Maternal obesity, AMPK and fetal brown adipogenesis

母体肥胖、AMPK与胎儿棕色脂肪生成 明杜发育生物学小组，华盛顿州立大学，普尔曼，华盛顿州99164 摘要 意义：高达35%的美国孕妇患有临床肥胖症，还有更多的孕妇患有肥胖症。 妊娠期糖尿病，影响胎儿发育并对后代健康产生长期影响的疾病， 包括肥胖和2型糖尿病的易感性。潜在的机制仍然没有明确的定义。 原理：棕色脂肪组织(BAT)和米色脂肪细胞燃烧脂肪来产生热量；因此，增强 BAT功能可预防肥胖、糖尿病和代谢紊乱。我们发现，母亲肥胖(MO)会损害 胎儿蝙蝠的发育对蝙蝠和米色脂肪细胞的产热有长期的负面影响 成年人。胎儿蝙蝠的发育包括棕色/米色脂肪生成，这需要PRDM16，和 不可或缺的转录因子。我们发现，MO抑制AMP激活的蛋白激酶(AMPK)，并降低 PRDM16通过阻断其启动子中的DNA去甲基化而表达。我们还发现α-酮戊二酸 AKG是组蛋白和DNA去甲基化的限速因子，组蛋白修饰指导DNA去甲基化 去甲基化。此外，MO和AMPK的抑制增加了胞质乙酰辅酶A(ACOA)的浓度，从而 应该促进白色脂肪的生成。因为米色和白色脂肪细胞具有共同的祖细胞 我们假设：MO抑制AMPK可减弱AKG介导的组蛋白去甲基化。 PRDM16启动子，加上ACOA水平升高，折衷棕色/米色，有利于白色脂肪生成 在胎儿发育过程中。具体目的：1)检测AKG在MO与受损组蛋白去甲基化之间的联系 Prdm16启动子在胎儿蝙蝠发育中的作用；2)研究提高了由于MO在增强白质中的ACOA 3)探讨AMPK在连接MO、AKG/ACOA比值和 棕色/米色与白色脂肪生成。创新：建议的研究基于我们的最新发现 AMPK/AKG轴调节Prdm16启动子的DNA去甲基化，这是棕色/米色所需的过程 脂肪生成，并将继续探索MO在组蛋白去甲基化中的作用，组蛋白去甲基化管理基因位点特异性 DNA去甲基化；我们将进一步探索AMPK在决定棕色/米色还是白色中的中介作用 MO对脂肪生成的影响。环境：所需的所有方法都已在我们的 实验室。发育生物学小组和生殖生物学中心提供了极好的 学术环境、动物和实验室设施。影响：拟议的研究将证明AMPK 和AKG/ACOA比率作为调节胎儿蝙蝠发育的关键因素，这将使其 可能使用现有的抗糖尿病药物，已知的AMPK激活剂，以防止胎儿蝙蝠的损伤 肥胖母亲的发展。考虑到最近大量存在的棕色/米色 成人脂肪细胞及其胎儿蝙蝠和米色脂肪细胞发育的长期影响 成人的生热功能，改善胎儿棕色/米色脂肪发育的干预措施将有助于 越来越多的肥胖孕妇和患有妊娠期糖尿病的妇女生产健康的孩子。

Maternal obesity, AMPK and fetal brown adipogenesis Min Du Developmental Biology Group, Washington State University, Pullman, WA 99164 ABSTRACT SIGNIFICANCE: Up to 35% of pregnant American women are clinically obese, and additional women are with gestational diabetes, conditions which affect fetal development with long-term consequences for offspring health, including pre-disposition to obesity and type 2 diabetes. The underlying mechanisms remain poorly defined. RATIONALE: Brown adipose tissue (BAT) and beige adipocytes burn lipids to generate heat; thus, enhancing BAT function prevents obesity, diabetes and metabolic disorders. We found that maternal obesity (MO) impairs fetal BAT development, which has long-term negative impacts on BAT and beige adipocyte thermogenesis in adults. Fetal BAT development involves both brown/beige adipogenesis, which requires PRDM16, an indispensable transcription factor. We found that MO inhibits AMP-activated protein kinase (AMPK) and reduces Prdm16 expression through blocking DNA demethylation in its promoter. We also found that α-ketoglutarate (aKG) is a rate limiting factor for both histone and DNA demethylations, and histone modifications guide DNA demethylation. In addition, MO and AMPK inhibition increase cytosolic acetyl-CoA (ACoA) concentration, which should promote white adipogenesis. Because beige and white adipogenesis share a common pool of progenitor cells, we HYPOTHESIZE: AMPK inhibition due to MO attenuates aKG-mediated histone demethylation in the Prdm16 promoter, coupled with elevated ACoA level, compromising brown/beige in favor of white adipogenesis during fetal development. SPECIFIC AIMS: 1) examine aKG in linking MO to impaired histone demethylation in the Prdm16 promoter during fetal BAT development; 2) study elevated ACoA due to MO in enhancing white adipogenesis within fetal BAT; and 3) explore the mediatory role of AMPK in linking MO, aKG/ACoA ratio and brown/beige versus white adipogenesis. INNOVATION: Proposed studies are based on our recent discovery that AMPK/aKG axis regulates DNA demethylation of the Prdm16 promoter, a process required for brown/beige adipogenesis, and will continue to explore the role of MO in histone demethylations, which governs locus-specific DNA demethylation; we will further explore the mediatory role of AMPK in determining brown/beige versus white adipogenesis affected by MO. ENVIRONMENT: All methodologies required have been established in our laboratory. The Developmental Biology Group and the Center for Reproductive Biology provide excellent academic environment, and animal and laboratory facilities. IMPACT: Proposed studies will demonstrate AMPK and aKG/ACoA ratio as key factors regulating fetal BAT development impaired due to MO, which will make it possible to use available anti-diabetic drugs, known activators of AMPK, to prevent impairment of fetal BAT development of obese mothers. Given the recent demonstration of abundant existence of brown/beige adipocytes in human adults and the long-term impact of fetal BAT and beige adipocyte development on their thermogenic function in adults, interventions to improve fetal brown/beige adipose development will help the increasing number of obese pregnant women and women with gestational diabetes to deliver healthy children.