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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.

总结