Effects of prenatal exposures to maternal obesity and gestational diabetes on metabolic decline from childhood to adolescence and underlying neurobiological pathways

产前暴露于母亲肥胖和妊娠糖尿病对儿童期至青春期代谢下降和潜在神经生物学途径的影响

• 批准号: 10682336
• 负责人: Kathleen Alanna Page
• 金额: $ 72.76万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-28 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10682336
• 关键词: Adolescence; Adolescent; Age; Animal Model; Animals; Behavior; Beta Cell; Biological; Body mass index; Brain; Brain Mapping; Caring; Cell physiology; Child; Childhood; Coupled; Cross-Sectional Studies; Data; Desire for food; Development; Diabetes Mellitus; Diet; Eating; Energy Intake; Event; Evolution; Exposure to; Food; Functional disorder; Future; Future Generations; Gestational Diabetes; Glucose; Hippocampus; Human; Hypothalamic structure; Impairment; Insulin Resistance; Intervention; Knowledge; Lead; Life; Life Style; Link; Longitudinal Studies; Measures; Mediating; Mediation; Metabolic; Methods; Modeling; Modification; Mothers; Neurobiology; Neurosecretory Systems; Non-Insulin-Dependent Diabetes Mellitus; OGTT; Obesity; Outcome; Pathogenesis; Pathway interactions; Personal Satisfaction; Phenotype; Physical activity; Predisposition; Pregnancy Complications; Prevalence; Puberty; Public Health; Regulation; Rewards; Risk; Risk Reduction; Rodent Model; Sampling; Satiation; Signal Transduction; Sleep; System; Testing; Time; Weight Gain; Work; Youth; biomarker identification; brain pathway; brain reward regions; cohort; critical developmental period; cue reactivity; diabetes risk; energy balance; fetal programming; follow-up; global health; human study; insulin secretion; insulin sensitivity; knowledge base; maternal diabetes; maternal obesity; metabolic phenotype; neural; neurodevelopment; neuroimaging; obesity development; obesity in children; obesity in pregnancy; obesity risk; offspring; postnatal; prenatal exposure; prepregnancy; recruit; response; transmission process; trend; type 2 diabetes in children

PROJECT SUMMARY/ABSTRACT Rising childhood obesity rates are coupled with an alarming increase in the prevalence of type 2 diabetes in children and adolescents. Evidence suggests that in utero exposures to maternal obesity and/or gestational diabetes mellitus (GDM) contribute to these upward trends, and the effects of these prenatal exposures on metabolic risk become more pronounced during adolescence. While the biological mechanisms of such maternal-fetal programming are poorly understood, compelling studies in rodent models show that in utero exposure to maternal obesity and/or diabetes causes abnormal development of brain pathways involved in energy balance regulation, leading to obesity and type 2 diabetes later in life. Our group was the first to study the effects in utero exposures to maternal obesity and GDM on brain pathways and metabolic outcomes in humans using a pioneering approach combining neuroimaging methods and metabolic phenotyping in children. To date, findings from cross-sectional studies in our BrainChild cohort provide strong support for the neuroendocrine programming effects seen in animal models. The earliest abnormality we have identified involves modification of brain pathways known to be involved in energy balance regulation. These brain modifications were predictive of increases in food intake and weight gain in children during short term follow-up and lead to the primary hypothesis of the present study: that differences in the neural markers observed in children at age 7-10 will be predictive of metabolic outcomes during the transition to adolescence, a critical time for brain development and metabolic decline. Child postnatal behaviors including physical activity, diet and sleep may also be mediating or modifying the effects of brain pathways linking in utero exposures to maternal GDM and obesity on child metabolic trajectories. We will include measures of these behaviors and explore these pathways to generate important data for future studies focusing on lifestyle behaviors. The proposed longitudinal study of the BrainChild cohort for up to six years of follow up provides the unique opportunity to advance our understanding of the interplay among brain changes, obesity, insulin resistance and beta cell function at early stages in the evolution of transgenerational transmission of obesity and diabetes risks. Given the growing number of pregnancies complicated by maternal obesity and GDM, the well-being of future generations may depend to an important degree on developing interventions that can break the vicious transgenerational cycle of obesity and diabetes. The proposed studies will contribute critical information to the knowledge base required for development of such interventions.

项目摘要/摘要 儿童肥胖率上升的率与2型糖尿病患病率的惊人增加 儿童和青少年。有证据表明，在子宫内暴露于孕产妇肥胖和/或妊娠 糖尿病（GDM）有助于这些向上趋势，这些产前暴露的影响对 在青春期，代谢风险变得更加明显。而这种生物学机制 孕产妇编程的理解很少，在啮齿动物模型中引人入胜的研究表明，在子宫内 暴露于孕产妇肥胖和/或糖尿病会导致涉及大脑途径的异常发育 能量平衡调节，导致肥胖症和2型糖尿病。 我们的小组是第一个研究子宫对孕产妇肥胖和GDM的影响的人 以及人类中的代谢结果，使用开创性方法结合神经影像学方法和 儿童代谢表型。迄今为止，我们的创意队列中的横断面研究的发现 为动物模型中看到的神经内分泌编程效应提供了强有力的支持。最早的 我们确定的异常涉及对已知参与能量平衡的大脑途径的修改 规定。这些大脑的修饰可预测儿童食物摄入量和体重增加的增加 在短期随访中，并导致本研究的主要假设： 在7-10岁的儿童中观察到的神经标记将预测过渡期间的代谢结果 至青春期，大脑发育和代谢下降的关键时刻。儿童出生后行为包括 体育锻炼，饮食和睡眠也可能正在介导或修改与 子宫对孕产妇GDM的暴露和肥胖症对儿童代谢轨迹的暴露。我们将包括 这些行为并探索这些途径，以生成重要的数据，以将来的研究重点关注生活方式 行为。 最多六年的《创意队列的纵向研究》提供了独特的。 有机会促进我们对大脑变化，肥胖，胰岛素抵抗和的相互作用的理解 在肥胖和糖尿病的转世传播演变中，早期阶段的β细胞功能 风险。鉴于孕产妇肥胖和GDM的怀孕越来越复杂， 子孙后代可能取决于制定可能破坏恶性的干预措施的程度 肥胖和糖尿病的转世周期。拟议的研究将为关键信息贡献 开发此类干预措施所需的知识库。