11β-HSD1 is the major regulator of the tissue-specific effects of circulating glucocorticoid excess

Morgan, Stuart; McCabe, Emma E.; Gathercole, Laura; Hassan‐Smith, Zaki; Larner, Dean P.; Bujalska, Iwona; Stewart, Paul M.; Tomlinson, Jeremy W.; Lavery, Gareth G.

doi:10.1073/pnas.1323681111

Cited by 246 publications

(257 citation statements)

References 33 publications

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“…We therefore confirmed many of our human findings in a mouse model of excessive glucocorticoid treatment, wherein the mice were treated under more controlled conditions. Studies using a Hsd11b1 knockout mouse showed similar findings to our data, including increased fat mass and decreased lean mass and strength, along with reduced insulin sensitivity (Morgan et al 2014). Transcriptionally both of our studies report increases in Dgat mRNA, though we observed no effects of Cushing's disease on lipolytic genes (Fig.…”

Section: Discussionsupporting

confidence: 88%

Gene expression changes in subcutaneous adipose tissue due to Cushing's disease

Hochberg

Harvey

Tran

et al. 2016

EJEA

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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 the subcutaneous adipose tissue from patients with Cushing's disease (nZ5) compared to patients with nonfunctioning pituitary adenomas (nZ11). We found a higher expression of transcripts involved in several metabolic pathways, including lipogenesis, proteolysis and glucose oxidation as well as a 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 comorbidities associated with chronic elevations of glucocorticoids.

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Section: Discussionsupporting

confidence: 88%

Gene expression changes in subcutaneous adipose tissue due to Cushing's disease

Hochberg

Harvey

Tran

et al. 2016

EJEA

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“…Many tissues, including adipose tissue, can convert the inactive cortisol metabolite cortisone back to biologically active cortisol via the enzyme 11‐β‐hydroxysteroid dehydrogenase type 1 (11‐β‐HSD1), resulting in increased tissue and intracellular levels of cortisol 34, 42. Rodent models and human studies both demonstrate 11‐β‐HSD1 overexpression in adipose tissue and associations between increases in local and systemic cortisol and development of insulin dysregulation and diabetes in the Metabolic Syndrome in people 43, 44, 45, 46, 47…”

Section: Discussionmentioning

confidence: 99%

Effect of Age, Season, Body Condition, and Endocrine Status on Serum Free Cortisol Fraction and Insulin Concentration in Horses

Hart

Wochele

Norton

et al. 2016

Veterinary Internal Medicne

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BackgroundIncreased free cortisol fraction is associated with insulin dysregulation (ID) in people with Metabolic Syndrome and Cushing's Disease. Free cortisol has not been investigated in equine endocrine disorders.Hypotheses(1) In healthy horses, sex, age, body condition score (BCS), and season impact free cortisol; (2) free cortisol is increased in horses with Pituitary Pars Intermedia Dysfunction (PPID) or Equine Metabolic Syndrome (EMS).AnimalsFifty‐seven healthy horses; 40 horses and ponies with PPID (n = 20) or EMS (n = 20).MethodsProspective study. Serum collected seasonally from healthy animals and archived serum from PPID and EMS animals was analyzed for insulin, total and free cortisol concentrations, and free cortisol fraction (FCF). Linear mixed models were used to determine effects of age, sex, season, and BCS on hormones in controls. Hormone measurements were compared between disease groups and age‐ and season‐matched controls with t‐tests. EMS and hyperinsulinemic PPID animals were combined in an ID (hyperinsulinemia) group.ResultsFree cortisol concentrations were increased in overweight/obese controls (0.3 ± 0.1 μg/dL) compared to lean controls (0.2 ± 0.1 μg/dL; P = .017). Mean FCF was significantly higher in animals with PPID (8.8 ± 5.8 μg/dL, P = .005) or ID (8.8 ± 10.2 μg/dL, P = .039) than controls (5.0 ± 0.9 μg/dL), but total cortisol concentrations were similar (P ≥ .350) (PPID: 4.2 ± 4.3 μg/dL; ID: 5.0 ± 4.5 μg/dL; controls: 4.6 ± 1.7 and 5.1 ± 2.1 μg/dL).Conclusions and Clinical ImportanceIncreased FCF is associated with obesity in healthy horses and with ID (hyperinsulinemia) in horses and ponies with endocrine disease. Decreased plasma cortisol‐binding capacity could be a component of these endocrine disorders in horses.

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“…They predominantly exert their effect via glucocorticoid receptors (GRs), which have multiple polymorphisms and isoforms that influence ligand-receptor binding and, consequently, downstream effects (37). The ideal glucocorticoid biomarker would also account for local tissue and intracellular generation of glucocorticoids via 11b-hydroxysteroid dehydrogenase type 1 (38) and expression of the efflux transporter P-glycoprotein (13). Plasma TSP1 concentrations were significantly increased in patients with secondary adrenal insufficiency 1 week after a small increase in the hydrocortisone dose; however, the extent of the response was variable between individuals.…”

Section: Discussionmentioning

confidence: 99%

Thrombospondin-1 is a glucocorticoid responsive protein in humans

Barclay

Petersons

Keshvari

et al. 2016

European Journal of Endocrinology

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Objective: Thrombospondin-1 (TSP1) is a matricellular protein whose gene expression has previously been shown to increase acutely after exposure to dexamethasone in vitro. The aim of this study was to determine if TSP1 is altered by acute and chronic states of glucocorticoid excess in human subjects. Design and methods: Three studies have been undertaken to assess the difference or change in TSP1 in response to altered glucocorticoid activity: i) an acute interventional study assessed the effects of a single 4 mg dose of dexamethasone in 20 healthy volunteers; ii) a cross-sectional study compared plasma TSP1 in 20 healthy volunteers and eight patients with Cushing's syndrome; iii) an interventional study assessed the effect on plasma TSP1 of an increase in hydrocortisone dose from %20 mg/day to 30 mg/day for 7 days in 16 patients with secondary adrenal insufficiency. Results: In healthy volunteers, 4 mg dexamethasone significantly increased peripheral blood mononuclear cell (PBMC) TSP1 mRNA levels (P!0.0001) and plasma TSP1 concentrations (P!0.0001), peaking at 12 h. Median (interquartile range) plasma TSP1 was higher in Cushing's, 638 (535-756) ng/ml, than in healthy volunteers, 272 (237-336) ng/ml (P!0.0001). Plasma TSP1 O400 ng/ml diagnosed Cushing's syndrome with sensitivity of 100% and specificity of 85%. The higher hydrocortisone dose increased plasma TSP1 from 139 (86-199) to 256 (133-516) ng/ml, (P!0.01) in patients with secondary adrenal insufficiency. Conclusions: TSP1 is a glucocorticoid responsive protein in humans. Further research is required to determine if plasma TSP1 has a role as a glucocorticoid biomarker.

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11β-HSD1 is the major regulator of the tissue-specific effects of circulating glucocorticoid excess

Cited by 246 publications

References 33 publications

Gene expression changes in subcutaneous adipose tissue due to Cushing's disease

Gene expression changes in subcutaneous adipose tissue due to Cushing's disease

Effect of Age, Season, Body Condition, and Endocrine Status on Serum Free Cortisol Fraction and Insulin Concentration in Horses

Thrombospondin-1 is a glucocorticoid responsive protein in humans

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