The Impact of Obesity on Somatotrope Function

肥胖对生长激素功能的影响

基本信息

批准号：
10656317
负责人：
GWEN V CHILDS
金额：
$ 57.24万
依托单位：
UNIV OF ARKANSAS FOR MED SCIS
依托单位国家：
美国
项目类别：
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/10656317
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 Gene Expression Profile Goals Hormonal Hormone secretion Hormones Hyperinsulinism Knowledge Laboratories Leptin Light Mediating Mediator 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 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 mRNA Translation miRNA expression profiling mouse model natural hypothermia obese person posttranscriptional progenitor response sensor sex single-cell RNA sequencing stem stem cells targeted treatment transdifferentiation

项目摘要

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.

概括成人极端肥胖的患病率正在急剧增加，如今已超过三分之一（39.8％）成年人肥胖。此外，肥胖状况的特征是反应和激素水平鼓励积累更多的脂肪。肥胖个体对抑制食欲的行动有抵抗力瘦素和通过瘦素调节葡萄糖调节，它们分泌降低脂肪溶液的水平，生长垂体前（AP）体育体的激素（GH）。关于 GH分泌抑制背后的机制。鉴于体育型作为代谢的重要性传感器和对GH生产的需求，迫切需要提高我们对人体对肥胖压力的反应。像所有AP细胞一样，体形表现出可塑性重塑以满足人体的荷尔蒙和性别特异性需求。瘦素可以直接调节种子可塑性，尽管机制尚不清楚。此外，瘦素的影响很广它会影响AP细胞的成熟。该实验室的长期目标是阐明该机制对AP细胞进行调节，以适当响应代谢信号。具有的特定目标本应用中描述的研究是为了确定瘦素信号的机制，包括在饮食条件下的基因表达变化和重塑的鉴定诱发肥胖症（DIO）。这项拟议的研究将检验中心假设，即肥胖状态会导致性别 - 特定的体育功能障碍并损害了对环境应力的反应。一个次要假设是转录后调节在促进AP中起关键作用重塑。 AIM 1研究将确定肥胖和恢复对正常体重的影响在体育型重塑和可塑性上。小鼠将受到饮食引起的肥胖症（DIO）的约束 dio后，热中性条件和第二个动物队列将恢复正常的体重。公正和有针对性的方法包括miRNA测序（miRNA-seq），单细胞RNA-sequing（SCRNA-SEQ）和多重蛋白质测定将识别信号通路介质和AP细胞反应模式。目标2 研究将确定肥胖症对压力的体育体反应的影响。 Dio小鼠将是受miRNA-Seq和Scrna-Seq评估的体温过低和反应挑战。 AIM 2也将测试 DIO和环境压力对缺乏翻译调节蛋白Musashi的小鼠的影响种子。这项研究解决了调节AP水平能量平衡的生物学机制并将阐明如何重塑体状，以应对性别特定的肥胖症的代谢压力方式。引入有针对性和公正的最先进技术提供了独特的机会对于更广泛的机械见解，这对于确定肥胖的治疗干预目标至关重要状态。