TableEdit

Ning, Y, Schuller, AG, Bradshaw, S, Rotwein, P, Ludwig, T, Frystyk, J and Pintar, JE (2006) Diminished growth and enhanced glucose metabolism in triple knockout mice containing mutations of insulin-like growth factor binding protein-3, -4, and -5. Mol. Endocrinol. 20:2173-86

IGF-I and IGF-II are essential regulators of mammalian growth, development and metabolism, whose actions are modified by six high-affinity IGF binding proteins (IGFBPs). New lines of knockout (KO) mice lacking either IGFBP-3, -4, or -5 had no apparent deficiencies in growth or metabolism beyond a modest growth impairment (approximately 85-90% of wild type) when IGFBP-4 was eliminated. To continue to address the roles of these proteins in whole animal physiology, we generated combinational IGFBP KO mice. Mice homozygous for targeted defects in IGFBP-3, -4, and -5 remain viable and at birth were the same size as IGFBP-4 KO mice. Unlike IGFBP-4 KO mice, however, the triple KO mice became significantly smaller by adulthood (78% wild type) and had significant reductions in fat pad accumulation (P < 0.05), circulating levels of total IGF-I (45% of wild type; P < 0.05) and IGF-I bioactivity (37% of wild type; P < 0.05). Metabolically, triple KO mice showed normal insulin tolerance, but a 37% expansion (P < 0.05) of beta-cell number and significantly increased insulin secretion after glucose challenge, which leads to enhanced glucose disposal. Finally, triple KO mice demonstrated a tissue-specific decline in activation of the Erk signaling pathway as well as weight of the quadriceps muscle. Taken together, these data provide direct evidence for combinatorial effects of IGFBP-3, -4, and -5 in both metabolism and at least some soft tissues and strongly suggest overlapping roles for IGFBP-3 and -5 in maintaining IGF-I-mediated postnatal growth in mice.

PubMed Online version:10.1210/me.2005-0196

Adipose Tissue; Animals; Body Weight; Carbohydrate Metabolism; Female; Glucose/metabolism; Homeostasis; Insulin/pharmacology; Insulin-Like Growth Factor Binding Protein 3/deficiency; Insulin-Like Growth Factor Binding Protein 3/genetics; Insulin-Like Growth Factor Binding Protein 3/metabolism; Insulin-Like Growth Factor Binding Protein 4/deficiency; Insulin-Like Growth Factor Binding Protein 4/genetics; Insulin-Like Growth Factor Binding Protein 4/metabolism; Insulin-Like Growth Factor Binding Protein 5/deficiency; Insulin-Like Growth Factor Binding Protein 5/genetics; Insulin-Like Growth Factor Binding Protein 5/metabolism; Islets of Langerhans/drug effects; Islets of Langerhans/metabolism; MAP Kinase Signaling System; Male; Mice; Mice, Knockout; Mutation/genetics; Organ Size