Figure 9.

Proposed role of liver-derived IGF-I. This figure shows the authors’ proposed endocrine effects of liver-derived IGF-I discussed in this review. It is clear that a major role of liver-derived IGF-I is to regulate GH secretion and that some of the phenotypes in the liver-specific IGF-I KO mice are indirect via reduced GH feedback, resulting in elevated pituitary GH secretion. The phenotypes proposed to be mediated via the altered GH feedback (right column) include insulin resistance, increased liver size, and affected sexually dimorphic liver functions, whereas other effects such as reduced cortical bone mass, reduced kidney size, reduced prostate size, increased peripheral vascular resistance, reduced spatial memory, reduced sodium retention, and reduced tumor progression (of some but not all tumors evaluated, see Ref. 5 for recent review; not discussed in this review) are proposed to be direct IGF-I effects (left column). In addition, liver-derived IGF-I has the capacity to stimulate longitudinal bone growth directly (left column), but it is not required for essentially normal bone growth in the presence of normal IGF-I expression in bone (= redundancy). Importantly, and in contrast to the regulation of longitudinal bone growth, locally derived-IGF-I cannot replace liver-derived IGF-I for the regulation of the other described phenotypes in this figure (= lack of redundancy).