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 by the adrenal gland. The secretion of glucocorticoid peaks before awakening, prompting the body to use fatty acids and sugar as sources of energy, and enabling us to start our 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 liver
To study glucocorticoids’ metabolic actions in the liver, the researchers characterised the activity of their receptor, called the glucocorticoid receptor, using novel high throughput techniques. They analysed mouse livers every 4 hours. 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. They showed how the majority of rhythmic gene activity is controlled by 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.
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. Dr Fabiana Quagliarini said “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”.
