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Diminished Growth and Enhanced Glucose Metabolism in Triple Knockout Mice Containing Mutations of Insulin-Like Growth Factor Binding Protein-3, -4, and -5

Department of Neuroscience and Cell Biology (Y.N., A.G.P.S., S.B., J.E.P.), University of Medicine and Dentistry of New Jersey, Piscataway, New Jersey 08854; Department of Biochemistry & Molecular Biology (P.R.), Oregon Health & Science University, Portland, Oregon 97201; Department of Pathology (T.L.), Columbia University, New York, New York 10032; and Institute of Experimental Clinical Research (J.F.), Aarhus University Hospital, Aarhus DK-8000, Denmark

Address all correspondence and requests for reprints to: John E. Pintar, Department of Neuroscience and Cell Biology, University of Medicine and Dentistry of New Jersey, Piscataway, New Jersey 08854. E-mail: pintar{at}cabm.rutgers.edu.

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 (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 ß-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.

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