The role of liver-derived insulin-like growth factor-I

Abstract

IGF-I is expressed in virtually every tissue of the body, but with much higher expression in the liver than in any other tissue. Studies using mice with liver-specific IGF-I knockout have demonstrated that liver-derived IGF-I, constituting a major part of circulating IGF-I, is an important endocrine factor involved in a variety of physiological and pathological processes. Detailed studies comparing the impact of liver-derived IGF-I and local bone-derived IGF-I demonstrate that both sources of IGF-I can stimulate longitudinal bone growth. We propose here that liver-derived circulating IGF-I and local bone-derived IGF-I to some extent have overlapping growth-promoting effects and might have the capacity to replace each other (= redundancy) in the maintenance of normal longitudinal bone growth. Importantly, and in contrast to the regulation of longitudinal bone growth, locally derived IGF-I cannot replace (= lack of redundancy) liver-derived IGF-I for the regulation of a large number of other parameters including GH secretion, cortical bone mass, kidney size, prostate size, peripheral vascular resistance, spatial memory, sodium retention, insulin sensitivity, liver size, sexually dimorphic liver functions, and progression of some tumors. It is clear that a major role of liver-derived IGF-I is to regulate GH secretion and that some, but not all, of the phenotypes in the liver-specific IGF-I knockout mice are indirect, mediated via the elevated GH levels. All of the described multiple endocrine effects of liver-derived IGF-I should be considered in the development of possible novel treatment strategies aimed at increasing or reducing endocrine IGF-I activity.

Figure 1

Hypotheses of GH-mediated regulation of postnatal longitudinal bone growth. The different hypotheses of the mode of action for GH on longitudinal bone growth are described in detail in the text of Section II. A, Hypothesis proposed 1950–1980; B, hypothesis proposed 1980–2000; and C, currently proposed hypothesis.

Figure 2

GH exerts direct effects not dependent on IGF-I on body length. Comparison of body length in GH receptor KO (GHR KO), IGF-I KO, IGF-I/GHR double KO (IGF-I + GHR DKO), and wild-type (WT) mice at 130 d of age. The figure is adapted from Table 3 in Lupu et al. (19). Importantly, these data demonstrate that IGF-I and GH exert at least partly independent and additive stimulatory effects on body length. Values are given as percentage of WT and are means ± sem.

Figure 3

The role of liver-derived IGF-I, the total pool of circulating endocrine IGF-I, and bone-derived IGF-I for body length and cortical bone mass. The bone length and the cortical bone mass in various IGF-I KO mouse models in relation to intact mice (A) and mice with total IGF-I inactivation (E, total IGF-KO) are summarized. The IGF-I KO models given in panels B–D are mice with liver-specific IGF-I inactivation (B, liver IGF-I KO); mice with dramatically reduced circulating endocrine IGF-I levels due to triple inactivation of liver IGF-I, total ALS, and total IGFBP-3 (C, endocrine IGF-I KO); and mice with bone-specific IGF-I inactivation (D, bone IGF-I KO). The total pool of circulating “endocrine” IGF-I in serum expressed as percentage of intact mice is given within parentheses for each mouse model. Blue X indicates inactivation/lack of this component. →, Unchanged compared with intact mice; ↓, reduced compared with intact mice but less reduced than in mice with total IGF-I KO; ↓↓, substantially reduced to the level seen in total IGF-I KO.

Figure 4

Proposed model for hypothalamic-pituitary-liver feedback axis of GH secretion and how it is affected by liver-specific IGF-I deletion. Mice with liver-specific IGF-I KO (right panel) have increased GH secretion. Increased GH levels in turn enhance the liver weight. In male mice with depletion of liver-derived IGF-I, the enhanced GH trough levels feminize liver functions regulated by the sexual dimorphism of GH secretion in rodents. The mechanism by which lack of liver-derived IGF-I increases GH secretion seems to involve increased expression of GHRH and ghrelin receptors (right panel) and augmented responsiveness to these ligands at the level of the pituitary. There is no evidence that lack of liver-derived IGF-I enhances GH secretion via an effect on the hypothalamus, possibly because enhanced pituitary GH and local hypothalamic IGF-I secretion partly counteract the effects of lack of liver-derived IGF-I on the hypothalamus.

Figure 5

Both hypothalamic somatostatin and liver-derived IGF-I reduce basal pituitary GH secretion. Proposed model is shown for the regulation of basal GH release from the pituitary by both intermittent somatostatin release from the hypothalamus and continuous IGF-I release from the liver in male rodents. The GH secretion in male rodents is intermittent, with low basal levels between pulses. In the normal situation (left panels), the low basal GH levels are due to suppression of GH release from the pituitary by pulses of hypothalamic somatostatin (upper left) that coincide with the low basal GH levels (middle left). In addition, basal GH levels are suppressed by continuous release of liver-derived IGF-I (lower left). Loss of either hypothalamic somatostatin (somatostatin depletion; central panels) or liver-derived IGF-I (liver IGF-I depletion; right panels) causes enhanced basal GH levels. Therefore, the effects of both somatostatin and IGF-I seem necessary to maintain low GH trough levels and thereby the masculinizing effect of pulsatile GH secretion in rodents. Arrows depict the effect of a GH pulse to initiate the somatostatin pulse during the next coming GH trough. Therefore, GH can inhibit its own secretion via a short loop feedback effect at the hypothalamic level, suggesting that the pulsatility of GH secretion is due to a reciprocal interplay between the hypothalamus and the pituitary and is not only due to an intrinsic rhythm of the hypothalamus itself.

Figure 6

Effects of depletion of liver IGF-I on carbohydrate metabolism. Lack of liver-derived IGF-I (right panel) causes enhanced GH secretion from the pituitary, which in turn results in insulin insensitivity in the liver, skeletal muscle, and adipose tissue. Therefore, more insulin is needed to prevent glucose secretion from the liver and to stimulate glucose uptake by skeletal muscle and adipose tissue. The mice with liver-specific IGF-I inactivation are normoglycemic but hyperinsulinemic.

Figure 7

Reduced spatial learning (A) and memory (B) in mice with liver-specific IGF-I inactivation. Reference memory was measured using the water maze test. During this test, the latency time for the mice to find a platform hidden in water is recorded. The release point, where the mice are let into the water, is randomly shifted. A, Latency time to find the escape platform in 15-month-old mice with liver-specific IGF-I KO (n = 9) and control mice (n = 9) during the first 5 d of the water maze. A two-way ANOVA for repeated measurements was performed, followed by Student Newman Keul’s post hoc test. B, Results of the spatial reference memory (probe) test at day 6. The reference memory (probe) test was performed in the absence of the platform, and percentage of time spent in the trained quadrant was recorded. In B, the given P value is based on an unpaired t test. Values are given as means ± sem. Adapted from Ref. .

Figure 8

Mice with liver-specific inactivation of IGF-I displayed reduced prostate weight. The clearly decreased prostate weight in mice with liver-specific IGF-I KO associated with decreased mRNA and protein levels of the AR in the ventral prostate. Thus, liver-specific IGF-I deletion reduces the number of ARs expressed in the prostate (right panel). Testosterone from the testicles is then less effective in increasing prostate size. This could, hence, be a mechanism for circulating IGF-I to converge with the androgenic pathway in the regulation of prostate size.

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. 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).