Regulation of 11β-HSD1 by GH/IGF-1 in key metabolic tissues may contribute to metabolic disease in GH deficient patients
| Autor: | Edward O. List, Gareth G. Lavery, Stuart A. Morgan, John J. Kopchick, Paul M. Stewart, Darlene E. Berryman |
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| Rok vydání: | 2022 |
| Předmět: |
medicine.medical_specialty
Hydrocortisone Endocrinology Diabetes and Metabolism Biology Growth hormone deficiency Mice chemistry.chemical_compound Endocrinology Insulin resistance Corticosterone 11β-hydroxysteroid dehydrogenase type 1 Internal medicine 11-beta-Hydroxysteroid Dehydrogenase Type 1 Acromegaly medicine Animals Humans Insulin-Like Growth Factor I Myopathy Glucocorticoids Human Growth Hormone medicine.disease chemistry Growth Hormone biology.protein Cattle Insulin Resistance Cortisone medicine.symptom hormones hormone substitutes and hormone antagonists Glucocorticoid medicine.drug |
| Zdroj: | Growth Hormone & IGF Research. 62:101440 |
| ISSN: | 1096-6374 |
| DOI: | 10.1016/j.ghir.2021.101440 |
| Popis: | Patients with growth hormone deficiency (GHD) have many clinical features in common with Cushing's syndrome (glucocorticoid excess) - notably visceral obesity, insulin resistance, muscle myopathy and increased vascular mortality. Within key metabolic tissues, 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) converts cortisone to the active glucocorticoid, cortisol (11-dehydrocorticosterone and corticosterone in rodents respectively), and thus amplifies local glucocorticoid action. We hypothesize that 11β-HSD1 expression is negatively regulated by growth hormone (GH), and that GHD patients have elevated 11β-HSD1 within key metabolic tissues (leading to increased intracellular cortisol generation) which contributes to the clinical features of this disease. To identify the impact of GH excess/resistance on 11β-HSD1 in vivo, we measured mRNA expression in key metabolic tissues of giant mice expressing the bovine GH (bGH) gene, dwarf mice with a disrupted GH receptor (GHRKO) gene and mice expressing a gene encoding a GH receptor antagonist (GHA). Additionally, we assessed urine steroid markers of 11β-HSD1 activity in both GHRKO and bGH animals. 11β-HSD1 expression was decreased in gastrocnemius muscle (0.43-fold, p 0.05), subcutaneous adipose (0.53-fold, p 0.05) and epididymal adipose tissue (0.40-fold, p 0.05), but not liver, in bGH mice compared to WT controls. This was paralleled by an increased percentage of 11-DHC (inactive glucocorticoid) present in the urine of bGH mice compared to WT controls (2.5-fold, p 0.01) - consistent with decreased systemic 11β-HSD1 activity. By contrast, expression of 11β-HSD1 was increased in the liver of GHRKO (2.7-fold, p 0.05) and GHA mice (2.0-fold, p 0.05) compared to WT controls, but not gastrocnemius muscle, subcutaneous adipose tissue or epididymal adipose tissue. In summary, we have demonstrated a negative relationship between GH action and 11β-HSD1 expression which appears to be tissue specific. These data provide evidence that increased intracellular cortisol production within key tissues may contribute to metabolic disease in GHD patients. |
| Databáze: | OpenAIRE |
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