title: A general IGF-I overexpression effectively rescued somatic growth and bone deficiency in mice caused by growth hormone receptor knockout.
abstract: Both growth hormone and insulin-like growth factor (IGF)-I are essential for postnatal somatic growth, while exerting distinct effects on energy homeostasis. Although growth hormone controls IGF-I production, whether IGF-I was the exclusive mediator of its growth promotion is still debated. In order to further explore their in vivo interactions in somatic growth as well as in energy homeostasis, we have crossed mutant (MT-IGF) transgenic mice onto the GHR - / - background. As expected, GHR gene deficiency caused growth retardation, including significant decreases in lumbar, femur and total body lengths, as well as decreased bone area, mineral content and mineral density. IGF-I overexpression alone in MT-IGF mice increased the weight, with no significant change in bone mineralization or longitudinal growth. Compared to GHR - / - littermates, overexpressed IGF-I in bitransgenic mice (GHR - / - and MT-IGF positive) exhibited fully restored body weight, lumbar (but not femur) and total body lengths, and normalized overall bone area, mineral content and density. On the other hand, there were significant changes in fasting glucose level, glucose tolerance, lean/fat masses and even adipose histology as a result of the transgenic/knockout double-crossing. IGF-I overexpression normalized glucose tolerance in GHR - / - mice. Intriguingly, on GHR+/ - background of partial growth hormone insensitivity, overexpression of IGF-I caused a significant weight gain. Our results thus establish that the growth defect and bone deficiency caused by lack of growth hormone signaling can be effectively restored by increasing IGF-I production in vivo.
authors.affiliation: Fraser Laboratories for Diabetes Research, Department of Medicine, McGill University Health Centre, Montreal, Quebec, Canada.
authors.forename: Kristine
authors.initials: K
authors.lastname: De Jesus
authors.forename: Xiao
authors.initials: X
authors.lastname: Wang
authors.forename: Jun-Li
authors.initials: JL
authors.lastname: Liu
mesh_terms: D017667:Adipocytes / Q000187:drug effects; D050154:Adiposity; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D001847:Bone Diseases / Q000188:drug therapy* / Q000503:physiopathology; D002113:Calcification, Physiologic / Q000187:drug effects; D005260:Female; D006130:Growth Disorders / Q000188:drug therapy* / Q000503:physiopathology; D013006:Growth Hormone / Q000378:metabolism; D007003:Hypoglycemia; D007328:Insulin / Q000494:pharmacology; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011986:Receptors, Somatotropin / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D007328:Insulin; D011986:Receptors, Somatotropin; D007334:Insulin-Like Growth Factor I; D013006:Growth Hormone