Mechanisms for gestational hypoxia reprogramming of adipose

妊娠期缺氧脂肪重编程机制

• 批准号: 9072346
• 负责人: Charles A Ducsay
• 金额: $ 20万
• 依托单位: LOMA LINDA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2021-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9072346
• 关键词: Address; Adipocytes; Adipose tissue; Adrenergic Receptor; Adult; Age; Agonist; Altitude; Animals; Apoptosis; Apoptotic; Birth; Blood Vessels; Brown Fat; Cardiovascular Diseases; Cells; Centers for Disease Control and Prevention (U.S.); Characteristics; Child; Childhood; Development; Disease; Endocrine; Environment; Epidemic; Exhibits; Family; Fatty acid glycerol esters; Fetal Development; Fetus; Fibroblast Growth Factor; Fibroblast Growth Factor Receptors; Gene Expression; Generations; Genes; Glucocorticoids; Hepatic; Human; Hypoxia; In Situ Hybridization; In Vitro; Infant; Intervention; Isoproterenol; Life; Lipid Mobilization; Measures; Mediator of activation protein; Metabolic Diseases; MicroRNAs; Modeling; Molecular; NRIP1 gene; Obesity; Phenotype; Placental Insufficiency; Plasma; Population; Pre-Eclampsia; Predisposition; Pregnancy; Premature Labor; Process; Receptor Activation; Reporting; Risk; Rodent; Role; Sheep; Smoking; Supraclavicular; Sympathetic Nervous System; Techniques; Testing; Thyroid Hormones; Time; Up-Regulation; abdominal fat; developmental plasticity; fetal; fetal programming; fetus hypoxia; fibroblast growth factor 21; high risk; immunocytochemistry; in utero; in vivo; member; nerve supply; obesity in children; offspring; osmotic minipump; postnatal; prenatal; programs; receptor expression; response; uncoupling protein 1

PROJECT SUMMARY Childhood obesity in the USA has increased ~7-fold over the past three decade. In a variety of species substantial evidence supports the concept that development under conditions of an `adverse intrauterine environment' permanently programs the fetus leading to obesity, metabolic disorders and cardiovascular disease as adults. Hypoxia is a major threat to the developing fetus, occurring in situations such as preeclampsia, preterm labor, maternal obesity, placental insufficiency, smoking and high altitude. We have a developed a model of long-term hypoxia (LTH) in sheep where the fetus is exposed to high altitude (3,280m) induced moderate hypoxia from ~40 days of gestation (dG) onward (term is ~146dG). We have reported a significant impact of LTH on perirenal fat (PRF) in the fetus with upregulation of expression of the thermogenic mediator uncoupling protein 1 (UCP1) and genes that support UCP1 expression similar to `brown' adipose tissue (BAT). Unlike true BAT however, PRF rapidly loses the BAT phenotype post- birth, while retaining/expanding the white adipose tissue (WAT) phenotype. Recently, beige/BRITE1 (`brown- in-white') adipocytes have been characterized that reside in WAT. This process, termed `beiging', and has been shown to be protective against obesity in rodents by virtue of lipid mobilization. However, this process has not been studied in animals such as sheep or humans where adipose expands and differentiates in utero. We found that by post-natal day 14 (PN14) LTH lambs exhibit a significant decrease in the BAT/beige molecular program (UCP1, DIO2, PRDM16, PGC1a) compared to control lambs, while retaining and/or amplifying genes of the WAT phenotype (e.g. RIP140, a key co-repressor of BAT genes) indicative of a decreased capacity for beiging and/or a potential loss of BRITE adipocytes, placing these animals at risk for later obesity. The global hypothesis is that gestational LTH reprograms the beiging capacity of PRF, reducing the favorable BRITE adipocyte population. The Specific Aims will focus on the role of key factors such as sympathetic innervation and fibroblast growth factor 21 (FGF21) on the BAT/beige molecular program in adipose tissue from near term fetuses and postnatal lambs utilizing both in vitro and in vivo studies. Western analysis, qRT-PCR, in situ hybridization and immunocytochemical techniques will be utilized. The results obtained from this Project will dramatically further our understanding of both the mechanism(s) by which moderate gestational hypoxia programs the developing adipose tissue as well as identifying potential means to ameliorate or reverse the impact of LTH on adipose tissue function in these offspring. If successful, our findings could provide both a means for identifying children at high risk for obesity as well as means for intervention of childhood obesity.

项目概要 过去三十年里，美国儿童肥胖症增加了约 7 倍。在各种物种中 大量证据支持这一概念，即在“不利的宫内发育”条件下的发育 环境对胎儿进行永久性编程，导致肥胖、代谢紊乱和心血管疾病 与成人一样的疾病。缺氧是胎儿发育的主要威胁，发生在以下情况： 先兆子痫、早产、产妇肥胖、胎盘功能不全、吸烟和高海拔。我们有一个 建立了羊的长期缺氧（LTH）模型，其中胎儿暴露在高海拔（3,280m） 从妊娠约 40 天 (dG) 开始（妊娠期约 146dG）引起中度缺氧。 我们报道了 LTH 对胎儿肾周脂肪 (PRF) 的显着影响，并上调 生热介质解偶联蛋白 1 (UCP1) 的表达和支持 UCP1 表达的基因 类似于“棕色”脂肪组织（BAT）。然而，与真正的 BAT 不同的是，PRF 后会迅速失去 BAT 表型。 出生，同时保留/扩大白色脂肪组织（WAT）表型。最近，米色/BRITE1（`棕色- 已鉴定出驻留在 WAT 中的脂肪细胞。这个过程被称为“beiging”，并且已经 已被证明可以通过脂质动员来预防啮齿动物的肥胖。然而，这个过程 尚未在绵羊或人类等动物身上进行研究，因为这些动物的脂肪在子宫内会扩张和分化。 我们发现，到出生后第 14 天 (PN14)，LTH 羔羊的 BAT/米色分子显着下降。 程序（UCP1、DIO2、PRDM16、PGC1a）与对照羔羊相比，同时保留和/或扩增基因 WAT 表型（例如 RIP140，BAT 基因的关键共阻遏物）表明 beiging 能力下降和/或 BRITE 脂肪细胞的潜在损失，使这些动物面临日后肥胖的风险。全局假设是 妊娠 LTH 重新编程 PRF 的米色能力，减少有利的 BRITE 脂肪细胞 人口。具体目标将重点关注关键因素的作用，例如交感神经支配和 近期脂肪组织中 BAT/米色分子程序中的成纤维细胞生长因子 21 (FGF21) 利用体外和体内研究对胎儿和产后羔羊进行研究。 Western 分析、qRT-PCR、原位 将利用杂交和免疫细胞化学技术。该项目获得的成果将 极大地加深了我们对中度妊娠缺氧的机制的理解 对发育中的脂肪组织进行编程，并确定改善或逆转脂肪组织的潜在方法 LTH 对这些后代脂肪组织功能的影响。如果成功的话，我们的发现可以提供 识别肥胖高危儿童的方法以及儿童肥胖干预方法。