The Role of Mediobasal Hypothalamic Gliosis in Gestational Weight Gain and Gestational Visceral Fat Accretion

项目总结 妊娠是一种独特的状态，在这种状态下，母亲的妊娠期体重增加(GWG)具有生理适应性 也是必要的。妊娠期体重过度增加(EGWG)是指体重增加超过指南，并导致 到长期的母体代谢功能障碍。虽然许多基于饮食和活动的干预试验 进行限制EGWG的研究，关于成功预防妊娠期EGWG的数据并不一致。 潜在地，成功缓解EGWG所面临的障碍来自于我们对以下方面缺乏清晰度 生理性GWG背后的机制。因此，饮食和体力活动这一概念充分说明了 妊娠期间GWG的定量变化过于简单化。体重调节是一个复杂的过程，涉及 多种神经生物学和内分泌通路之间的相互作用，但中枢控制占主导地位 发生在下丘脑内侧基底核(MBH)，特别是弓状核。关于非妊娠的最新研究 人类证明，MBH中的胶质增生(一种细胞炎症反应)与肥胖有关。 对接触高脂饮食的啮齿动物的研究表明，MBH胶质细胞增生先于体重增加，这些胶质细胞 炎症反应对体重增加既是必要的，也是充分的。在人类中，T2信号增加 T2加权脑MRI是胶质细胞增生症的放射学标志。MBH中T2信号的增加与肥胖有关， 胰岛素抵抗和内脏脂肪组织(VAT)增加，与体重指数(BMI)无关。增值税，脂肪 腹内实体器官周围，产生比皮下脂肪更多的促炎细胞因子和 与代谢性疾病风险增加有关。我们和其他人已经证明了 增值税增加和妊娠代谢性疾病。因此，根据啮齿动物的文献和研究结果， 孕妇，MBH胶质细胞增生症似乎与病理性GWG有关或影响 怀孕期间优先缴纳增值税。此R21计划书中的基础数据将提供第一个 关于妊娠期间体重异常或病理性增加的神经机制的信息。

PROJECT SUMMARY Pregnancy is a unique state in which maternal gestational weight gain (GWG) is physiologically adaptive and necessary. Excessive gestational weight gain (EGWG) is weight gain exceeding guidelines and contributes to long term maternal metabolic dysfunction. While many diet- and activity-based intervention trials have been performed to limit EGWG, the data are inconsistent regarding successfully preventing EGWG in pregnancy. Potentially, the impediments faced in successfully mitigating EGWG arise from our lack of clarity about mechanisms underlying physiologic GWG. Therefore, the concept that diet and physical activity fully account for quantitative GWG variation in pregnancy is far too simplistic. Weight regulation is a complex process involving interactions among multiple neurobiological and endocrine pathways, but the central control predominantly occurs in the mediobasal hypothalamus (MBH), specifically the arcuate nucleus. Recent studies in nonpregnant humans demonstrate that gliosis (a cellular inflammatory response) in the MBH is associated with obesity. Studies in rodents exposed to a high-fat diet show that MBH gliosis precedes weight gain and that these glial inflammatory responses are both necessary and sufficient for weight gain. In humans, increased T2 signal on T2-weighted brain MRI is a radiologic marker of gliosis. Increased T2 signal in the MBH associates with obesity, insulin resistance and increased visceral adipose tissue (VAT), independent of body mass index (BMI). VAT, fat surrounding intra-abdominal solid organs, produces more pro-inflammatory cytokines than subcutaneous fat and is associated with increased risk for metabolic disease. We, and others, have shown associations between increased VAT and gestational metabolic disease. Therefore, based on rodent literature and findings in non- pregnant humans, it seems plausible that MBH gliosis could associate with pathological GWG or affect preferential deposition of VAT during pregnancy. Foundational data from this R21 proposal will provide the first information regarding a neural mechanism underlying dysregulated or pathological weight gain in pregnancy.