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The Cushing's disease adipose gene expression profile reveals effects of long term glucocorticoids on adipose tissue lipid, protein and glucose metabolism

ABSTRACT: Glucocorticoids have major effects on adipose tissue metabolism. To study tissue mRNA expression changes induced by chronic elevated endogenous glucocorticoids, we performed RNA sequencing on subcutaneous adipose tissue from patients with Cushing’s disease (n=5) compared to patients with non-functioning pituitary adenomas (n=11). We found higher expression of transcripts involved in several metabolic pathways, including lipogenesis, proteolysis and glucose oxidation as well as decreased expression of transcripts involved in inflammation and protein synthesis. To further study this in a model system, we subjected mice to dexamethasone treatment for 12 weeks and analyzed their inguinal (subcutaneous) fat pads, which led to similar findings. Additionally, mice treated with dexamethasone showed drastic decreases in lean body mass as well as increased fat mass, further supporting the human transcriptomic data. These data provide insight to transcriptional changes that may be responsible for the co-morbidities associated with chronic elevations of glucocorticoids

ORGANISM(S): Homo sapiens

PROVIDER: GSE66446 | GEO | 2015/08/01

SECONDARY ACCESSION(S): PRJNA276977

REPOSITORIES: GEO

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Project description:Full title: Expression data from human primary subcutaneous preadipocytes treated with glucocorticoids prior to the initiation of differentiation. Preadipocytes are continuously exposed to glucocorticoids in situ due to both steroid present in the circulatory system as well as adipose tissue specific 11Î²HSD1 activity. While the effects of glucocorticoids during differentiation are well studied, the effect of exposure of preadipocytes to glucocorticoids prior to differentiation is unknown. We therefore treated confluent human primary preadipocytes drived from subcutaneous adipose tissue with the synthetic glucocorticoid dexamethasone for 48 hours prior to the initiation of differentiation and assessed what effect this had on their subsequent potential to differentiate. We found that pretreatment with glucocorticoids had a priming effect and resulted in increased differentiation of these preadipocytes. Furthermore, this treatment was additive to the effects of glucocorticoids during the initial phase of adipogenesis. Microarray analysis performed subsequent to the pretreatment with glucocorticoids (at the time point at which preadipocytes would have been induced to differentiate) identified glucocorticoid-responsive, candidate genes whose altered expression could mediate these effects. keywords: glucocorticoids, glucocorticoid receptor, preadipocytes, adipogenesis, human primary preadipocytes, subcutaneous, adipose tissue Experiment Overall Design: Human subcutaneous primary preadipocytes were purchased from Zen-Bio Inc. Preadipocytes from 5 female donors (average BMI 22.5Â±0.2kg/m2) were pooled prior to the initial seeding in T75 flasks. Cells were maintained at 5% CO2 in DMEM with 1.0g/L glucose, 20% calf serum, 100U/ml penicillin, 100mg/ml streptomycin and 50U/ml nystatin. Cells were expanded once prior to seeding in Nunc-brand 12-well dishes. Upon reaching confluence (24 h post-splitting), preadipocytes were stimulated with vehicle or 1uM dex for 48 hours in growth media containing 3% calf serum. Microarray analysis was performed on duplicate samples.

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The Cushing's disease adipose gene expression profile reveals effects of long term glucocorticoids on adipose tissue lipid, protein and glucose metabolism

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