Early life n-3 fatty acids increase novel Adipogenesis-regulatory cells to condition adipogenesis in a NR2F2 dependent manner
生命早期 n-3 脂肪酸增加新型脂肪生成调节细胞,以 NR2F2 依赖性方式调节脂肪生成
基本信息
- 批准号:9807608
- 负责人:
- 金额:$ 11.66万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-08-01 至 2019-12-23
- 项目状态:已结题
- 来源:
- 关键词:AddressAdipocytesAdipose tissueAdolescentAdultAffectAgeAttenuatedBiological AssayBloodBody fatBreastfed infantCCAAT-Enhancer-Binding ProteinsCaenorhabditis elegansCancer BurdenCell CountCell Culture TechniquesCellsCellular MorphologyCellularityChildCoculture TechniquesDNA MethylationDataDevelopmentDietDiseaseEpigenetic ProcessExposure toF3 geneFASN geneFatty AcidsFatty acid glycerol estersFlow CytometryFosteringFrequenciesGenetic TranscriptionGrowthHeart DiseasesHistologyIn VitroIncidenceIndividualInfantInsuranceLeptinLifeLinkLipidsLoxP-flanked alleleMagnetic ResonanceMeasuresMediatingMediator of activation proteinMedicalMesenchymal Stem CellsMessenger RNAMetabolicModalityModernizationMolecularMorphologyMothersMusNeonatalNon-Insulin-Dependent Diabetes MellitusNutritionalObesityOmega-3 Fatty AcidsOverweightPatternPeroxisome Proliferator-Activated ReceptorsPhenotypePlayPolyunsaturated Fatty AcidsPopulationPregnancyProliferatingProteinsQuality of lifeRNAResearchResolutionRoleSignal TransductionStem cellsStimulusSystemTechniquesTestingTherapeuticTimeTissue ExpansionWell in selfYouthapoAI regulatory protein-1cancer typegenetic manipulationin vivoinsulin sensitivitylipid biosynthesislive cell imagingmother nutritionneonatenovelobesity in childrenobesity preventionoffspringparacrineperinatal developmentpostnatalprecursor cellprogenitorpublic health relevancepupresponsesingle-cell RNA sequencingstemtranscriptome sequencing
项目摘要
ABSTRACT
Nearly 20% of children are obese or overweight. It is anticipated half of childhood obesity will occur by age 5
and more than half of existing children will develop obesity by age 35. Maternal diet-derived nutritional signals
transmitted during perinatal development condition metabolic responses later in life. We found high n-6 to n-3
(n6/n3) fatty acid exposures positively associate with increased infant body fat accumulation; and in mice,
lowering n6/n3 exposure conditioned neonatal adipogenesis epigenetically, imparting long-lasting metabolic
benefit to adults. Our findings led to the central hypothesis:
Low n6/n3 exposure during development conditions adipogenesis via cellular and functional
responses within stem-like adipocyte precursor populations.
Adipocyte precursor cell (APC) subtypes include progenitors, preadipocytes, and newly discovered
“Adipogenesis-regulatory” cells (Areg). Aregs attenuate adipose tissue expansion (ATE) in a cell number
and paracrine way. Importantly, we observe attenuated neonatal body fat accumulation, morphology, and
cellularity from low n6/n3 exposure in mice. This phenotype supports that patterning of ATE is sensitive to early
life n6/n3, yet, the APC subtype frequencies and molecular diversity regulated by low n6/n3 stimuli remain
unknown.
We began addressing this gap by isolating primary APCs from fat depots of pups with high and low n6/n3
exposure. Preliminary bulk RNA-seq analysis identified increased Areg subtype markers from low n6/n3
exposure. Included is NR2F2 -a key transcriptional regulator linked to attenuated adipogenesis. In co-culture,
APCs conditioned in vivo by low n6/n3 proliferated slower and differentiated less. These findings suggest
increases Areg cell number (or their activity) might attenuate detrimental ATE in neonates.
This proposal combines state-of-the-art single cell RNA-sequencing, modern flow cytometry techniques,
genetic manipulation of n6/n3 ratios and NR2F2, real-time live cell imaging, and in vitro primary APC culture to
achieve two primary objectives:
SA1. To quantify Areg cell number simultaneously with Areg specific mRNA signatures triggered by
high and low n6/n3 postnatal exposures.
SA2. To determine if NR2F2 mediates the low n6/n3 dependent effect on in vivo adipogenesis, APC
populations, and APC adipogenic potential.
Impact. Defining molecular responses and cellular diversity of APC subtypes that can condition early life ATE in
vivo could help inform new modalities of obesity prevention.
摘要
近20%的儿童肥胖或超重。预计一半的儿童肥胖症将在5岁时发生
超过一半的现有儿童将在35岁时患上肥胖症。母体膳食来源的营养信号
在围产期发育过程中传播的条件代谢反应以后的生活。我们发现高n-6到n-3
(n6/n3)脂肪酸暴露与婴儿体内脂肪积累增加正相关;在小鼠中,
降低n6/n3暴露调节新生儿脂肪形成表观遗传,赋予持久的代谢
对成年人有好处。我们的发现引出了中心假设:
在发育条件下低n6/n3暴露通过细胞和功能性脂肪形成
干细胞样脂肪细胞前体群体内的反应。
脂肪细胞前体细胞(APC)亚型包括祖细胞、前脂肪细胞和新发现的前脂肪细胞。
“脂肪生成调节”细胞(Areg)。在细胞数量方面,AEGF-A减弱脂肪组织扩张(ATE)
和旁分泌的方式。重要的是,我们观察到新生儿体内脂肪积累,形态,
小鼠中低N6/N3暴露的细胞构成。这种表型支持ATE的模式化对早期细胞凋亡敏感。
然而,低n6/n3刺激调节的APC亚型频率和分子多样性仍然存在,
未知
我们通过从具有高和低n6/n3的幼仔的脂肪库中分离初级APC开始解决这一差距
exposure.初步的批量RNA-seq分析鉴定了来自低n6/n3的增加的Areg亚型标志物
exposure.包括NR 2F 2-一种与脂肪生成减弱相关的关键转录调节因子。在共培养中,
低n6/n3的APC在体内增殖较慢,分化较少。
增加Areg细胞数量(或其活性)可能会减弱新生儿中有害的ATE。
该提案结合了最先进的单细胞RNA测序,现代流式细胞术技术,
n6/n3比率和NR 2F 2的遗传操作、实时活细胞成像和体外原代APC培养,
实现两个主要目标:
SA 1.为了定量Areg细胞数量,同时使用Areg特异性mRNA签名,
高和低n6/n3出生后接触。
SA 2.为了确定NR 2F 2是否介导对体内脂肪形成的低n6/n3依赖性作用,APC
群体和APC脂肪形成潜力。
冲击确定APC亚型的分子反应和细胞多样性,这些亚型可以调节早期生命中的ATE,
vivo可以帮助提供预防肥胖的新模式。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
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Michael C. Rudolph其他文献
Total daily energy expenditure has declined over the past three decades due to declining basal expenditure, not reduced activity expenditure
在过去的三十年中,由于基础代谢率下降,而非活动代谢率降低,每日总能量消耗有所下降。
- DOI:
10.1038/s42255-023-00782-2 - 发表时间:
2023-04-26 - 期刊:
- 影响因子:20.800
- 作者:
John R. Speakman;Jasper M. A. de Jong;Srishti Sinha;Klaas R. Westerterp;Yosuke Yamada;Hiroyuki Sagayama;Philip N. Ainslie;Liam J. Anderson;Lenore Arab;Kweku Bedu-Addo;Stephane Blanc;Alberto G. Bonomi;Pascal Bovet;Soren Brage;Maciej S. Buchowski;Nancy F. Butte;Stefan G.J.A. Camps;Jamie A. Cooper;Richard Cooper;Sai Krupa Das;Peter S. W. Davies;Lara R. Dugas;Ulf Ekelund;Sonja Entringer;Terrence Forrester;Barry W. Fudge;Melanie Gillingham;Santu Ghosh;Annelies H. Goris;Michael Gurven;Lewis G. Halsey;Catherine Hambly;Hinke H. Haisma;Daniel Hoffman;Sumei Hu;Annemiek M. Joosen;Jennifer L. Kaplan;Peter Katzmarzyk;William E. Kraus;Robert F. Kushner;William R. Leonard;Marie Löf;Corby K. Martin;Eric Matsiko;Anine C. Medin;Erwin P. Meijer;Marian L. Neuhouser;Theresa A. Nicklas;Robert M. Ojiambo;Kirsi H. Pietiläinen;Jacob Plange-Rhule;Guy Plasqui;Ross L. Prentice;Susan B. Racette;David A. Raichlen;Eric Ravussin;Leanne M. Redman;Susan B. Roberts;Michael C. Rudolph;Luis B. Sardinha;Albertine J. Schuit;Analiza M. Silva;Eric Stice;Samuel S. Urlacher;Giulio Valenti;Ludo M. Van Etten;Edgar A. Van Mil;Brian M. Wood;Jack A. Yanovski;Tsukasa Yoshida;Xueying Zhang;Alexia J. Murphy-Alford;Cornelia U. Loechl;Anura Kurpad;Amy H. Luke;Herman Pontzer;Matthew S. Rodeheffer;Jennifer Rood;Dale A. Schoeller;William W. Wong - 通讯作者:
William W. Wong
Dietary oleic acid drives obesogenic adipogenesis via modulation of LXRα signaling
膳食油酸通过调节 LXRα 信号通路驱动致肥胖性脂肪生成。
- DOI:
10.1016/j.celrep.2025.115527 - 发表时间:
2025-04-22 - 期刊:
- 影响因子:6.900
- 作者:
Allison Wing;Elise Jeffery;Christopher D. Church;Jennifer Goodell;Rocío del M. Saavedra-Peña;Moumita Saha;Brandon Holtrup;Maud Voisin;N. Sima Alavi;Mariana Floody;Zenan Wang;Thomas E. Zapadka;Michael J. Garabedian;Rohan Varshney;Michael C. Rudolph;Matthew S. Rodeheffer - 通讯作者:
Matthew S. Rodeheffer
Hypothalamic melanocortin-4 receptors on astrocytes mediate inflammation and body weight homeostasis
星形胶质细胞上的下丘脑黑皮质素 4 受体介导炎症和体重稳态
- DOI:
10.1101/2022.12.01.518727 - 发表时间:
2022 - 期刊:
- 影响因子:0
- 作者:
Nicole L Eliason;Kevin Pham;R. Varshney;Jacob W Farriester;Charles I. Lacy;Heather C. Rice;Michael C. Rudolph;Willard M. Freeman;A. Sharpe - 通讯作者:
A. Sharpe
Functional Characteristics of Tumor-Associated Protein Spot14 and Interacting Proteins in Mouse Mammary Epithelial and Breast Cancer Cell Lines
小鼠乳腺上皮细胞和乳腺癌细胞系中肿瘤相关蛋白 Spot14 和相互作用蛋白的功能特征
- DOI:
- 发表时间:
2009 - 期刊:
- 影响因子:0
- 作者:
Michael C. Rudolph - 通讯作者:
Michael C. Rudolph
How array analysis can help us understand complex developmental switches: molecular regulation of the initiation of lactation
阵列分析如何帮助我们了解复杂的发育开关:泌乳起始的分子调控
- DOI:
- 发表时间:
2005 - 期刊:
- 影响因子:0
- 作者:
Michael C. Rudolph;M. Neville - 通讯作者:
M. Neville
Michael C. Rudolph的其他文献
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{{ truncateString('Michael C. Rudolph', 18)}}的其他基金
Early Life Fatty Acid Exposures Dictate Obesity Predisposition
生命早期的脂肪酸暴露决定了肥胖倾向
- 批准号:
10212714 - 财政年份:2020
- 资助金额:
$ 11.66万 - 项目类别:
Early Life Fatty Acid Exposures Dictate Obesity Predisposition
生命早期的脂肪酸暴露决定了肥胖倾向
- 批准号:
10391129 - 财政年份:2020
- 资助金额:
$ 11.66万 - 项目类别:
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- 批准号:81970721
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