Brown adipose tissue development and fetal growth

棕色脂肪组织发育和胎儿生长

• 批准号: 10687215
• 负责人: Jianhua Shao
• 金额: $ 19.75万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-19 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10687215
• 关键词: Ablation; Adipocytes; Adult; Animals; Attention; Beta Cell; Biomedical Research; Birth; Birth Weight; Blood; Blood Glucose; Body Weight; Body Weight decreased; Breeding; Brown Fat; Catecholamines; Cell Proliferation; Circulation; Coculture Techniques; Data; Defect; Development; Elderly; Endocrine system; Energy Metabolism; Energy consumption; Ensure; Environment; Exhibits; Fetal Development; Fetal Growth; Fetal Reduction; Fetal Tissues; Fetal Weight; Fetus; Foundations; Future; Gene Deletion; Genes; Genetic; Genotype; Glucose; Growth; Heterozygote; Homeostasis; Impairment; In Vitro; Insulin; Insulin-Like Growth Factor I; Islets of Langerhans; Knock-out; Late pregnancy; Length; Life; Link; Lipids; Low Birth Weight Infant; Mammals; Messenger RNA; Metabolic; Metabolic Diseases; Metabolism; Mus; Nature; Neonatal; Nutrient; Obesity; Organ; Phenotype; Placenta; Placental Lactogen; Play; Protein Secretion; Reporting; Role; Scheme; Series; Shotguns; Solid; Somatomedins; Structure; System; Thermogenesis; Tissues; Uterus; Weight; cytokine; endocrine pancreas development; experimental study; fetal; genetic approach; glucose metabolism; glucose transport; insight; islet; knockout gene; metabolic phenotype; mouse model; neonate; novel; obesity development; passive transport; pregnant; prenatal; success; transcriptome sequencing; uncoupling protein 1

SUMMARY Brown adipose tissue (BAT) is developed before birth and exerts the thermogenic function at the maximal level immediately after delivery. Due to the energy-consuming nature of non-shivering thermogenesis, the contribution of BAT activation in energy metabolism and the development of obesity has caught our attention. Our recent study demonstrated that BAT/thermogenesis is significantly reduced during late pregnancy, which actively contributes to maternal metabolic adaptation. In this study, we observed a significant reduction of fetal body weight from UCP1 gene knockout dams. Due to the unique function of BAT in neonatal life, this intriguing phenotype led us to carry out a series of experiments to determine the effect of fetal BAT on fetal development. By knocking out the Ucp1 gene and genetic ablating brown adipocytes in fetuses, our preliminary study generates a shred of solid evidence indicating that fetal BAT development and activation are closely associated with fetal growth. The initial studies also showed that fetal Ucp1 knockout and BAT ablation significantly reduced placenta weight without alternation in placental structure. The metabolic phenotypes of elevated blood glucose concentrations and decreased blood insulin levels in Ucp1-/- and BAT-null fetuses suggest a defect in fetal islet development in these fetuses. Together, these preliminary data led us to hypothesize that there is intra-organ crosstalk between fetal BAT, the placenta, and fetal pancreatic islets at late pregnancy. Through these crosstalks, intrauterine metabolism, fetal tissue development, and growth are regulated. A series of animal studies will be performed to verify this hypothesis. We will use genetic mouse models and in vitro approaches to demonstrate the BAT/Placenta/Islet crosstalk in late pregnancy. The state- of-art system will be employed to determine if fetal brown adipocytes secret unique batokines and through which interact with other fetal organs. This proposal's success will lay down a foundation for future studies to elucidating the function of fetal BAT in intrauterine metabolism and fetal growth.

概括 棕色脂肪组织（BAT）是在出生前开发的，并在 交付后立即最大水平。由于非震动热发生的能量性质， 蝙蝠激活在能量代谢中的贡献和肥胖的发展使我们 注意力。我们最近的研究表明，蝙蝠/热发生后期显着降低 怀孕，积极地有助于孕产妇的代谢适应。在这项研究中，我们观察到了重要的 UCP1基因基因敲除大坝的胎儿体重减少。由于蝙蝠在新生儿中的独特功能 生活，这种有趣的表型使我们进行了一系列实验，以确定胎儿对 胎儿发育。通过淘汰胎儿中的UCP1基因和遗传烧蚀棕色脂肪细胞，我们 初步研究产生了大量的良好证据，表明胎儿的发育和激活是 与胎儿生长密切相关。最初的研究还表明，胎儿UCP1敲除和蝙蝠消融 显着减少了胎盘重量，而没有胎盘结构的交替。代谢表型 UCP1 - / - 和BAT-NULL胎儿的血糖浓度升高和血液胰岛素水平降低 提示这些胎儿的胎儿胰岛发育缺陷。这些初步数据一起导致我们 假设在胎儿，胎盘和胎儿胰岛之间存在器质内串扰 怀孕晚期。通过这些串扰，宫内代谢，胎儿组织发育和生长是 受监管。将进行一系列动物研究以验证这一假设。我们将使用遗传小鼠 模型和体外方法，以证明妊娠晚期的蝙蝠/胎盘/胰岛串扰。国家 - 将采用ART系统来确定胎儿棕色脂肪细胞是否秘密独特的跳球运动以及通过 与其他胎儿器官相互作用。该提议的成功将为以后的研究奠定基础 阐明胎儿在宫内代谢和胎儿生长中的功能。