**2.3 The new GH-V variant**

As with 22 kDa GH-N, the GH-V also undergoes alternative splicing during gene transcription, resulting from a 45 bp deletion produced by the use of an alternative acceptor site within exon 3 [46]. This group studied the effects of a 7-day treatment with 22 kDa hGH-N or 20 kDa hGH-V, administered subcutaneously (sc) in the same dose on the body composition and the endocrine and metabolic profiles in young male Wistar rats fed either with chow or a high-fat (HF) diet for 4 weeks post-weaning. Total body growth in the 20 kDa hGH-V-treated animals was intermediary between that of control and hGH-N-treated animals. Both 22 kDa hGH-N and 20 kDa hGH-V significantly reduced total body fat mass compared with control animals, and there were no differences between the GH isoforms in anti-lipogenic activity in animals fed the HF diet. Fasting plasma insulin and C peptide were significantly increased in animals on the HF diet and further increased by hGH-N but were unchanged in 20 kDa hGH-V-treated animals compared with saline-treated controls. Plasma volume was increased in hGH-N-treated animals but was unchanged in 20 kDa hGH-V-treated animals compared with controls. Furthermore, 20 kDa hGH-V had reduced lactogenic activity characteristic of hGH-N as tested in vitro compared with the 20 kDa hGH-N and 22 kDa hGH-N variants [46]. In summary, placental 20 kDa hGH-V retains some of the growth-promoting and all antilipogenic activities of pituitary 22 kDa hGH-N but has diminished diabetogenic and lactogenic properties compared with the native 22 kDa hGH-N [46]. These results indicate that some clear differences exist between 20 kDa GH-N and 20 kDa GH-V, perhaps indicating the different metabolic needs existing between not pregnant and pregnant women. A further very recent study was conducted to better characterize the in vivo activities of GHv (current name for this 20 kDa GH-V variant) in both sexes of a GH-deficient model of mice (GH−/− mice). GHv-treated GH−/− mice had significant increases to serum IGF-1, femur length, body length, body weight, and lean body mass and reduced body fat mass similar to mice receiving usual GH treatment. GH-N treatment increased circulating insulin levels and impaired insulin sensitivity; in contrast, both measures were unchanged in GHv-treated mice. The study also tested the ability of GH-N and GHv to stimulate the proliferation of human cancer cell lines and found that GHv has a decreased proliferative response in cancers with high PRLR (GHv is unable to bind to prolactin receptor) [5]. Their findings demonstrate that GHv can stimulate IGF-I and subsequent longitudinal body growth in GH-deficient mice similar to GH-N, but unlike it, GHv promoted growth without inhibiting insulin action and without promoting the growth of PRLR-positive cancers in vitro. Thus, GHv may represent improvements to current GH therapies especially for individuals at risk for metabolic syndrome or PRLR-positive cancers [5]. These results are surprising, especially if we think that this GHv comes from the placenta. What is the reason for showing such improved effects compared with those produced by the classic pituitary GH-N? Is GHv also expressed in tissues other than the placenta? Hopefully in the coming years we will have the answer to this question and, perhaps, many more surprises regarding this variant of GH, although it must be taken into account that these two studies have been carried out in two species, rats and mice, quite different from humans, including the GH that they produce.
