The 20  <scp>kDa</scp> isoform of the human growth hormone variant alters adipose and muscle gene expression differently than human growth hormone

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 log₂ 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.