Stuart A. Morgan , Darlene E. Berryman , Edward O. List , Gareth G. Lavery , Paul M. Stewart , John J. Kopchick
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引用次数: 2
Abstract
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.
期刊介绍:
Growth Hormone & IGF Research is a forum for research on the regulation of growth and metabolism in humans, animals, tissues and cells. It publishes articles on all aspects of growth-promoting and growth-inhibiting hormones and factors, with particular emphasis on insulin-like growth factors (IGFs) and growth hormone. This reflects the increasing importance of growth hormone and IGFs in clinical medicine and in the treatment of diseases.