Regulation of 11β-HSD1 by GH/IGF-1 in key metabolic tissues may contribute to metabolic disease in GH deficient patients.

Autor: Morgan SA; Institute of Metabolism & Systems Research, College of Medical and Dental Sciences, Institute of Biomedical Research, University of Birmingham, Birmingham B15 2TT, UK. Electronic address: S.A.MORGAN@BHAM.AC.UK., Berryman DE; Edison Biotechnology Institute, Ohio University/The Ridges, 1 Water Tower Drive, Building #25, Athens, OH 45701, USA., List EO; Edison Biotechnology Institute, Ohio University/The Ridges, 1 Water Tower Drive, Building #25, Athens, OH 45701, USA., Lavery GG; Institute of Metabolism & Systems Research, College of Medical and Dental Sciences, Institute of Biomedical Research, University of Birmingham, Birmingham B15 2TT, UK., Stewart PM; Institute of Metabolism & Systems Research, College of Medical and Dental Sciences, Institute of Biomedical Research, University of Birmingham, Birmingham B15 2TT, UK; Faculty of Medicine and Health, University of Leeds, Leeds, UK., Kopchick JJ; Edison Biotechnology Institute, Ohio University/The Ridges, 1 Water Tower Drive, Building #25, Athens, OH 45701, USA.
Jazyk: angličtina
Zdroj: Growth hormone & IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society [Growth Horm IGF Res] 2022 Feb; Vol. 62, pp. 101440. Date of Electronic Publication: 2021 Nov 17.
DOI: 10.1016/j.ghir.2021.101440
Abstrakt: 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.
(Copyright © 2021 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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