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。越来越多的证据表明， 子宫内条件在形成肥胖易感性中的重要作用（胎儿 起源概念）。然而，在决定因素、结果和 基本机制。首先，虽然母体代谢和压力激素分别被认为是 被确定为胎儿编程的关键生物效应子，它们的相互作用尚未被证实。 在此背景下审查。第二，虽然已经很好地证明了它本身不是BMI， 但多余的脂肪量及其相对分布（腹腔内，肝脏），这是基础 肥胖的有害影响，目前还不知道胎儿编程是否影响 脂肪组织质量的分布。第三，虽然线粒体的功能-中央 细胞能量产生、储存和使用的调节剂-已被确定为 胰岛素抵抗（IR）和应激/皮质醇在糖尿病发病中的作用 肥胖，它的作用作为一个假定的机制，在胎儿编程尚未被 测定Lauren Gyllenhammer博士的K99/R 00提案解决了这3个知识 利用互补设计（观察和实验）、最新技术水平 方法（磁共振（MR）和双能X射线吸收测定（DXA）成像），以及 多水平分析（细胞到体内生理学），以检验母体的假设 产前应激/皮质醇增强妊娠IR对后代脂肪的不利影响 组织质量/分布，由后代线粒体功能介导。在K99辅导阶段， 博士Gyllenhammer将利用并增加措施，以进行NIH资助的产前观察 队列，现有母体产前皮质醇和空腹代谢指标， 在N=100个母亲/儿童对中进行连续%脂肪量测量（从出生到5岁的DXA）。她将 增加了基于MR的脂肪组织分布和线粒体的新指标 功能，并检查母亲之间的统计相互作用 皮质醇和空腹胰岛素抵抗标志物对这些结果的影响。她将进一步了解胎儿 编程，妊娠/发育生物学，并获得先进的工作台和分析 与DOHaD研究相关的技术（细胞生物学/线粒体实验室训练， 生物信息学分析方法，新生儿和年轻人的尖端MRI方法 通过对这些目标的调查，广泛的实践培训，会议， 说教式的指导，以及来自受人尊敬的研究人员组成的多元化咨询委员会的指导。在 在R 00阶段，她将招募一个新的、独立的N=80名孕妇队列，并使用 实验交叉研究设计，以量化产前应激的生理相互作用 和IR前瞻性预测新生儿线粒体功能和脂肪量及分布 从出生到6月龄的轨迹。通过利用K99阶段的培训，她将探索 产前编程的新细胞机制，并揭示 母体产前心理和代谢应激对子代肥胖发育的影响。 这些补充研究的结果将提高对早期风险因素的理解， 儿童期肥胖症，可能提供细胞和行为干预目标， 预防和治疗，并将进一步博士Gyllenhammer的职业目标，以发展和建立 作为独立调查员。