Overexpression of Insulin-Like Growth Factor-Binding Protein-2 in Transgenic Mice Reduces Postnatal Body Weight Gain

Abstract

Insulin-like growth factor (IGF)-binding protein-2 (IGFBP-2) has been shown to inhibit IGF-dependent cell proliferation in a number of in vitro studies. However, no in vivo model of IGFBP-2 overexpression has been established so far. Therefore, we have generated transgenic mice, in which expression of a mouse IGFBP-2 complementary DNA is controlled by the cytomegalovirus (CMV) promoter. In two independent transgenic strains, transgene expression was highest in pancreas and stomach, followed by skeletal muscle, heart, colon, spleen, adipose tissue, brain, and kidney. Within the pancreas, IGFBP-2 expression was found in the islets but not in the exocrine part. Serum IGFBP-2 levels of CMV-IGFBP-2 transgenic mice were about 3-fold (P < 0.05) increased, compared with controls, whereas serum levels of IGF-I and IGF-II were unaffected by IGFBP-2 overexpression. Fasted serum glucose and fasted insulin levels were slightly reduced in transgenic mice, compared with controls. Postprandial serum glucose insulin levels were not affected by the genotype. At days later than 23, body weights of transgenic mice were significantly (P < 0.05) reduced in both sexes, compared with nontransgenic littermates. This reduction in body weight was mainly attributable to significantly (P < 0.05) lower carcass weights of CMV-IGFBP-2 transgenic vs. control mice. In contrast, absolute organ weights were not (or only as a tendency) reduced, except for the weight of the spleen, which was significantly (P < 0.05) lower in male transgenic than in control mice. Our data suggest that IGFBP-2 represents a negative regulator of postnatal growth in mice, potentially by reducing the bioavailability of IGF-I.

IGFBP-2 - taking the lead in growth, metabolism and cancer

“…3), is unclear. However, it is important to highlight that in both studies (Hoeflich et al 1999(Hoeflich et al , 2001), IGFBP-2 was constitutively over-expressed in most tissues resulting in very high local levels of IGFBP-2, such that overexpression of IGFBP-2 at supraphysiological levels may be different from more physiological alterations and therefore more profoundly affected local activities of IGFBP-2.…”

Dissociation of somatic growth, time of sexual maturity, and life expectancy by overexpression of an RGD ‐deficient IGFBP ‐2 variant in female transgenic mice

“…On a tissue level (Fig. 2), overexpression of wild‐type IGFBP‐2 in female D‐mice resulted in stronger weight reductions in skeletal muscles than in the liver, heart, or brain, which is in accordance with previous results (Hoeflich et al ., 1999). At 10 weeks of age, the effects of RGD‐deficient IGFBP‐2 in E‐mice were comparable to those in D‐mice for body weight and weights of isolated muscle, liver, heart, perinephric, brown fat, and gonadal fat.…”

“…For studying long‐term survival, mice older than 490 days were used. In study I, male and female hemizygous IGFBP‐2 transgenic mice and controls (C57BL/6) as described in (Hoeflich et al ., 1999) were kept at the Gene Center, LMU Munich. In study II, IGFBP‐2 transgenic mice and controls were used from a mixed genetic background (C57BL/6 × NMRI) (Hoeflich et al ., 2001) and were maintained in the mouse facility of the Institute of Veterinary Pathology (LMU Munich).…”

“…Owing to mutations of the GHR in Laron dwarfs and corresponding mouse mutants being associated with a drastic reduction of growth, it was investigated whether moderate growth impairment, for example, caused by overabundance of IGF1 inhibitory binding proteins (Hoeflich et al ., 2004), may still have significant consequences for life expectancy and sexual development. Consequently, two different IGFBP‐2 transgenic mouse models (Hoeflich et al ., 1999, 2002) overexpressing either wild‐type mouse IGFBP‐2 (D‐mice) or mutated IGFBP‐2 lacking the RGD‐motif required for integrin binding (Pereira et al ., 2004) and carrying an RGE‐sequence instead (E‐mice) were investigated. Circulating IGF1 levels and IGFBP‐2 transgene expression levels in different tissues and compartments were similar in both transgenic lines, and this was due to the fact that identical expression vectors were used for generation of both mouse models (Hoeflich et al ., 2002).…”

“…In fact, by direct comparison of D‐ and E‐mice, we were able to demonstrate that the RGD‐motif present in IGFBP‐2 is involved in the regulation of GLUT4 trafficking and glucose clearance after oral glucose administration (Reyer et al ., 2015). The RGD‐motif is distinct from the two IGF‐binding sites and both variants of IGFBP‐2 bind IGF2 with high affinity as demonstrated by Western ligand blotting (Hoeflich et al ., 1999, 2002). Here, our experimental system was used for testing other pleiotropic functions of wild‐type vs. mutant IGFBP‐2 overabundance on somatic growth, time of sexual maturity, and lifespan.…”