Institute of Metabolism & Systems Research, College of Medical and Dental Sciences, Institute of Biomedical Research, University of Birmingham, Birmingham B15 2TT, UK.
Edison Biotechnology Institute, Ohio University/The Ridges, 1 Water Tower Drive, Building #25, Athens, OH 45701, USA.
Growth Horm IGF Res. 2022 Feb;62:101440. doi: 10.1016/j.ghir.2021.101440. Epub 2021 Nov 17.
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.
患有生长激素缺乏症（GHD）的患者与库欣综合征（糖皮质激素过多）有许多共同的临床特征 - 特别是内脏肥胖、胰岛素抵抗、肌肉肌病和血管死亡率增加。在关键的代谢组织中，11β-羟类固醇脱氢酶 1 型（11β-HSD1）将皮质酮转化为活性糖皮质激素皮质醇（分别为 11-脱氢皮质酮和皮质酮在啮齿动物中），从而放大局部糖皮质激素作用。我们假设 11β-HSD1 的表达受生长激素（GH）的负调控，并且 GHD 患者在关键代谢组织中具有升高的 11β-HSD1（导致细胞内皮质醇生成增加），这有助于该疾病的临床特征。为了确定 GH 过多/抵抗对体内 11β-HSD1 的影响，我们测量了表达牛 GH（bGH）基因的巨型小鼠、具有破坏的 GH 受体（GHRKO）基因的矮小鼠和表达编码 GH 受体拮抗剂（GHA）的基因的小鼠的关键代谢组织中的 mRNA 表达。此外，我们评估了 GHRKO 和 bGH 动物尿液中的类固醇 11β-HSD1 活性标志物。与 WT 对照相比，bGH 小鼠的比目鱼肌（0.43 倍，p <0.05）、皮下脂肪（0.53 倍，p <0.05）和附睾脂肪组织（0.40 倍，p <0.05）中的 11β-HSD1 表达降低，但肝脏中没有。这与 bGH 小鼠尿液中 11-DHC（无活性糖皮质激素）的百分比增加相对应（2.5 倍，p <0.01） - 与全身 11β-HSD1 活性降低一致。相比之下，与 WT 对照相比，GHRKO（2.7 倍，p <0.05）和 GHA 小鼠（2.0 倍，p <0.05）的肝脏中 11β-HSD1 的表达增加，但比目鱼肌、皮下脂肪组织或附睾脂肪组织没有增加。总之，我们已经证明了 GH 作用与 11β-HSD1 表达之间存在负相关关系，这种关系似乎是组织特异性的。这些数据提供了证据，表明关键组织内细胞内皮质醇生成的增加可能导致 GHD 患者的代谢疾病。
