Diminished growth and enhanced glucose metabolism in triple knockout mice containing mutations of insulin-like growth factor binding protein-3,-4, and-5
Diminished growth and enhanced glucose metabolism in triple knockout mice containing mutations of insulin-like growth factor binding protein-3,-4, and-5
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DOI：
10.1210/me.2005-0196
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发表时间：
2006-09-01
影响因子：
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通讯作者：
Pintar, John E.
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文献类型：
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作者：
Ning, Yun;Schuller, Alwin G. P.;Pintar, John E.
胰岛素样生长因子-I（IGF - I）和胰岛素样生长因子 - II（IGF - II）是哺乳动物生长、发育和代谢的重要调节因子，其作用受六种高亲和力的胰岛素样生长因子结合蛋白（IGFBPs）调节。新的基因敲除（KO）小鼠品系，分别缺失IGFBP - 3、 - 4或 - 5，除了在IGFBP - 4缺失时出现适度的生长障碍（约为野生型的85% - 90%）外，在生长或代谢方面没有明显缺陷。为了继续探究这些蛋白质在整体动物生理学中的作用，我们培育了组合型IGFBP基因敲除小鼠。IGFBP - 3、 - 4和 - 5基因靶向缺陷的纯合子小鼠能够存活，出生时与IGFBP - 4基因敲除小鼠大小相同。然而，与IGFBP - 4基因敲除小鼠不同的是，三重基因敲除小鼠到成年时体型明显更小（为野生型的78%），脂肪垫积累显著减少（P < 0.05），总IGF - I循环水平（为野生型的45%；P < 0.05）和IGF - I生物活性（为野生型的37%；P < 0.05）也显著降低。在代谢方面，三重基因敲除小鼠胰岛素耐受性正常，但β细胞数量增加了37%（P < 0.05），葡萄糖刺激后胰岛素分泌显著增加，这导致葡萄糖处置增强。最后，三重基因敲除小鼠表现出Erk信号通路激活的组织特异性下降以及股四头肌重量减轻。综上所述，这些数据为IGFBP - 3、 - 4和 - 5在代谢以及至少一些软组织中的组合效应提供了直接证据，并有力地表明IGFBP - 3和 - 5在维持小鼠IGF - I介导的出生后生长方面具有重叠作用。
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 ( similar to 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.