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首页> 外文期刊>The journals of gerontology.Series A. Biological sciences and medical sciences >17 alpha-Estradiol Modulates IGF1 and Hepatic Gene Expression in a Sex-Specific Manner
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17 alpha-Estradiol Modulates IGF1 and Hepatic Gene Expression in a Sex-Specific Manner

机译：17α-雌二醇以性别特异性方式调节IGF1和肝基因表达

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摘要

Aging is the greatest risk factor for most chronic diseases. The somatotropic axis is one of the most conserved biological pathways that regulates aging across species. 17 alpha-Estradiol (17 alpha-E2), a diastereomer of 17 beta-estradiol (17 beta-E2), was recently found to elicit health benefits, including improved insulin sensitivity and extend longevity exclusively in male mice. Given that 17 beta-F2 is known to modulate somatotropic signaling in females through actions in the pituitary and liver, we hypothesized that 17 alpha-E2 may be modulating the somatotropic axis in males, thereby contributing to health benefits. I lerein, we demonstrate that 17 alpha-E2 increases hepatic insulin-like growth factor 1 (IGF1) production in male mice without inducing any changes in pulsatile growth hormone (GH) secretion. Using growth hormone receptor knockout (GHRKO) mice, we subsequently determined that the induction of hepatic IGF1 by 17 alpha-F2 is dependent upon GH signaling in male mice, and that 17 alpha E2 elicits no effects on IGF1 production in female mice. We also determined that 17 alpha-E2 failed to feminize the hepatic transcriptional profile in normal (N) male mice, as evidenced by a clear divergence between the sexes, regardless of treatment. Conversely, significant overlap in transcriptional profiles was observed between sexes in GHRKO mice, and this was unaffected by 17 alpha-E2 treatment. Based on these findings, we propose that 17 alpha-E2 acts as a pleiotropic pathway modulator in male mice by uncoupling IGF1 production from insulin sensitivity. In summary, 17 alpha-E2 treatment upregulates IGF1 production in wild-type (and N) male mice in what appears to be a GH-dependent fashion, while no effects in female IGF1 production are observed following 17 alpha-E2 treatment.
机译：衰老是大多数慢性病的最大风险因素。促生长轴是调节物种衰老的最保守的生物途径之一。17-α-雌二醇（17-α-E2）是17-β-雌二醇（17-β-E2）的非对映异构体，最近发现它对健康有益，包括改善胰岛素敏感性和延长雄性小鼠的寿命。鉴于已知17β-F2通过垂体和肝脏的作用调节女性的促生长信号，我们假设17α-E2可能调节男性的促生长轴，从而有助于健康。lerein，我们证明17α-E2增加雄性小鼠肝脏胰岛素样生长因子1（IGF1）的产生，而不引起搏动性生长激素（GH）分泌的任何变化。使用生长激素受体敲除（GHRKO）小鼠，我们随后确定17α-F2对雄性小鼠肝脏IGF1的诱导依赖于GH信号，17αE2对雌性小鼠IGF1的产生没有影响。我们还确定，17α-E2未能使正常（N）雄性小鼠的肝脏转录谱女性化，这一点可以从性别之间的明显差异中得到证明，无论是否接受治疗。相反，在GHRKO小鼠中观察到性别间转录谱的显著重叠，而17α-E2处理对其没有影响。基于这些发现，我们提出17-α-E2通过将IGF1的产生与胰岛素敏感性分离，在雄性小鼠中充当多效性途径调节剂。总之，17α-E2治疗以生长激素依赖的方式上调野生型（和N）雄性小鼠的IGF1生成，而在17α-E2治疗后未观察到对雌性IGF1生成的影响。

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