For the first time, a study headed by the Munich Helmholtz Centre and the German Center for Diabetes Research shows how glucocorticoid hormones such as cortisol control sugar and fat levels. In particular, the difference in these levels between day and night, food intake, and fasting, as well as rest and activity, were observed over a period of 24 hours.
The mice research has clearly shown that the daytime-dependent metabolic cycle is altered by a high-calorie diet. The results published in the journal Molecular Cell suggest that slim and obese patients may react differently to steroid therapy. Furthermore, the study illustrates the biological function of the daily rhythm of hormone release - high before waking up and eating, 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 the daily release of large amounts of stress hormones, the influence of these hormones on our internal clock and their role in daily metabolic cycles.
In order to investigate the metabolic functions of glucocorticoids in the liver, the researchers characterized the activity of their receptor, the glucocorticoid receptor, using new high-throughput technologies. Every four hours, day and night, they analyzed the liver of mice.
The mice were fed either normal or high-fat food. Using state-of-the-art methods from genomics, proteomics, and bioinformatics, the team was able to gain an idea of when and where the glucocorticoid receptor exerts its metabolic effect. The researchers analyzed the effects of the daily fluctuations in glucocorticoid release in the 24-hour cycle of liver metabolism. They were able to illustrate how glucocorticoids regulate metabolism differently during fasting (when the mice sleep) and during food intake (when they are active) by time-dependent binding to the genome.
The study also shows how the majority of rhythmic gene activity is controlled by these hormones. If this control is lost (in so-called knockout mice), this affects the sugar and fat levels in the blood. This explains how the liver controls the sugar and fat levels in the blood differently during day and night.
Since the glucocorticoid receptor is frequently used in immunotherapy, the team then investigated its genomic effects after the injection of the drug dexamethasone. "With this experiment," explains Dr. Fabiana Quagliarini, "we found that the drug response in obese mice differs from that in slim mice. This was the first time we were able to show that nutrition can change the hormonal and drug reactions of metabolism".
"If we understand how glucocorticoids control the 24-hour cycles of gene activity in the liver and thus the sugar and fat levels in the blood, we will gain new insights for 'chronomedicine' and the development of metabolic diseases. We were able to describe a new relationship between lifestyle, hormones, and physiology at the molecular level. This suggests that obese people may react differently to daily hormone release or glucocorticoid preparations. These mechanisms are the basis for the development of future therapies," explains Prof. Henriette Uhlenhaut.
Prof. Uhlenhaut headed the research team of the Institute of Diabetes and Obesity, and the Institute of Diabetes and Cancer at the Munich Helmholtz Centre, the German Center for Diabetes Research (German acronym: DZD), the Max Planck Institute of Biochemistry, the Northwestern University’s Feinberg School of Medicine in Chicago, and the Weihenstephan School of Life Sciences at the Munich Technical University (German acronym: 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