The Impact of Obesity on Somatotrope Function

摘要 成年人中极度肥胖的患病率正在急剧上升，今天超过三分之一(39.8%) 的成年人患有肥胖症。此外，肥胖症的特点是反应和激素水平 鼓励积累更多的脂肪。肥胖者对抑制食欲的行为有抵抗力 瘦素和瘦素对血糖的调节，以及它们分泌的脂解激素水平降低，生长 生长激素(GH)来自垂体前叶(AP)生长激素。在对以下方面的认识上存在很大差距 生长激素分泌抑制背后的机制。鉴于生长激素作为新陈代谢的重要性 传感器及其生产GH的需要，迫切需要提高我们对GH的认识 生长抑素对肥胖应激的反应。像所有AP细胞一样，生长激素细胞显示出其可塑性 经过改装，以满足身体不断变化的荷尔蒙和性别需求。瘦素可能直接调节 促生长激素可塑性，尽管机制尚不清楚。此外，瘦素的影响是广泛的，因为 它影响AP细胞的成熟。这个实验室的长期目标是阐明 AP细胞受到调节，以便对代谢信号做出适当的反应。的具体目标 本申请中描述的研究是为了确定瘦素向生长激素发出信号的机制， 包括识别在饮食条件下发生的基因表达变化和重塑 诱导性肥胖(DIO)。这项拟议的研究将检验肥胖状态导致性行为的中心假设-- 特定的促生长激素功能障碍和对环境压力的妥协反应。一个 第二个假说是转录后调控在促进AP中起着关键作用 改建。目标1研究将确定肥胖和恢复正常体重的影响 论促生长激素重塑和可塑性。小鼠将受到饮食诱导的肥胖(DIO)的影响 在中温条件下，第二组动物将在DIO后恢复正常体重。不偏不倚， 有针对性的方法包括miRNA测序(miRNA-seq)、单细胞RNA测序(scRNA-seq)和 多重蛋白质分析将确定信号通路介体和AP细胞反应模式。目标2 研究将确定肥胖对压力下的促生长激素反应的影响。迪奥老鼠将会是 用miRNA-seq和scRNA-seq评估对低温攻击的反应。AIM 2还将测试 DIO和环境应激对缺乏翻译调节蛋白的小鼠的影响 生长激素。本研究从AP水平探讨了调节能量平衡的生物学机制。 并将阐明生长激素是如何重塑的，以应对特定性别的肥胖的代谢应激 举止。有针对性和不偏不倚的最先进技术的引入提供了一个独特的机会 以获得对确定肥胖症治疗干预目标至关重要的更广泛的机械性见解 州政府。

SUMMARY The prevalence of extreme obesity in adults is increasing precipitously and today more than one-third (39.8%) of adults are obese. Furthermore, the obese condition is characterized by responses and hormone levels that encourage the accumulation of more fat. Obese individuals are resistant to the appetite suppressing actions of leptin and to glucose regulation by leptin and they secrete reduced levels of the lipolytic hormone, growth hormone (GH) from anterior pituitary (AP) somatotropes. There are significant gaps in knowledge about mechanisms behind the suppression in GH secretion. In light of the importance of somatotropes as metabolic sensors and the need for their production of GH, there is a critical need to improve our understanding of somatotrope responses to the stress of obesity. Like all AP cells, somatotropes display plasticity as they are remodeled to meet fluctuating hormonal and gender-specific needs of the body. Leptin may directly modulate somatotrope plasticity, although mechanisms are unknown. Furthermore, the impact of leptin is broad in that it impacts AP cell maturation. The long-term goal of this laboratory is to elucidate the mechanisms by which AP cells are regulated in order to respond appropriately to metabolic signals. The specific objectives with the studies described in this application are to determine the mechanisms by which leptin signals somatotropes, including the identification of gene expression changes and remodeling that occurs under conditions of diet induced obesity (DIO). This proposed study will test the central hypothesis that the obese state causes sex- specific somatotrope dysfunction and compromises responses to environmental stresses. A secondary hypothesis is that post-transcriptional regulation plays a key role in facilitating AP remodeling. Aim 1 studies will determine the impact of obesity and recovery to normal weight on somatotrope remodeling and plasticity. Mice will be subject to diet-induced obesity (DIO) under thermoneutral conditions and a second cohort of animals will recover normal weight after DIO. Unbiased and targeted approaches including miRNA sequencing (miRNA-seq), single cell RNA-sequencing (scRNA-seq) and multiplex protein assays will identify signaling pathway mediators and AP cellular response patterns. Aim 2 studies will ascertain the impact of obesity on somatotrope responses to stress. DIO mice will be challenged with hypothermia and responses assessed by miRNA-seq and scRNA-seq. Aim 2 will also test the impact of DIO and environmental stress on mice lacking the translational regulatory protein, Musashi in somatotropes. This study addresses the biological mechanisms regulating energy balance at the level of the AP and will clarify how somatotropes are remodeled to respond to the metabolic stress of obesity in a sex-specific manner. The introduction of targeted and unbiased state-of-the-art technologies presents a unique opportunity for broader mechanistic insights that are critical to identify targets for therapeutic intervention in the obese state.