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:9981427
- 负责人:
- 金额:$ 31.75万
- 依托单位:
- 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:
- 关键词:5&apos-AMP-activated protein kinaseAcetyl Coenzyme AAdipocytesAdipose tissueAdultAffectAmericanAntidiabetic DrugsAttenuatedBirthBrown FatBurn injuryCardiovascular DiseasesCellsCellular Metabolic ProcessChildCitric Acid CycleClinicalCoupledCyclic AMP-Dependent Protein KinasesDNADevelopmentDevelopmental BiologyDiabetes MellitusEnvironmentEnzymesFatty AcidsFatty acid glycerol estersFetal DevelopmentGenesGestational DiabetesGlucoseHealthHistonesImpairmentInterventionLaboratoriesLinkLipidsLysineMediatingMediator of activation proteinMetabolic DiseasesMetabolic dysfunctionMetabolismMethodologyMixed Function OxygenasesNon-Insulin-Dependent Diabetes MellitusObesityPPAR gammaPlatelet-Derived Growth Factor alpha ReceptorPredispositionPregnant WomenPrevalenceProcessProtein IsoformsProtein KinaseProteinsReactionReproductive BiologyRoleSourceStructureThermogenesisTimeTissuesUniversitiesWashingtonWomanWorkadipocyte differentiationalpha ketoglutarateanimal facilityattenuationbasedemethylationfetalhistone methylationhistone modificationimprovedlaboratory facilitylipid biosynthesismaternal obesitynegative affectobese mothersobesity developmentoffspringpregnantpreventprogenitorprogramspromoterstem cellstherapeutic targettranscription 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.
母体肥胖、AMPK与胎儿棕色脂肪形成
Min Du发育生物学小组,华盛顿州立大学,普尔曼,华盛顿州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PRDM 16,
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Prdm 16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
肥胖母亲的发育。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。
项目成果
期刊论文数量(0)
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科研奖励数量(0)
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MIN DU其他文献
MIN DU的其他文献
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{{ truncateString('MIN DU', 18)}}的其他基金
Maternal obesity, AMPK and fetal brown adipogenesis
母亲肥胖、AMPK 和胎儿棕色脂肪形成
- 批准号:
9380079 - 财政年份:2010
- 资助金额:
$ 31.75万 - 项目类别:
Maternal Obesity affects AMP-Kinase in Muscle Cell Differentiation
母亲肥胖影响肌细胞分化中的 AMP 激酶
- 批准号:
8023008 - 财政年份:2010
- 资助金额:
$ 31.75万 - 项目类别:
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 - 财政年份:2010
- 资助金额:
$ 31.75万 - 项目类别:
Maternal obesity, AMPK and fetal brown adipogenesis
母亲肥胖、AMPK 和胎儿棕色脂肪形成
- 批准号:
10220090 - 财政年份:2010
- 资助金额:
$ 31.75万 - 项目类别:
Maternal Obesity affects AMP-Kinase in Muscle Cell Differentiation
母亲肥胖影响肌细胞分化中的 AMP 激酶
- 批准号:
8306744 - 财政年份:2010
- 资助金额:
$ 31.75万 - 项目类别:
Maternal obesity, AMPK and Developmental Programming
孕产妇肥胖、AMPK 和发育规划
- 批准号:
10535287 - 财政年份:2010
- 资助金额:
$ 31.75万 - 项目类别:
Maternal Obesity affects AMP-Kinase in Muscle Cell Differentiation
母亲肥胖影响肌细胞分化中的 AMP 激酶
- 批准号:
8705552 - 财政年份:2010
- 资助金额:
$ 31.75万 - 项目类别:
Maternal obesity, AMPK and Developmental Programming
孕产妇肥胖、AMPK 和发育规划
- 批准号:
10672327 - 财政年份:2010
- 资助金额:
$ 31.75万 - 项目类别:
Maternal Obesity affects AMP-Kinase in Muscle Cell Differentiation
母亲肥胖影响肌细胞分化中的 AMP 激酶
- 批准号:
8150408 - 财政年份:2010
- 资助金额:
$ 31.75万 - 项目类别:
Maternal Obesity affects AMP-Kinase in Muscle Cell Differentiation
母亲肥胖影响肌细胞分化中的 AMP 激酶
- 批准号:
8510700 - 财政年份:2010
- 资助金额:
$ 31.75万 - 项目类别:
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