Transgenerational inheritance of the insulin-resistant phenotype in embryo-transferred intrauterine growth-restricted adult female rat offspring
Transgenerational inheritance of the insulin-resistant phenotype in embryo-transferred intrauterine growth-restricted adult female rat offspring
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DOI：
10.1152/ajpendo.00462.2006
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发表时间：
2007-05-01
影响因子：
5.1
通讯作者：
Devaskar, Sherin U.
中科院分区：
文献类型：
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作者：
Thamotharan, Manikkavasagar;Garg, Meena;Devaskar, Sherin U.
为了确定宫内生长受限的第二代成年女性（F2 IUGR）跨代存在代谢紊乱的机制，尽管子宫内代谢环境正常化，我们研究了体内葡萄糖动力学和体外骨骼肌胰岛素后受体信号转导后，胚胎移植的第一代（F1 IUGR），以控制母体环境。雌性F2大鼠，生育的F1出生前和出生后的营养和生长限制（IUGR）的母亲，但胚胎转移到怀孕的对照母亲，进行了比较，与同样怀孕的年龄和性别匹配的控制（CON）F2后代。虽然出生体重或出生后生长模式没有差异，但与F2 CON相比，F2 IUGR的肝脏重量增加，空腹高血糖，高胰岛素血症和未抑制的肝脏葡萄糖产生，葡萄糖无效循环或清除率没有变化。这些激素和代谢异常与骨骼肌总GLUT 4和pAkt浓度增加有关，但与质膜相关GLUT 4降低有关。总pPKC zeta和PKC zeta酶活性，与F2 CON相比，IUGR F2中总SHP 2和PTP 1B浓度没有变化。我们得出结论，F2 IUGR成年雌性后代的异常葡萄糖/胰岛素代谢和骨骼肌胰岛素信号传导的跨代存在与直接的宫内环境无关，支持导致2型糖尿病流行的营养诱导的遗传机制。
To determine mechanisms underlying the transgenerational presence of metabolic perturbations in the intrauterine growth-restricted second-generation adult females (F2 IUGR) despite normalizing the in utero metabolic environment, we examined in vivo glucose kinetics and in vitro skeletal muscle postinsulin receptor signaling after embryo transfer of first generation (F1 IUGR) to control maternal environment. Female F2 rats, procreated by F1 pre- and postnatally nutrient- and growth-restricted (IUGR) mothers but embryo transferred to gestate in control mothers, were compared with similarly gestating age- and sex-matched control (CON) F2 progeny. Although there were no differences in birth weight or postnatal growth patterns, the F2 IUGR had increased hepatic weight, fasting hyperglycemia, hyperinsulinemia, and unsuppressed hepatic glucose production, with no change in glucose futile cycling or clearance, compared with F2 CON. These hormonal and metabolic aberrations were associated with increased skeletal muscle total GLUT4 and pAkt concentrations but decreased plasma membrane-associated GLUT4, total pPKC zeta, and PKC zeta enzyme activity, with no change in total SHP2 and PTP1B concentrations in IUGR F2 compared with F2 CON. We conclude that transgenerational presence of aberrant glucose/insulin metabolism and skeletal muscle insulin signaling of the adult F2 IUGR female offspring is independent of the immediate intrauterine environment, supporting nutritionally induced heritable mechanisms contributing to the epidemic of type 2 diabetes mellitus.