The Impact of Obesity on Somatotrope Function

肥胖对生长激素功能的影响

• 批准号: 10453474
• 负责人: GWEN V CHILDS
• 金额: $ 58.45万
• 依托单位: UNIV OF ARKANSAS FOR MED SCIS
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-17 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10453474
• 关键词: Address; Adult; Animals; Anterior Pituitary Gland; Anterior Pituitary Hormones; Attenuated; Biological; Biological Assay; Body Weight decreased; Cell Maturation; Cells; Desire for food; Disease; Exposure to; Fatty acid glycerol esters; Functional disorder; Gender; Gene Expression; Genetic Transcription; Genetic Translation; Goals; Hormonal; Hormone secretion; Hormones; Knowledge; Laboratories; Leptin; Light; Mediating; Mediator of activation protein; Messenger RNA; Metabolic; Metabolic dysfunction; Metabolic stress; Molecular; Morbid Obesity; Mus; Obese Mice; Obesity; Pathway interactions; Pattern; Pituitary Gland; Play; Population; Post-Transcriptional Regulation; Prevalence; Production; Proteins; Recovery; Regulation; Regulatory Pathway; Research; Resistance; Sex Differences; Signal Pathway; Signal Transduction; Somatotrope Cell; Somatotropin; Stress; Technology; Testing; Therapeutic Intervention; United States National Institutes of Health; Weight; adult obesity; base; blood glucose regulation; cell type; cohort; diet-induced obesity; energy balance; environmental stressor; genetic regulatory protein; growth hormone deficiency; improved; insight; insulin regulation; leptin receptor; miRNA expression profiling; mouse model; natural hypothermia; obese person; progenitor; response; sensor; sex; single-cell RNA sequencing; stem; stem cells; targeted treatment; transdifferentiation

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.

总结 成年人极度肥胖的患病率急剧增加，今天超过三分之一（39.8%） 的成年人肥胖。此外，肥胖状况的特征在于反应和激素水平， 促进更多脂肪的积累。肥胖的人对抑制食欲的作用有抵抗力， 瘦素和葡萄糖调节瘦素和他们分泌的脂解激素水平降低，生长 来自垂体前叶（AP）促生长素激素（GH）。在以下方面的知识存在重大差距： 抑制GH分泌的机制。鉴于促生长素作为代谢产物的重要性， 传感器和需要他们的生产生长激素，有一个迫切需要提高我们的理解， 对肥胖压力的生长激素反应。像所有的AP细胞一样，生长激素细胞表现出可塑性， 重塑以满足波动的荷尔蒙和身体的性别特异性需求。瘦素可能直接调节 生长激素可塑性，尽管机制尚不清楚。此外，瘦素的影响广泛， 它影响AP细胞的成熟。该实验室的长期目标是阐明 AP细胞被调节以适当地响应代谢信号。具体目标与 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， 包括在饮食条件下发生的基因表达变化和重塑的鉴定 肥胖症（DIO）。这项拟议中的研究将检验肥胖状态导致性行为的核心假设- 具体的生长激素功能障碍和妥协的反应，环境压力。一 第二个假设是转录后调节在促进AP中起关键作用 重塑目标1研究将确定肥胖和恢复到正常体重的影响 生长激素的重塑和可塑性小鼠将在24小时内经受饮食诱导的肥胖症（DIO）。 在热中性条件下，第二组动物将在DIO后恢复正常体重。无偏见和 靶向方法包括miRNA测序（miRNA-seq）、单细胞RNA测序（scRNA-seq）和 多重蛋白质分析将鉴定信号传导途径介体和AP细胞应答模式。目的2 研究将确定肥胖对生长激素对压力的反应的影响。DIO小鼠将 用低体温攻击并通过miRNA-seq和scRNA-seq评估应答。Aim 2还将测试 DIO和环境应激对缺乏翻译调节蛋白Musashi的小鼠的影响 生长激素本研究探讨了AP水平上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，以应对肥胖的代谢压力，在性别特异性 方式引入有针对性和公正的最先进的技术提供了一个独特的机会 更广泛的机制见解，这对于确定肥胖症治疗干预的目标至关重要。 状态