Maternal obesity, AMPK and fetal brown adipogenesis

母亲肥胖、AMPK 和胎儿棕色脂肪形成

• 批准号: 9751350
• 负责人: MIN DU
• 金额: $ 31.16万
• 依托单位: WASHINGTON STATE UNIVERSITY
• 依托单位国家: 美国
• 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/9751350
• 关键词: 5' -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; Genetic Transcription; 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; Modification; Non-Insulin-Dependent Diabetes Mellitus; Obesity; PDGFRB gene; Peroxisome Proliferator-Activated Receptors; Predisposition; Pregnant Women; Prevalence; Process; Protein Isoforms; Protein Kinase; Proteins; Reaction; Receptor Activation; Reproductive Biology; Role; Source; Stem cells; Structure; Thermogenesis; Time; Tissues; Universities; Washington; Woman; Work; adipocyte differentiation; animal facility; attenuation; base; demethylation; fetal; histone methylation; histone modification; improved; laboratory facility; lipid biosynthesis; maternal obesity; negative affect; obese mothers; obesity development; offspring; pregnant; prevent; progenitor; programs; promoter; receptor expression; therapeutic target; transcription factor

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 -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，还有更多的女性患有肥胖症 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， 包括易患肥胖症和 2 型糖尿病。根本机制仍然不明确。 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 成年人。胎儿 BAT 发育涉及棕色/米色脂肪生成，这需要 PRDM16， 不可缺少的转录因子。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 去甲基化。此外，MO 和 AMPK 抑制会增加胞质乙酰辅酶 A (ACoA) 浓度，从而 应促进白色脂肪生成。因为米色和白色的脂肪生成共享一个共同的祖细胞库 细胞中，我们假设：MO 引起的 AMPK 抑制会减弱 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 在胎儿发育期间。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 MO 在增强白色时导致 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。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 MO 影响。环境：我们已建立了所有所需的方法 实验室。发育生物学组和生殖生物学中心提供优秀的 学术环境以及动物和实验室设施。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 肥胖母亲的发育。鉴于最近大量存在棕色/米色 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。