Maternal obesity, AMPK and fetal brown adipogenesis

母亲肥胖、AMPK 和胎儿棕色脂肪形成

基本信息

批准号：
10220090
负责人：
MIN DU
金额：
$ 31.11万
依托单位：
WASHINGTON STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-27 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10220090
关键词：
5&apos -AMP-activated protein kinase Acetyl Coenzyme A Adipocytes Adipose tissue Adult Affect American Antidiabetic Drugs Attenuated Birth Brown Fat Burn injury Cardiovascular Diseases Cells Cellular Metabolic Process Child Citric Acid Cycle Clinical Coupled Cyclic AMP-Dependent Protein Kinases DNA Development Developmental Biology Diabetes Mellitus Environment Enzymes Fatty Acids Fatty acid glycerol esters Fetal Development Genes Gestational Diabetes Glucose Health Histones Impairment Intervention Laboratories Link Lipids Lysine Mediating Mediator of activation protein Metabolic Diseases Metabolic dysfunction Metabolism Methodology Mixed Function Oxygenases Non-Insulin-Dependent Diabetes Mellitus Obesity PPAR gamma Platelet-Derived Growth Factor alpha Receptor Predisposition Pregnant Women Prevalence Process Protein Isoforms Protein Kinase Proteins Reaction Reproductive Biology Role Source Structure Thermogenesis Time Tissues Universities Washington Woman Work adipocyte differentiation alpha ketoglutarate animal facility attenuation base demethylation fetal histone methylation histone modification improved laboratory facility lipid biosynthesis maternal obesity negative affect obese mothers obesity development obesity prevention offspring pregnant prevent progenitor programs promoter stem cells therapeutic target transcription factor

项目摘要

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.

母亲肥胖、AMPK 和胎儿棕色脂肪形成杜敏发育生物学组，华盛顿州立大学，普尔曼，WA 99164 抽象的意义：高达 35% 的美国孕妇患有临床肥胖，还有更多女性患有肥胖症妊娠糖尿病，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，其潜在机制仍不清楚。基本原理：棕色脂肪组织（BAT）和米色脂肪细胞燃烧脂质产生热量，从而增强； 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 BAT 发育，对 BAT 和米色脂肪细胞生热作用具有长期负面影响成人胎儿 BAT 发育涉及棕色/米色脂肪形成，这需要 PRDM16，一种我们发现 MO 抑制 AMP 激活蛋白激酶 (AMPK) 并减少。 Prdm16通过阻断其启动子中的DNA去甲基化来表达我们还发现α-酮戊二酸。 (aKG) 是组蛋白和 DNA 去甲基化的速率限制因素，组蛋白修饰引导 DNA 此外，MO 和 AMPK 抑制会增加胞质乙酰辅酶 A (ACoA) 浓度，从而导致去甲基化。应该促进白色脂肪生成，因为米色和白色脂肪生成共享一个共同的祖细胞库。细胞，我们假设：MO 引起的 AMPK 抑制减弱了 aKG 介导的组蛋白去甲基化 Prdm16 启动子，加上 ACoA 水平升高，损害棕色/米色，有利于白色脂肪生成具体目标： 1) 检查 aKG 将 MO 与受损的组蛋白去甲基化联系起来。胎儿 BAT 发育过程中的 Prdm16 启动子；2) 研究由于 MO 增强白色而导致的 ACoA 升高胎儿 BAT 内的脂肪生成；3) 探索 AMPK 在连接 MO、aKG/ACoA 比率和棕色/米色与白色脂肪生成的比较创新：拟议的研究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，组蛋白去甲基化控制位点特异性 DNA 去甲基化；我们将进一步探讨 AMPK 在确定棕色/米色与白色中的中介作用脂肪生成受环境影响：我们已建立了所有所需的方法。发育生物学组和生殖生物学中心提供了优秀的实验室。学术环境、动物和实验室设施的影响：拟议的研究将证明 AMPK。 aKG/ACoA 比值是调节胎儿 BAT 发育的关键因素，MO 导致胎儿 BAT 发育受损，这将使其可以使用现有的抗糖尿病药物、已知的 AMPK 激活剂来防止胎儿 BAT 受损鉴于最近大量存在棕色/米色的情况，肥胖母亲的发展。成人脂肪细胞以及胎儿 BAT 和米色脂肪细胞发育对其的长期影响成人的产热功能，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糖尿病的妇女生出健康的孩子。