Altered growth of mice divergently selected for body weight is associated with complex changes in the growth hormone/insulin-like growth factor system

Abstract

Mice investigated in this study were generated by selecting a sub-population of the NMRI out-bred stock (C), for high (H) or low (L) 8-week body weight. After 58 generations of selection, 8-week body weights of the sub-populations were markedly different if compared to controls. To investigate endocrine changes causing the altered growth performance in the different lines of mice, we analysed several components of the growth hormone (GH)/insulin-like growth factor (IGF) system. Pituitary weights of male and female L mice were significantly smaller than those of C and H mice. Relative to body weight, pituitary weights of male mice from the three lines did not differ, however pituitary weight-to-body weight-ratios of female L mice were significantly greater than those of H females. Mean volume densities of somatotropic cells were significantly smaller in L mice than in C and H mice. Serum IGF-I concentrations were significantly lower in the L line than in the C and H lines. H mice displayed significantly increased serum insulin levels both after ad libitum feeding and after a 14 hour fasting period. Ligand blot analysis of serum IGF-binding proteins (IGFBPs) revealed a significant reduction of circulating IGFBP-3 in L mice as compared to C and H mice. In contrast, serum IGFBP-2 mRNA levels were significantly increased in male L mice and showed non significant increases in female L mice. Hepatic IGFBP-2 mRNA levels were significantly increased in L mice and decreased in H mice as compared to C mice. Expression of IGFBP-4 mRNA in the liver was significantly decreased in both selection lines (L, H) as compared to the random-bred controls. Our findings demonstrate that altered growth of mice resulting from selection for body weight is associated with complex changes in the endocrine network of the GH/IGF system.