Chronic glucocorticoid treatment induced circadian clock disorder leads to lipid metabolism and gut microbiota alterations in rats

• Published in: Life sciences (1973) 2018-01, Vol.192, p.173-182
• Main Authors: Wu, Tao, Yang, Luna, Jiang, Jianguo, Ni, Yinhua, Zhu, Jiawei, Zheng, Xiaojun, Wang, Qi, Lu, Xin, Fu, Zhengwei
• Format: Article
• Language: English
• Subjects: Accumulation; Adipose Tissue - drug effects; Adipose Tissue - metabolism; Adrenal glands; Animal diseases; Animal tissues; Animals; Body weight; Body weight gain; Cecum - drug effects; Cecum - microbiology; Circadian Clocks - drug effects; Circadian rhythm; Circadian rhythms; Colon; Colon - drug effects; Colon - metabolism; Colon - microbiology; Corticosterone; Corticosterone - blood; Dexamethasone; Dexamethasone - pharmacology; Eating - drug effects; Flora; Food intake; Gastrointestinal Microbiome - drug effects; Gene expression; Gene sequencing; Genes; Glucocorticoid; Glucocorticoids; Glucose and lipid metabolism; Glucose Tolerance Test; Glycolipids - metabolism; Gut microbiota; Hormones; Infiltration; Inflammation; Intestinal microflora; Intestine; Lipid metabolism; Lipid Metabolism - drug effects; Lipid Metabolism - genetics; Liver; Liver - drug effects; Liver - metabolism; Male; Medical treatment; Metabolic syndrome; Metabolism; Microbiota; Mitochondria; Mitochondria - drug effects; Mitochondria - metabolism; mRNA; Mucus; Next-generation sequencing; Oral administration; Rats; Rats, Wistar; Receptors, Glucocorticoid - biosynthesis; Rodents; rRNA 16S; Secretion; Signaling; Sodium; Sodium phosphate; Steroid hormones; Weight Gain - drug effects; Weight reduction
• ISSN: 0024-3205; 1879-0631
• DOI: 10.1016/j.lfs.2017.11.049

Glucocorticoids (GCs), steroid hormones synthetized by the adrenal gland, are regulated by circadian cycles, and dysregulation of GC signaling can lead to the development of metabolic syndrome. The effects and potential mechanism of GCs in physiology were investigated in the present study. Male Wistar rats were orally administered dexamethasone sodium phosphate (DEX, 0.01 and 0.05mg/kg body weight per day) for 7weeks. DEX treatment attenuated body weight gain and reduced food intake, whereas it induced the accumulation of fat. Administration of DEX induced dysregulation of the expression of lipogenic genes in both fat and liver. Moreover, the mRNA levels of genes related to mitochondrial biogenesis and function were significantly downregulated in the liver and fat of DEX-treated rats. Furthermore, DEX treatment caused a significant reduction in the richness and diversity of the microbiota in the colon, as assessed using high-throughput sequencing of the 16s rRNA gene V3–V4 region, an increase in inflammatory cell infiltration, and a decrease in mucus secretion in the colon. Additionally, DEX administration induced phase shift or loss of circadian rhythmicity of clock-related genes in peripheral tissues. These results were associated with higher serum corticosterone levels and upregulation of GC receptor (GR) expression in peripheral tissues. Our findings indicate that long-term administration of GC caused lipid accumulation, changes in the structure of the intestinal flora, and reduced colonic mucus secretion in vivo. The mechanism of these physiological changes may involve a circadian rhythm disorder and dysregulation of GR expression.