Mechanisms Underlying the Association between Maternal and Offspring Obesity

描述（由申请人提供）：我是一名四年级博士后，准备转到初级教师职位。在博士后培训期间，我一直积极从事关于儿童肥胖风险产前规划的研究。正如我的出版记录所表明的那样，我为这项研究带来了心理学、行为神经科学、营养学和新陈代谢方面的多样化培训背景。在这个关键时刻，我寻求niddk赞助的K01奖，以支持一个研究产前编程机制的项目，同时为我提供机会，在儿童肥胖的生理和行为预测方面获得进一步的培训。此外，我将利用这段受保护的时间来培训临床试验的设计和实施，特别是与纵向结果有关的行为干预。这些活动最终将帮助我建立一个职业生涯，将基础研究的发现转化为可行的行为干预措施，以降低肥胖女性后代的肥胖风险。我将在阿拉巴马大学伯明翰分校（UAB）进行我的职业发展计划。这个非常成功的机构为培训初级调查人员提供了一个支持性的环境，并拥有许多促进研究和培训的资源。我选择了一个由两位专业互补的导师组成的团队，其中一位是UAB外部的，但在产妇肥胖和产前编程领域是领导者。他们帮助我选择了三名顾问，他们将监督研究方案的实施，以及一个由三名成员组成的职业咨询小组，他们将监督我的职业进展以及我的短期和长期目标的实现。本申请中描述的修订后的项目和培训计划反映了该团队每个成员的投入。该项目将研究母亲肥胖和代谢健康对后代肥胖风险的独立影响。至少有一部分后代肥胖的风险被认为是由于向发育中的胎儿输送了过多的燃料，这会改变胎儿的代谢程序，最终可能导致脂肪组织的过度沉积。因此，肥胖女性的后代面临更大的风险，因为肥胖相关的代谢异常，如胰岛素敏感性降低和底物代谢异常，会增加胎儿的燃料供应。然而，尚不清楚在没有不良代谢健康的情况下，母亲肥胖是否会导致后代肥胖的风险。同样，体重正常的女性也可分为代谢健康状况良好和代谢健康状况不佳的两种。本研究的总体目标是验证肥胖但代谢健康的女性的后代比代谢不健康的女性的后代患肥胖的风险更低的假设。采用双向因子设计，女性将被招募到正常体重组与肥胖组，高空腹血糖组与低空腹血糖组。将严格评估葡萄糖和脂质代谢，以检查空腹血糖是否是妊娠期间代谢健康不良的有用筛查工具（特定目标1）。将评估产妇肥胖和代谢健康对新生儿肥胖和脐带c肽的独立影响（具体目标2）。最后，将测试一个假设的途径，将母体体重和底物代谢、胎儿胰岛素和随后的0- 3岁体重增加联系起来（特定目标3）。本研究的新颖之处在于研究了母亲肥胖和代谢健康对儿童肥胖风险产前规划机制的独立影响。如果像假设的那样，母体代谢健康比母体肥胖对后代风险的影响更大，那么未来的干预措施可以集中在孕期保持最佳代谢健康，而不考虑体重状况。

DESCRIPTION (provided by applicant): I am a 4th year postdoctoral fellow preparing to transition to a junior faculty position. During my postdoctoral training, I have been actively engaged in research regarding prenatal programming of childhood obesity risk. I bring to this research a diverse training background in psychology, behavioral neuroscience, nutrition, and metabolism, as indicated by my publishing record. At this juncture, I seek an NIDDK-sponsored K01 award to support a project that will investigate mechanisms underlying prenatal programming, while concurrently providing me with the opportunity to obtain further training in physiological and behavioral predictors of childhood obesity. In addition, I will use this protected time to train in the design and conduct of clinical trials, particularly pertaining to behavioral interventions with longitudinal outcomes. These activities will ultimately help me to build a career in translating findings from basic research into feasible behavioral interventions to reduce the risk of obesity among offspring of obese women. The institution within which I will undertake my Career Development Plan is the University of Alabama at Birmingham (UAB). This highly successful institution maintains a supportive environment for training junior investigators, with many resources that facilitate both research and training. I have selected a team of two mentors with complementary expertise, one of whom is external to UAB but is a leader in the field of maternal obesity and prenatal programming. They have helped me to select three consultants who will oversee the implementation of research protocols, and a three-member career advisory panel that will monitor the progress of my career and the achievement of my short- and long-term goals. The revised project and training plan described in this application reflect the input of each member of this team. The proposed project will examine independent effects of maternal obesity and metabolic health on offspring risk for obesity. At least a portion of the risk for offspring obesity is believed to be attributable to excess fuel delivery to the developing fetus, which alters programming of fetal metabolism that ultimately may contribute to excess deposition of adipose tissue. Consequently, offspring of obese women are at greater risk because obesity-related metabolic abnormalities, such as reduced insulin sensitivity and abnormal substrate metabolism, increase the availability of fuel to the fetus. It is not known, however, whether maternal obesity in the absence of poor metabolic health will contribute to offspring risk for obesity. Similarly, normal weight women may be dichotomized into those of good or poor metabolic health. The overall goal of this study is to test the hypothesis that offspring of obese but metabolically healthy women have less risk for obesity as compared to offspring of metabolically unhealthy women. Using a two-way factorial design, women will be recruited to fill normal weight vs. obese, high vs. low fasting glucose groups. Glucose and lipid metabolism will be rigorously assessed to examine whether fasting glucose is a useful screening tool for poor metabolic health during pregnancy (Specific Aim 1). The independent effects of maternal obesity and metabolic health on neonatal adiposity and umbilical cord C-peptide will be assessed (Specific Aim 2). Finally, a hypothesized pathway linking maternal weight and substrate metabolism, to fetal insulin, and to subsequent weight gain at 0- 3 years will be tested (Specific Aim 3). The novelty of the proposed study lies in the examination of the independent effects of maternal obesity and metabolic health on mechanisms underlying the prenatal programming of childhood obesity risk. If, as hypothesized, maternal metabolic health has a greater influence on offspring risk than does maternal obesity, future intervention efforts can focus on maintaining optimal metabolic health during pregnancy, irrespective of weight status.