Alpha Lipoic Acid as a Maternal Supplement in Obese Pregnancies

在美国，50%的孕妇超重或肥胖，不仅使母亲的健康处于危险之中，而且在他们出生之前就给后代带来了巨大的医疗保健负担。母亲孕前肥胖与过度妊娠期体重增加（GWG）和子宫内和出生后环境中的代谢不良相关，这些代谢不良使后代暴露于夸大的发育信号（如激素、葡萄糖、脂质和炎症介质），对成年期的疾病风险结果产生负面影响。医学研究所建议超重/肥胖的准妈妈接受饮食和运动咨询，以限制GWG，然而，大多数肥胖妇女在怀孕期间对生活方式干预表现出适度和可变的反应，原因是各种实际（缺乏时间，动机）和生理（食欲变化，疲劳）。虽然妇女可能有动机改善饮食模式，但据报道，怀孕前和怀孕期间的饮食质量都没有改善。此外，尽管孕前被认为是生活方式改变可以防止有害儿童结局的关键窗口，但高计划外怀孕率（美国为51%）并没有提供这种机会。考虑到目前生活方式干预措施在改善孕产妇孕前BMI和限制GWG方面的局限性，严重缺乏有效解决孕产妇肥胖问题的治疗方案。一个有希望的，但基本上未探索的选择可能是在膳食补充天然保健产品与既定的抗肥胖和促进代谢健康的反应。α-硫辛酸（α LPA）在营养品中是值得注意的，因为它提供了广泛的代谢益处，具有据称的抗肥胖、抑制食欲、降低葡萄糖和胰岛素增敏作用。然而，它尚未被审查的背景下，产妇肥胖症作为一种预防性治疗，以防止不良的编程结果。因此，我们的建议有两个具体目的：i）描述肥胖妊娠中母体和胎儿对膳食α LPA补充剂的代谢适应性; ii）确定母体α LPA补充剂在整个生命过程中对预防围产期肥胖和后代相关代谢功能障碍的影响。我们将使用一个充分表征的饮食诱导的肥胖妊娠大鼠模型，使胎儿胰腺β细胞功能和下丘脑食欲调节神经肽信号传导发生异常，从而导致成年期肥胖和葡萄糖耐受不良。将探索在整个孕前、妊娠期和哺乳期母体α LPA补充的安全性和有效性，作为预防肥胖妊娠后代适应不良编程反应的一种方法。本提案中的想法应被视为高度探索性的，如果成功，将对早期肥胖预防策略产生高度影响，并为推进α LPA的新应用提供知情理解。

Fifty-percent of pregnant women in the US are overweight or obese, putting not only the mother’s health at risk but also placing a substantial health care burden on future generations before they are even born. Maternal pre-pregnancy obesity is associated with excessive gestational weight gain (GWG) and metabolic adverse in utero and postnatal environments that expose offspring to exaggerated developmental signals (e.g. hormones, glucose, lipids, and inflammatory mediators) that negatively impact disease risk outcomes in adulthood. The Institute of Medicine recommends that overweight/obese expectant mothers receive dietary and exercise counselling to limit GWG, however, most obese women demonstrate modest and variable responses to lifestyle interventions during pregnancy for various practical (lack of time, motivation) and physiological (change in appetite, fatigue) reasons. Although women may be motivated to improve eating patterns, a lack of improvement in dietary quality both before and during pregnancy has been reported. Further, although the pre-pregnancy period is regarded as a critical window where lifestyle changes could prevent harmful child outcomes, the high rate of unplanned pregnancies (51% in the US) do not provide this opportunity. Given the breadth of current limitations in lifestyle interventions to improve maternal pre-pregnancy BMI and limit GWG, there is a serious lack of treatment options that effectively address the ever-growing problem of maternal obesity. A promising, yet essentially unexplored, option may be found in dietary supplementation of natural health products with established anti-obesity and metabolic health-promoting responses. α-lipoic acid (αLPA) is notable amongst nutraceuticals as it offers a wide array of metabolic benefits with purported anti-obesity, appetite-suppressing, glucose lowering, and insulin sensitizing effects. However, it has yet to be examined in the context of maternal obesity as a preventative therapy to protect against adverse programming outcomes. Therefore, our proposal has two Specific Aims: i) To characterize maternal and fetal metabolic adaptations to dietary αLPA supplementation in obese pregnancies; and ii) To determine the influence of maternal αLPA supplementation in protecting against perinatal programming of obesity and associated metabolic dysfunction in offspring throughout the life course. We will use a well-characterized diet-induced obese pregnancy rat model to malprogram fetal pancreatic beta cell function and hypothalamic appetite-regulating neuropeptide signaling resulting in adult-onset obesity and glucose intolerance. The safety and efficacy of maternal αLPA supplementation throughout pre- pregnancy, gestation, and lactation will be explored as a means to protect against maladaptive programming responses in offspring from obese pregnancies. The ideas in this proposal should be considered highly exploratory that, if successful, would have a high degree of impact for early obesity prevention strategies and provide an informed understanding to advance novel applications for αLPA.