Developmental programming of brown adipose tissue sympathetic tone

拟议的研究将以棕色脂肪组织(BAT)为平台，阐明出生后发育影响如何控制交感神经系统(SNS)输入的神经解剖结构，以及这些变化如何对全身生理和疾病风险的易感性产生持久和特定的影响。广泛的发育暴露会影响SNS对代谢相关器官的音调，包括胰腺、肾脏、脂肪组织和心脏。到目前为止，关于发育对社交网络音调的影响和器官功能之间关系的证据纯粹是相互关联的。直接调查SNS编程对成年生理的贡献的一个障碍是，在发育过程中对其活动进行实验操作可能会对器官功能产生影响，从而影响动物的整体健康，这将扰乱对结果的解释。我们发现了两种出生后早期暴露的情况，它们具体减少了投射到蝙蝠(SGBAT)的星状神经节中的交感神经元的数量，但对健康成年人的生理挑战做出了不同的反应。在30°C的温度下饲养会对冷饮食的反应性产生持久的影响，但不会对高脂肪饮食产生影响，而在小胎仔(SL)中哺乳则对饮食引起的肥胖敏感，但不会对寒冷产生影响。这里概述的研究将建立新的系统来测试SGBAT数量的变化是否影响BAT的神经支配和SNS音调(目标1)，以及它们是否必要和充分地计划对器官功能和对寒冷和饮食挑战的生理反应的持久影响(目标2)。我们将利用我们发现的分子上不同的SGBAT神经元亚群和在30°C与22°C饲养的小鼠BAT中差异表达的基因，来揭示SNS电路中编程的分子媒介(目标3)。我们将在BAT和SG中进行平行转录分析，以确定在发育的关键时期对窝产仔大小或温度操纵的功能反应中的特异性来源。由于SGBAT亚类的转录信号被所有SG神经元共享，这些研究的经验教训可以应用于其他出生后暴露和器官系统，这些系统与疾病风险的发育编程有关。

The proposed studies will use brown adipose tissue (BAT) as a platform to elucidate how postnatal developmental influences control the neuroanatomical structure of sympathetic nervous system (SNS) inputs and how these changes impart lasting and specific effects on whole body physiology and susceptibility to disease risk. A wide range of developmental exposures influence SNS tone onto metabolically-relevant organs, including pancreas, kidney, adipose tissue and heart. To date, evidence for a relationship between developmental influences on SNS tone and organ function is purely correlational. An obstacle to direct investigations of the contributions of SNS programming to adult physiology is that experimental manipulations of their activity during development would likely have impacts on organ function that affect the overall health of the animal, which would confound interpretation of the results. We identified two early postnatal exposures that specifically reduce the number of sympathetic neurons in the stellate ganglion that project to BAT (SGBAT), but program disparate responses to physiological challenges in healthy adults. Housing at 30°C leads to lasting effects on responsiveness to cold but not high fat diet, while lactation in a small litter (SL) programs susceptibility to diet-induced obesity but not cold. Studies outlined here will establish novel systems to test whether changes in SGBAT number impact innervation and SNS tone onto BAT (Aim 1), and whether they are necessary and sufficient to program lasting effects on organ function and physiological responses to cold and diet challenges (Aim 2). We will leverage our discovery of molecularly distinct subpopulations of SGBAT neurons and differentially expressed genes in BAT from mice raised at 30°C vs. 22°C to uncover molecular mediators of programming in SNS circuits (Aim 3). We will perform parallel transcriptomic analyses in BAT and SG to identify sources of specificity in the functional responses to manipulations of litter size or temperature during a critical period of development. Because transcriptional signatures of SGBAT subclasses are shared by all SG neurons, lessons from these studies can be applied to other postnatal exposures and organ systems that have been implicated in developmental programming of disease risk.