Abstract
Glucocorticoids play important roles in the regulation of distinct aspects of adipocyte biology. Excess glucocorticoids in adipocytes are associated with metabolic disorders, including central obesity, insulin resistance and dyslipidemia. To understand the mechanisms underlying the glucocorticoid action in adipocytes, we used chromatin immunoprecipitation sequencing to isolate genome-wide glucocorticoid receptor (GR) binding regions (GBRs) in 3T3-L1 adipocytes. Furthermore, gene expression analyses were used to identify genes that were regulated by glucocorticoids. Overall, 274 glucocorticoid-regulated genes contain or locate nearby GBR. We found that many GBRs were located in or nearby genes involved in triglyceride (TG) synthesis (Scd-1, 2, 3, GPAT3, GPAT4, Agpat2, Lpin1), lipolysis (Lipe, Mgll), lipid transport (Cd36, Lrp-1, Vldlr, Slc27a2) and storage (S3-12). Gene expression analysis showed that except for Scd-3, the other 13 genes were induced in mouse inguinal fat upon 4-day glucocorticoid treatment. Reporter gene assays showed that except Agpat2, the other 12 glucocorticoid-regulated genes contain at least one GBR that can mediate hormone response. In agreement with the fact that glucocorticoids activated genes in both TG biosynthetic and lipolytic pathways, we confirmed that 4-day glucocorticoid treatment increased TG synthesis and lipolysis concomitantly in inguinal fat. Notably, we found that 9 of these 12 genes were induced in transgenic mice that have constant elevated plasma glucocorticoid levels. These results suggested that a similar mechanism was used to regulate TG homeostasis during chronic glucocorticoid treatment. In summary, our studies have identified molecular components in a glucocorticoid-controlled gene network involved in the regulation of TG homeostasis in adipocytes. Understanding the regulation of this gene network should provide important insight for future therapeutic developments for metabolic diseases.
Highlights
Glucocorticoids regulate many facets of energy metabolism
We used PinkThing to assign GR binding regions (GBRs) to mouse genes based on proximity, and target sites were grouped depending on their position relative to the nearest gene
glucocorticoid receptor (GR) preferentially bound in the intron regions (48%, Fig. 1B). 13% of GBRs were located between 5–50 kb 59 of transcription start site (TSS), whereas 17% were located within 50 kb from 39 of stop codon (Fig. 1B)
Summary
Glucocorticoids regulate many facets of energy metabolism. Excessive glucocorticoid exposure, whether exogenous or endogenous, is associated with the development of metabolic syndrome, a constellation of metabolic risk factors that include insulin resistance, central obesity, dyslipidemia and hypertension [1,2]. Several studies have shown that increasing active glucocorticoid levels in adipocytes can cause metabolic syndrome [8,9]. Transgenic mice that have decreased levels of active glucocorticoids in adipocytes are protected from diet-induced obesity and have improved glucose tolerance and insulin sensitivity [10]. These data highlight the critical role of adipocytes in glucocorticoid-regulated energy homeostasis and demonstrate that modulating glucocorticoid signaling in this cell type exclusively can have significant impacts on whole body metabolism
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