Synergistic effect of maternal insulin-resistance and cortisol in pregnancy on fetal programming of child mitochondrial function and obesity risk

妊娠期母体胰岛素抵抗和皮质醇对胎儿线粒体功能和肥胖风险的协同作用

• 批准号: 10628030
• 负责人: Lauren Elizabeth Gyllenhammer
• 金额: $ 24.9万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10628030
• 关键词: Abdomen; Address; Adipose tissue; Advisory Committees; Age; Animals; Area Under Curve; Behavior Therapy; Bioinformatics; Biological; Biological Products; Birth; Body Composition; Body fat; Body mass index; Cell Culture Techniques; Cells; Cellular biology; Child; Childhood; Citrate (si)-Synthase; Clinical; Cross-Over Studies; Crossover Design; Data; Development; Development Plans; Developmental Biology; Drug or chemical Tissue Distribution; Dual-Energy X-Ray Absorptiometry; Enrollment; Ensure; Exposure to; Fasting; Fatty acid glycerol esters; Funding; Gestational Age; Glucose; Goals; Health; Hepatic; Homeostasis; Hormones; Human; Hydrocortisone; Image; Individual Differences; Infant; Instruction; Insulin; Insulin Resistance; Intra-abdominal; Investigation; Knowledge; Late pregnancy; Magnetic Resonance; Magnetic Resonance Imaging; Maternal Age; Measures; Mediating; Mediator; Mentors; Metabolic; Metabolic dysfunction; Metabolic stress; Methodology; Methods; Mitochondria; Mitochondrial DNA; Modeling; Mothers; Newborn Infant; Nuclear; OGTT; Obesity; Observational Study; Outcome; Pathogenesis; Peripheral Blood Mononuclear Cell; Phase; Physiological; Physiology; Predisposition; Pregnancy; Pregnant Women; Prevention; Production; Psychological Stress; Public Health; Randomized; Research; Research Design; Research Personnel; Respiratory Chain; Risk Factors; Role; Salivary; Science; Shapes; Standardization; Statistical Models; Stratification; Stress; Techniques; Testing; Time; Training; Training Activity; Treatment Efficacy; Trier Social Stress Test; Umbilical Cord Blood; United States National Institutes of Health; Weight; acute stress; career; career development; cohort; design; experience; fasting glucose; fetal; fetal programming; improved; in utero; in vivo; indexing; infancy; infant adiposity; maternal stress; novel; obesity in children; obesity risk; offspring; population based; postnatal; prenatal; prenatal stress; prepregnancy; prospective; response; sex; stress reduction; subcutaneous; symposium

Childhood obesity represents a major public health challenge. Growing evidence supports an important role for intrauterine conditions in shaping susceptibility for obesity (the fetal origins concept). However, many key questions remain regarding determinants, outcomes and underlying mechanisms. First, although maternal metabolic and stress hormones have separately been identified as key biological effectors of fetal programming, their interaction has not yet been examined in this context. Second, although it’s well established that it is not BMI, per se, but excess fat mass and its relative distribution (intra-abdominal, hepatic) that underlies the detrimental effects of obesity, it is not yet known whether fetal programming influences the distribution of adipose tissue mass. Third, although mitochondrial function-the central modulator of cellular energy production, storage and use-has been identified as a key mediator of the effects of insulin- resistance (IR) and stress/cortisol on the development and pathogenesis of obesity, its role as a putative mechanism in fetal programming has yet to be determined. Dr. Lauren Gyllenhammer’s K99/R00 proposal addresses these 3 knowledge gaps using complementary designs (observational and experimental), state-of-the-art methods (Magnetic Resonance (MR) and Dual Energy X-Ray Absorptiometry (DXA) imaging), and multiple levels of analysis (cells to in vivo physiology), to test the hypothesis that maternal prenatal stress/cortisol potentiates the unfavorable effects of gestational IR on offspring adipose tissue mass/distribution, mediated by offspring mitochondrial function. In the K99 mentored phase, Dr. Gyllenhammer will leverage and add measures to an ongoing NIH-funded prenatal observational cohort, with existing maternal prenatal cortisol and fasting metabolic measures and offspring serial % fat mass measures (DXA from birth to 5yrs) in N=100 mother/child dyads. She will add novel measures of MR-based adipose tissue distribution and mitochondrial function in the 5 yr old children, and examine the statistical interaction between maternal cortisol and fasting markers of IR on these outcomes. She will advance her knowledge of fetal programming, gestational/developmental biology, and obtain advanced bench and analysis techniques relevant for DOHaD research (cellular biology/mitochondria bench training, bioinformatics analysis methods, cutting-edge MRI methods in newborns and young children) through investigation of these aims, extensive hands-on training, conferences, didactic instruction, and guidance from a diverse advisory committee of respected researchers. In the R00 phase, she will enroll a new, independent cohort of N=80 pregnant women and use an experimental cross-over study design to quantify the physiological interaction of prenatal stress and IR to prospectively predict newborn mitochondrial function and adipose mass and distribution trajectory from birth till 6 mo age. By utilizing training from the K99 phase, she will explore novel cellular mechanisms of prenatal programming, and uncover relationships between maternal prenatal psychological and metabolic stress on offspring adiposity development. Findings from these complementary studies will improve the understanding of early risk factors for child- hood obesity, potentially provide cellular and behavioral interventional targets for prevention and treatment, and will further Dr. Gyllenhammer’s career goal to develop and establish herself as an independent investigator.

儿童肥胖是一个重大的公共卫生挑战。越来越多的证据支持 内部条件的重要作用在塑造物体的敏感性（胎儿） 起源概念）。但是，关于决定者，结果和 基本机制。首先，尽管主要的代谢和应力激素已分别是 被确定为胎儿编程的关键生物学效应，它们的相互作用尚未 在这种情况下检查。其次，尽管已经确定它不是BMI，本身， 但是超过脂肪质量及其相对分布（腹内，肝内），其基础 肥胖的有害影响，尚不知道胎儿编程是否影响 脂肪组织质量的分布。第三，尽管线粒体功能 - 中央 蜂窝能量生产，存储和使用的调节剂被确定为关键介体 胰岛素抵抗（IR）和应激/皮质醇对发育和发病机理的影响 肥胖，其作为胎儿编程中推定机制的作用尚未 决定。 Lauren Gyllenhammer博士的K99/R00提案介绍了这3个知识 使用完整设计（观察性和实验性）的差距，最先进 方法（磁共振（MR）和双能X射线吸收仪（DXA）成像）和 多个分析级别（细胞到体内生理学），以检验母体的假设 产前压力/皮质醇增强妊娠红外对后代脂肪的不利影响 组织质量/分布，通过线粒体功能介导。在K99 Mendored阶段， Gyllenhammer博士将利用并为正在进行的NIH资助的产前观察性添加测量 队列，现有的母校产前皮质醇和禁食代谢措施和后代 n = 100母/儿童二元组中的序列％脂肪质量测量（从出生到5年）。她会的 添加基于MR的脂肪组织分布和线粒体的新型度量 在5岁的孩子中发挥作用，并检查母体之间的统计相互作用 这些结果的IR的皮质醇和禁食标记。她将提高她对胎儿的了解 编程，妊娠/发育生物学，并获得高级基准和分析 与DOHAD研究相关的技术（细胞生物学/线粒体台训练， 生物信息学分析方法，新生儿和年轻人的尖端MRI方法 儿童）通过调查这些目标，广泛的动手培训，会议， 教学教学和受人尊敬的研究人员的潜水咨询委员会的指导。 R00阶段，她将招募一个新的独立队列n = 80位孕妇，并使用 实验性跨界研究设计，以量化产前应力的物理相互作用 IR预测新生儿线粒体功能和脂肪质量和分布 从出生到6个月的轨迹。通过使用K99阶段的培训，她将探索 产前编程的新型细胞机制，并发现 母体产前心理和代谢压力对后代肥胖的发展。 这些完整研究的发现将改善对早期风险因素的理解 儿童肥胖，有可能为细胞和行为介入目标提供 预防和治疗，并将进一步吉伦哈默（Gyllenhammer）博士发展和建立的职业目标 自己是独立调查员。