Abstract
Forced expression of insulin-like growth factor binding proteins (IGFBPs) in transgenic mice has clearly revealed inhibitory effects on somatic growth. However, by this approach, it cannot be solved if or how IGFBPs rule insulin-like growth factor (IGF)-dependent growth under normal conditions. In order to address this question, we have used growth-selected mouse models (obese and lean) and studied IGF-1 and IGFBPs in serum with respect to longitudinal growth activity in males and females compared with unselected controls. In mice of both genders, body weights were recorded and daily weight gains were calculated. Between 2 and 54 weeks of age, serum IGF-1 was determined by ELISA and intact IGFBP-2, -3 and -4 were quantified by Western ligand blotting. The molar ratio of IGF-1 to the sum of IGFBP-2 to -4 was calculated for all groups and plotted against the daily weight gain curve. Growth-selected mice are characterized by higher daily weight gains and extended periods of elevated growth activity if compared to matched unselected controls. Therefore, adult mice from the obese and lean groups can achieve more than twofold increased body weight in both genders (p < 0.001). Between 2 and 11 weeks of age, in obese and lean mice of both genders, serum IGF-1 concentrations are increased more prominently if compared to unselected controls (p < 0.001). Instead, substantial decreases of IGFBPs, particularly of IGFBP-2, are observed in males and females of all groups at the age of 2 to 4 weeks (p < 0.001). Due to the strong increase of IGF-1 but not of IGFBPs between two and four weeks of age, the ratio of IGF-1 to IGFBP-2 to -4 in serum significantly increased in all groups and genders (p < 0.05). Notably, the IGF-1 to IGFBP ratio was higher in male and female obese mice if compared to unselected controls (p < 0.05).
Highlights
Long-term selection for high body weight goes back to 1930, when Goodale initiated an experiment to explore the boundaries of growth in mice [1]
Body weight was recorded in mice selected for high body mass at the age of 42 days, in mice selected for high protein amount, and in unselected controls (Figure 1)
At an age of 11 weeks in females and 16 weeks in males, body weights were significantly different between obese, lean, and control mice
Summary
Long-term selection for high body weight goes back to 1930, when Goodale initiated an experiment to explore the boundaries of growth in mice [1]. After 35 generations of selection, the mice had increased. Most probably due to inbreeding effects, additional selection for 49 generations did not further increase body weight to a significant extent [2]. Starting from an outbred background and under avoidance of inbreeding in the present selection experiment, substantial increases (+144%) of male body weight at the age of six weeks were achieved after. 146 generations of selection in the obese mouse line (DU6) [3]. This finding underlines the potential of non-inbred backgrounds for functional genome analysis but even more importantly proves the idea that growth is a complex trait regulated by a multitude of effectors [4]. We have used two separate growth selected mouse models for the study of longitudinal regulation of the IGF-system
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