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.

Keywords::

• Adiposity
• bone mineralization
• hypoglycemia
• insulin sensitivity
• adipocyte

Acknowledgements

This work was supported by funding from National Science and Engineering Research Council of Canada (341205-07) and Canadian Institutes of Health Research (CCI-85675). Scholarship support to JLL was provided by Fonds de la recherché en santé Quebec. KDJ received studentship support from the Research Institute of McGill University Health Centre. XW was supported by the National Natural Science Foundation of China (30700382). MT-IGF mice were provided by Dr J. D'Ercole of University of North Carolina; GHR − / − mice by Dr J. J. Kopchick of Ohio University.

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.