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Growth hormone deficiency is a condition that results from insufficient production and secretion of growth hormone (GH) from the pituitary gland. Since GH has numerous physiological activities and acts on most tissues of the body, recombinant GH has been approved for treatment of GH deficiency in children and adults (Hintz, 2004). However, while GH is crucial for proper growth and development and maintenance of body composition, it also has covert actions that can be detrimental to health. These covert actions include 1) GH has diabetogenic activity (inhibits insulin action) (Ader et al., 1987; Bornstein et al., 1969; Cameron & Kostyo, 1987; Houssay, 1936; Lostroh, 1974; Luft & Cerasi, 1968; Rabinowitz et al., 1965; Rabinowitz & Zierler, 1963; Takahashi et al., 2001) 2) GH downregulates xenobiotic metabolizing enzymes which impairs stress resistance (Amador-Noguez et al., 2004, 2007; Jiang et al., 2013; Steinbaugh et al., 2012) 3) GH can increases fibrosis (Kopchick et al., 2022) and 4) GH can promote the growth of certain cancers. Since GH binds with high affinity to the GH receptor (GHR) and the prolactin receptor (PRLR), GH’s proliferative effect on cancer is thought to be mediated though GHR as well as PRLR signaling (Cunningham et al., 1990; Jacobson et al., 2010; Neradugomma et al., 2014; Thomas et al., 2015; Wen et al., 2014). As such, the lactogenic action of GH (GH signaling through the PRLR) has positive and negative health effects as it helps promote lactation but also promotes the growth of PRLR positive cancers. The presence of these covert actions may partially explain why GH is described as a pro-aging hormone (i.e., elevated GH levels are associated with decreased lifespan while reduced GH action is associated with increased lifespan in numerous species (Berryman et al., 2008; Junnila et al., 2013)). Because of this, our laboratory is studying a variant of GH (GHv) that has diminished diabetogenic and lactogenic activities in efforts to determine if it is a healthier alternative to GH. Our lab has recently shown in GH deficient (GH-/-) mice that GHv has full ability to stimulate longitudinal bone growth and regulate body composition but lacks diabetogenic and lactogenic activities (List et al., 2020). Our lab also showed in PRLR+ human cancer cell lines that GHv has greatly diminished proliferative action compared to GH (List et al., 2020). As a next step in understanding this promising therapeutic, I utilized an unbiased transcriptomics approach on liver, adipose tissue, and skeletal muscle collected from GH-/- mice injected with saline, GH or GHv and identified differences in gene expression and molecular pathways. These results showed that a large number of hepatic xenobiotic metabolizing enzyme genes were strongly downregulated with GH treatment (in agreement with the literature) but not to the same extent with GHv treatment. This result indicates that an additional health benefit to GHv treatment compared to GH treatment is improved stress resistance. To begin the process of determining if our results from mice translated to humans, I treated primary human hepatocytes with GH and GHv, isolated RNA and performed RNA sequencing analysis. Similar to results in mice, a large number of xenobiotic metabolizing enzyme genes in human hepatocytes were upregulated in the comparison of GHv vs GH treatment. In summary, these studies provide for the first time a snapshot of the transcriptomic changes that occur with GHv treatment in mice and in human cultured cells and indicate that an additional health benefit to GHv treatment is that it has a diminished ability to downregulate xenobiotic metabolizing pathways compared to GH. Accordingly, GHv may represent an improved therapeutic option for individuals requiring GH replacement. |
