Epigenetics of programmed obesity: alteration in IUGR rat hepatic IGF1 mRNA expression and histone structure in rapid vs. delayed postnatal catch-up growth.
Epigenetics of programmed obesity: alteration in IUGR rat hepatic IGF1 mRNA expression and histone structure in rapid vs. delayed postnatal catch-up growth.
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DOI：
10.1152/ajpgi.00052.2010
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发表时间：
2010-11
期刊：
影响因子：
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通讯作者：
D. Tosh;Q. Fu;C. Callaway;R. McKnight;I. McMillen;M. Ross;R. Lane;M. Desai
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文献类型：
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作者：
D. Tosh;Q. Fu;C. Callaway;R. McKnight;I. McMillen;M. Ross;R. Lane;M. Desai
母亲在怀孕期间的食物限制（FR）会导致胎儿宫内生长受限（IUGR），表现出快速追赶生长，并发展为代谢综合征和成人肥胖。然而，在哺乳期间持续的营养限制会延迟追赶性生长并防止肥胖的发展。IGF 1的表观遗传调节，它调节生长并由肝脏合成和分泌，可能在这些疾病的发展中发挥作用。对照组（AdLib）妊娠大鼠在妊娠期和哺乳期自由进食，FR母鼠在第10 - 21天暴露于50%限食。FR幼仔由自由采食对照母鼠（FR/AdLib）或FR母鼠（FR/FR）喂养。所有幼仔均断奶，自由采食。母亲FR导致IUGR新生儿肝脏重量显着降低，并与使用染色质免疫沉淀，减少二甲基化H3 K4在IGF 1区域观察。肥胖的成年FR/AdLib男性在IGF 1区域的H3 K4的二甲基化减少，三甲基化增加。这对应于与AdLib/AdLib对照组相比，FR/AdLib中IGF 1-A（134 ± 5%）、IGF 1-B（165 ± 6%）、IGF 1外显子1（149 ± 6%）和IGF 1外显子2（146 ± 7%）的mRNA表达增加。相比之下，非肥胖FR/FR的IGF 1-B mRNA水平（147 ± 19%）显著高于对照组，IGF 1-A外显子1或外显子2无差异。因此，调节IUGR新生儿追赶生长的速率可以防止IGF 1表观遗传修饰，从而防止肥胖和相关的代谢异常。
Maternal food restriction (FR) during pregnancy results in intrauterine growth-restricted (IUGR) offspring that show rapid catch-up growth and develop metabolic syndrome and adult obesity. However, continued nutrient restriction during nursing delays catch-up growth and prevents development of obesity. Epigenetic regulation of IGF1, which modulates growth and is synthesized and secreted by the liver, may play a role in the development of these morbidities. Control (AdLib) pregnant rats received ad libitum food through gestation and lactation, and FR dams were exposed to 50% food restriction from days 10 to 21. FR pups were nursed by either ad libitum-fed control dams (FR/AdLib) or FR dams (FR/FR). All pups were weaned to ad libitum feed. Maternal FR resulted in IUGR newborns with significantly lower liver weight and, with the use of chromatin immunoprecipitation, decreased dimethylation at H3K4 in the IGF1 region was observed. Obese adult FR/AdLib males had decreased dimethylation and increased trimethylation of H3K4 in the IGF1 region. This corresponded to an increase in mRNA expression of IGF1-A (134 ± 5%), IGF1-B (165 ± 6%), IGF1 exon 1 (149 ± 6%), and IGF1 exon 2 (146 ± 7%) in the FR/AdLib compared with the AdLib/AdLib control group. In contrast, nonobese FR/FR had significantly higher IGF1-B mRNA levels (147 ± 19%) than controls with no difference in IGF1-A, exon 1 or exon 2. Modulation of the rate of IUGR newborn catch-up growth may thus protect against IGF1 epigenetic modifications and, consequently, obesity and associated metabolic abnormalities.