time, a study led by Helmholtz Zentrum München and the German Center for Diabetes Research (DZD) shows how glucocorticoid hormones, such as cortisol, control sugar and fat levels. In particular, the difference between day and night, food intake and fasting as well as rest and activity was observed over a period of 24 hours.
The research on mice makes it clear that the daytime-dependent metabolic cycle is altered by a high-calorie diet. The in the journal Molecular Cell Published results suggest that lean and obese patients may respond differently to steroid therapy. Furthermore, the study illustrates the biological function of the daily rhythm of hormone release – high before waking and feeding, low during sleep and fasting – as well as the daily cycles of sugar and fat storage or release by the liver.
The aim of the research team was to understand the importance of daily release of high levels of stress hormones, the impact of these hormones on our internal clock and their role in daily metabolic cycles.
Metabolic processes of glucocorticosteroids in the liver
To study the metabolic functions of glucocorticoids in the liver, researchers characterized the activity of their receptor, the glucocorticoid receptor, with new high-throughput technologies. Every four hours, day and night, they analyzed the liver of mice. Mice were fed either normal or high fat diet. Using state-of-the-art genomics, proteomics and bioinformatics techniques, the team was able to gain an idea of when and where the glucocorticoid receptor exerts its metabolic effects. The researchers analyzed the effects of daily fluctuations in glucocorticoid release in the 24-hour cycle of liver metabolism. They were able to illustrate how glucocorticoids regulate their metabolism during fasting (when the mice are asleep) and when eating (when they are active) by time-dependent binding to the genome. The study also shows how the majority of the rhythmic gene activity is controlled by these hormones. If this control is lost (in so-called knockout mice), this will affect the sugar and fat levels in the blood. This explains how the liver controls the amount of sugar and fat in the blood differently during the day and night.
As the glucocorticoid receptor is commonly used in immunotherapy, the team then examined its genomic effects after injection of the drug dexamethasone in a next step. "With this experiment," explains Dr. Fabiana Quagliarini, "We found that the drug response in obese mice differs from that in lean mice, demonstrating for the first time that diet can alter the hormonal and metabolic responses of the metabolism."
New insights for Chronomedizin and the therapy of metabolic diseases
"Understanding how glucocorticoids control the 24-hour cycles of liver gene activity and thus blood sugar and fat levels, we gain new insights into chronomedicine and the development of metabolic diseases At the molecular level, lifestyle, hormones and physiology are described, suggesting that obese people may react differently to daily hormone release or to glucocorticoid preparations, which are the basis for the development of future therapies, "explains Prof. Henriette Uhlenhaut.
Uhlenhaut headed the research team of the Institute for Diabetes and Obesity, Diabetes and Cancer at Helmholtz Zentrum München, the German Center for Diabetes Research (DZD), the Max Planck Institute of Biochemistry, Northwestern University's Feinberg School of Medicine in Chicago and the School of Life Sciences Weihenstephan at the Technical University of Munich (TUM).
Quagliarini et al., 2019: Cistromic reprogramming of the diurnal glucocorticoid hormone response by high-fat diet. Molecular Cell, DOI: 10.1016 / j.molcel.2019.10.007