Department of Veterinary Clinical and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Groennegaardsvej 7, DK-1870 Frederiksberg, Denmark.
J Endocrinol. 2013 Feb 25;216(3):389-402. doi: 10.1530/JOE-12-0389. Print 2013 Mar.
Mounting evidence led us to hypothesize that i) function of the thyroid hormone (TH) axis can be programed by late gestation undernutrition (LG-UN) and ii) early-postnatal-life overnutrition (EL-ON) exacerbates the fetal impacts on TH axis function. In a 2 × 2 factorial experiment, 21 twin-bearing sheep were fed one of two diets during late gestation: NORM (fulfilling energy and protein requirements) or LOW (50% of NORM). From day 3 to 6 months after birth (around puberty), the twin lambs were assigned to each their diet: conventional (CONV) or high-carbohydrate, high-fat, where after half the lambs were killed. Remaining sheep (exclusively females) were fed the same moderate diet until 2 years of age (young adults). At 6 months and 2 years of age, fasting challenges were conducted and target tissues were collected at autopsy. LG-UN caused adult hyperthyroidism associated with increased thyroid expression of genes regulating TH synthesis and deiodination. In one or more of the target tissues, liver, cardiac muscle, and longissimus dorsi muscle, gene expressions were increased by LG-UN for TH receptors (THRA and THRB) and deiodinases but were decreased in visceral and subcutaneous adipose tissues. EL-ON increased TH levels in adolescent lambs, but this was reversed after diet correction and not evident in adulthood. We conclude that LG-UN programed TH axis function at the secretory level and differentially in target tissues, which was increasingly manifested with age. Differential TH signaling in adipose vs other tissues may be part of a mechanism whereby fetal malnutrition can predispose for obesity and other metabolic disorders.
i）甲状腺激素（TH）轴的功能可以在妊娠晚期营养不良（LG-UN）下编程，ii）出生后早期过度营养（EL-ON）加剧了胎儿对 TH 轴功能的影响。在一项 2×2 析因实验中，21 只怀有双胞胎的绵羊在妊娠晚期接受以下两种饮食中的一种：NORM（满足能量和蛋白质需求）或 LOW（NORM 的 50%）。从出生后第 3 天到 6 个月（青春期左右），双胞胎羔羊被分配到各自的饮食：常规（CONV）或高碳水化合物、高脂肪，之后一半的羔羊被处死。其余的羊（专门是雌性）一直被喂食同样的中等饮食，直到 2 岁（年轻成年人）。在 6 个月和 2 岁时，进行禁食挑战，并在尸检时采集目标组织。LG-UN 导致成年甲状腺功能亢进症，与调节 TH 合成和脱碘的基因表达增加有关。在一个或多个目标组织（肝脏、心肌和平滑肌）中，TH 受体（THRA 和 THRB）和脱碘酶的基因表达因 LG-UN 而增加，但内脏和皮下脂肪组织中的基因表达减少。EL-ON 在青少年羔羊中增加了 TH 水平，但在饮食纠正后这种情况得到逆转，在成年期并不明显。我们得出结论，LG-UN 在分泌水平上编程了 TH 轴功能，并且在不同的靶组织中表现不同，随着年龄的增长而逐渐显现。TH 在脂肪组织和其他组织中的信号传导不同，这可能是胎儿营养不良易患肥胖和其他代谢紊乱的部分机制。
