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.

总结 棕色脂肪组织（BAT）在出生前发育，并在出生时发挥产热功能。 分娩后立即达到最高水平。由于非颤抖产热的能量消耗性质， BAT激活在能量代谢和肥胖发展中的作用已经引起了我们的注意。 关注我们最近的研究表明，BAT/产热在晚期显着减少 怀孕，积极促进母体代谢适应。在这项研究中，我们观察到一个显著的 UCP 1基因敲除母鼠的胎儿体重减轻。由于BAT在新生儿中的独特功能， 这种有趣的表型使我们进行了一系列实验，以确定胎儿BAT对 胎儿发育通过敲除Ucp 1基因和基因切除胎儿棕色脂肪细胞， 初步研究产生了一丝确凿的证据，表明胎儿BAT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Ucp 1敲除和BAT消融， 显著降低胎盘重量，而胎盘结构无改变。代谢表型 Ucp 1-/-和BAT-无效胎儿的血糖浓度升高和血胰岛素水平降低 提示这些胎儿胰岛发育缺陷。综合这些初步数据， 假设胎儿BAT、胎盘和胎儿胰岛之间存在器官内串扰， 怀孕晚期。通过这些串扰，宫内代谢，胎儿组织发育和生长， 监管.将进行一系列动物研究以验证这一假设。我们将使用基因鼠 模型和体外方法来证明妊娠晚期的BAT/胎盘/胰岛串扰。国家- 将采用最先进的系统来确定胎儿棕色脂肪细胞是否分泌独特的细胞因子， 与其他胎儿器官相互作用该方案的成功将为今后的研究奠定基础， 阐明胎儿BAT在宫内代谢和胎儿生长中的作用。