The Impact of Obesity on Somatotrope Function

肥胖对生长激素功能的影响

• 批准号: 10316310
• 负责人: GWEN V CHILDS
• 金额: $ 58.23万
• 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/10316310
• 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.

概括 成人极度肥胖的患病率正在急剧增加，目前已超过三分之一 (39.8%) 的成年人肥胖。此外，肥胖状况的特点是反应和激素水平 促进更多脂肪的积累。肥胖者对食欲抑制作用有抵抗力 瘦素和瘦素对葡萄糖的调节，它们分泌的脂肪分解激素水平降低，生长 来自垂体前叶 (AP) 生长激素的激素 (GH)。相关知识存在重大差距 GH 分泌抑制背后的机制。鉴于生长激素作为代谢的重要性 传感器及其生产 GH 的需要，迫切需要提高我们对 生长激素对肥胖压力的反应。与所有 AP 细胞一样，生长激素表现出可塑性 重塑以满足身体波动的荷尔蒙和性别特定的需求。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其机制 AP 细胞受到调节，以便对代谢信号做出适当的反应。具体目标与 本申请中描述的研究旨在确定瘦素向生长激素发出信号的机制， 包括识别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 特定的生长激素功能障碍并损害对环境压力的反应。一个 第二个假设是转录后调控在促进 AP 中发挥关键作用 重塑。目标 1 研究将确定肥胖和恢复正常体重的影响 关于生长激素重塑和可塑性。小鼠将遭受饮食诱导肥胖（DIO） 在热中性条件下，第二组动物在 DIO 后将恢复正常体重。不偏不倚且 靶向方法包括 miRNA 测序 (miRNA-seq)、单细胞 RNA 测序 (scRNA-seq) 和 多重蛋白质检测将鉴定信号通路介质和 AP 细胞反应模式。目标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 体温过低的挑战以及通过 miRNA-seq 和 scRNA-seq 评估的反应。目标 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。这项研究探讨了调节 AP 水平能量平衡的生物机制 并将阐明生长激素如何被重塑以应对特定性别的肥胖代谢应激 方式。引入有针对性且公正的最先进技术提供了独特的机会 获得更广泛的机制见解，这对于确定肥胖症治疗干预的目标至关重要 状态。