Young Jonathan A, Bogart Jolie, Buchman Mat, Duran-Ortiz Silvana, Bell Stephen, Kopchick John J, Berryman Darlene E, List Edward O
Department of Biomedical Sciences, Ohio University Heritage College of Osteopathic Medicine, Athens, Ohio, USA.
Edison Biotechnology Institute, Ohio University Heritage College of Osteopathic Medicine, Athens, Ohio, USA.
J Neuroendocrinol. 2025 Jun 16:e70059. doi: 10.1111/jne.70059.
The 20 kDa isoform of human growth hormone variant (20K hGH-V) (derived from the GH2 gene) has previously been shown to promote growth but lacks the diabetogenic and lactogenic activities of human GH (derived from the GH1 gene). That is, 20K hGH-V-treated mice have similar body size and composition to hGH-treated mice, as well as improved insulin sensitivity despite having similar adipose tissue mass. Furthermore, 20K hGH-V-treated prolactin receptor-positive cancer cells exhibited significantly less growth compared to hGH treatment. The aim of this study was to use transcriptomics to compare the effects of 20K hGH-V injection to that of hGH injection on adipose and muscle tissue. GH knockout (GHKO) mice, which do not produce endogenous GH, were injected with hGH or 20K hGH-V daily for 5 days and dissected 4 h after the final injection. RNA was extracted from inguinal subcutaneous adipose tissue and quadriceps muscle and subjected to RNA sequencing. When comparing hGH to 20K hGH-V, there were 73 genes that were significantly altered (q value <.05 and log fold change >1 or < -1) in adipose and 32 in muscle, with two genes (Cish and Sv2b) common to both tissues. Gene set enrichment analysis (GSEA) indicated that the adipose tissue of the 20K hGH-V-treated mice had decreased enrichment of genes associated with T and B lymphocytes compared to hGH-treated adipose tissue. Furthermore, 20K hGH-V treatment resulted in increased enrichment of genes associated with adipogenesis and carbon metabolism compared to hGH treatment. In muscle tissue, the electron transport chain and muscle contraction pathways were upregulated in 20K hGH-V-treatment, while cell cycle, extracellular matrix organization, and xenobiotic metabolism pathways were negatively enriched. While most genes and signalling pathways were similar between the two hormone treatments, the differentially expressed genes identified may help explain some of the phenotypic differences between 20K hGH-V and hGH treatment and also suggest additional novel differences, notably muscle fibre type, immune cell infiltration, and fibrosis.
人类生长激素变体（20K hGH-V）的20千道尔顿同工型（源自GH2基因）先前已被证明能促进生长，但缺乏人类生长激素（源自GH1基因）的致糖尿病和催乳活性。也就是说，用20K hGH-V处理的小鼠与用hGH处理的小鼠具有相似的体型和组成，尽管脂肪组织量相似，但胰岛素敏感性有所提高。此外，与hGH处理相比，用20K hGH-V处理的催乳素受体阳性癌细胞生长明显减少。本研究的目的是利用转录组学比较注射20K hGH-V和注射hGH对脂肪组织和肌肉组织的影响。对不产生内源性生长激素的生长激素基因敲除（GHKO）小鼠，每天注射hGH或20K hGH-V，持续5天，并在最后一次注射后4小时进行解剖。从腹股沟皮下脂肪组织和股四头肌中提取RNA并进行RNA测序。将hGH与20K hGH-V进行比较时，脂肪组织中有73个基因显著改变（q值<.05且对数倍变化>1或<-1），肌肉组织中有32个基因显著改变，两种组织共有两个基因（Cish和Sv2b）。基因集富集分析（GSEA）表明，与hGH处理的脂肪组织相比，20K hGH-V处理的小鼠脂肪组织中与T和B淋巴细胞相关的基因富集减少。此外，与hGH处理相比，20K hGH-V处理导致与脂肪生成和碳代谢相关的基因富集增加。在肌肉组织中，20K hGH-V处理上调了电子传递链和肌肉收缩途径，而细胞周期、细胞外基质组织和外源性代谢途径则呈负富集。虽然两种激素处理之间的大多数基因和信号通路相似，但鉴定出的差异表达基因可能有助于解释20K hGH-V和hGH处理之间的一些表型差异，也提示了其他新的差异，特别是肌纤维类型、免疫细胞浸润和纤维化。
