The investigation in mice showed that the daytime-dependent metabolic cycle is altered by high-calorie diet. Because glucocorticoids are widely used drugs for the treatment of inflammatory diseases, these results published in Molecular Cell suggest that lean and obese patients may respond differently to steroid therapy. Finally, the biological function of the daily rhythms of hormone secretion (high before waking up and feeding, low during sleep and fasting) as well as the daily cycles of sugar and fat storage or release by the liver are shown.
Every cell in the human body is driven by an internal clock that follows the daily rhythm of 24 hours. It is synchronized with the natural cycle of day and night mainly by sunlight, but also by social habits. In a healthy system, glucocorticoid stress hormones are produced every morning by the adrenals. The secretion of glucocorticoid tips before awakening causes the body to use fatty acids and sugars as energy sources, and allows us to begin our daily activities. When the circadian rhythm is disturbed (eg, through shift work or jet lag) and / or when the glucocorticoid level changes (eg, Cushing's syndrome or long-term clinical use), severe metabolic dysregulation may occur ̵
Metabolic effects of glucocorticosteroids in the liver
To investigate the metabolic effects of glucocorticosteroids in the liver, researchers characterized the activity of their receptor, the so-called glucocorticoid receptor, using novel high-throughput techniques. They analyzed mouse liver every 4 hours during the day and night. The mice were either normal or fed on high-fat diet. They then used state-of-the-art genomics, proteomics and bioinformatics technologies to determine when and where the glucocorticoid receptor exerts its metabolic effects. The researchers studied the effects of daily increases in glucocorticoid release in the 24-hour cycle of liver metabolism. They could illustrate how glucocorticoids regulate metabolism differently during fasting (when the mice are asleep) and during feeding (when active) by binding to the genome on a time-dependent basis. In addition, they showed how much of the rhythmic gene activity is controlled by these hormones. If this control is lost (in so-called knockout mice), the sugar and fat levels in the blood are impaired. This explains how the liver regulates blood sugar and fat levels differently, day and night.
Since the glucocorticoid receptor is a widely used drug for immunotherapies, they next examined its genomic effects following 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 in obese mice was different from that in lean mice, and it is the first time that the diet has been able to alter hormonal and drug responses in metabolic tissues." 19659003] New insights for the treatment of chronic medical and metabolic diseases
Glucocorticoids are a group of natural and synthetic steroid hormones such as cortisol. They have strong anti-inflammatory and immunosuppressive properties that can control the activity of the immune system. That is why they are widely used in medicine. The main disadvantage is that glucocorticoids also cause serious side effects because of their ability to regulate sugar and fat metabolism: Patients may develop overweight, hypertriglyceridemia, fatty liver, high blood pressure or type 2 diabetes.
"Understanding how corticosteroids control 24-hour cycles of gene activity in the liver and thus blood sugar levels and fat content provides new insights into" chronic medicine "and the development of metabolic diseases Relationship between lifestyle, hormones and physiology describe at the molecular level, suggesting that obese people may respond differently to daily hormone secretion or to glucocorticoid medications, which are the basis for designing future therapies, "emphasizes Prof. Henriette Uhlenhaut ,
Uhlenhaut headed the research team of the Institute for Diabetes and Obesity, Diabetes and Cancer at the Helmholtz Zentrum München, German Center for Diabetes Research (DZD), Max Planck Institute of Biochemistry, Feinberg University of Applied Sciences, Northwestern University in Chicago and the School of Life Sciences Weihenstephan at the Technical University of Munich (TUM).
Quagliarini et al ., 2019: Cistromic Reprogramming of the Daily Glucocorticoid Hormone Response by High Fat Nutrition. Molecuar Cell DOI: 10.1016 / j.molcel.2019.10.007
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