Patients with growth hormone deficiency (GHD) have many clinical features in common with Cushings syndrome (glucocorticoid excess) - notably visceral obesity, insulin resistance, osteoporosis and increased vascular mortality. Within key metabolic tissues, 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) converts cortisone to the active glucocorticoid, cortisol, and thus amplifies local glucocorticoid action. We hypothesise that 11β-HSD1 expression is negatively regulated by growth hormone (GH), and that GHD patients have elevated 11β-HSD1 levels (leading to increased intracellular cortisol generation) which contributes to the clinical features of this disease. To identify the impact of GH excess / deficiency 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). In male bGH mice, 11β-HSD1 expression was decreased in gastrocnemius muscle (0.43-fold, P<0.05), epididymal adipose tissue (0.38-fold, P<0.05) and subcutaneous adipose tissue (0.57-fold, P<0.05), but not liver. By contrast, male GHRKO mice had increased 11β-HSD1 expression in the liver (2.8-fold, P<0.05), with no differences in expression levels in gastrocnemius muscle, epididymal adipose tissue or subcutaneous adipose tissue. Likewise, male GHA mice had increased 11β-HSD1 expression in liver (2.3-fold, P<0.05), with no difference in expression in gastrocnemius muscle, epididymal adipose tissue or subcutaneous adipose tissue. In summary, we have found GH to negatively regulate 11β-HSD1 expression in a tissue specific manner. As such, providing evidence that increased intracellular cortisol production within key tissues may contribute to metabolic disease in GHD patients.
Declaration of interest: There is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.
Funding: No specific grant from any funding agency in the public, commercial or not-for-profit sector.