Maternal obesity, AMPK and fetal brown adipogenesis

母体肥胖、AMPK与胎儿棕色脂肪形成 华盛顿州立大学，普尔曼，WA 99164 摘要 重要性：高达35%的美国孕妇患有临床肥胖症， 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， 包括易患肥胖症和2型糖尿病。基本的机制仍然不明确。 依据：棕色脂肪组织（BAT）和米色脂肪细胞燃烧脂质产生热量;因此， 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）损害 胎儿BAT发育，这对BAT和米色脂肪细胞产热有长期的负面影响， 成年人了胎儿BAT发育涉及棕色/米色脂肪形成，这需要PRDM16， 不可缺少的转录因子。我们发现MO抑制AMP活化蛋白激酶（AMPK）， 通过阻断Prdm 16启动子中的DNA去甲基化来表达Prdm 16。我们还发现α-酮戊二酸 (aKG)是组蛋白和DNA去甲基化的速率限制因子，组蛋白修饰引导DNA 去甲基化此外，MO和AMPK抑制增加细胞溶质乙酰辅酶A（ACoA）浓度， 应该促进白色脂肪形成。因为米色和白色的脂肪形成有共同的祖细胞库 细胞，我们假设：由于MO抑制AMPK减弱aKG介导的组蛋白去甲基化， Prdm 16启动子，加上升高的ACoA水平，使棕色/米色妥协，有利于白色脂肪形成 在胎儿发育期间。具体目的：1）检查aKG在连接MO与受损的组蛋白去甲基化中的作用， 在胎儿BAT发育过程中Prdm 16启动子; 2）研究由于MO在增强白色中升高的ACoA 3）探讨AMPK在连接MO、aKG/ACoA比值和 棕色/米色对比白色脂肪形成。创新：建议的研究是基于我们最近的发现 AMPK/aKG轴调节Prdm16启动子的DNA去甲基化，这是棕色/米色 脂肪形成，并将继续探讨MO在组蛋白去甲基化中的作用，这决定了基因座特异性 DNA去甲基化;我们将进一步探讨AMPK在确定棕色/米色与白色之间的介导作用。 脂肪生成受MO影响。环境：我们已经建立了所需的所有方法 实验室发育生物学小组和生殖生物学中心提供了优秀的 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比值作为调节胎儿BAT发育的关键因素，由于MO而受损，这将使其 可能使用可用的抗糖尿病药物，已知的AMPK激活剂，以防止胎儿BAT受损 肥胖母亲的发展。鉴于最近大量存在棕色/米色的证据， 以及胎儿BAT和米色脂肪细胞发育对其发育的长期影响。 在成年人的产热功能中，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糖尿病的妇女能够生下健康的孩子。

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.