The Renin-Angiotensin System in Air Pollution-Mediated Exacerbation of Obesity.

空气污染介导的肥胖加剧中的肾素-血管紧张素系统。

基本信息

批准号：
10654124
负责人：
Amie Kathleen Lund
金额：
$ 43.6万
依托单位：
UNIVERSITY OF NORTH TEXAS
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-06-01 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10654124
关键词：
16S ribosomal RNA sequencing Adipocytes Adipose tissue Adult Agonist Air Pollution Angiotensin II Animals Attenuated Bifidobacterium Biological Process Body mass index C57BL/6 Mouse Cell Culture Techniques Child Data Desire for food Disease Endocrine Energy Metabolism Engine Exhaust Enzyme-Linked Immunosorbent Assay Exposure to Female Future GLP-I receptor Gene Expression Genes Growth Growth and Development function Health Hormones Human Hypertrophy Immunofluorescence Immunologic In Vitro Individual Infiltration Inflammation Inflammatory Inhalation Inhalation Exposure Insulin Resistance Interleukin-6 Intervention Intestines L Cell (Intestine)L Cells Laboratories Lactobacillus Leptin Link Lipids Lipolysis Macrophage Measures Mediating Metabolic Metabolic Diseases Metabolic hormone Metabolic syndrome Methodology Mus Neurosecretory Systems Nutrient Obesity Outcome Particulate Matter Pathogenesis Pathologic Pathway interactions Pharmacologic Substance Phenotype Placebos Plasma Population Predisposition Prevalence Probiotics Publishing Randomized Receptor Signaling Regulation Renin-Angiotensin System Reporting Risk Factors Role Saline Signal Pathway Signal Transduction Small Interfering RNA Source Sterility Structure Testing Tissues Type 2 Angiotensin II Receptor Volatile Fatty Acids Weight Gain Youth adipokines adiponectin air filter ambient air pollution drinking water environmental particulate epidemiology study experimental study fecal microbiota glucagon-like peptide 1 glucose metabolism gut microbiome gut microbiota hormonal signals hormone resistance in vivo inflammatory marker innovation insight insulin secretion insulin tolerance knock-down lipid biosynthesis lipid metabolism liraglutide male microbiota profiles nano-string next generation next generation sequencing novel obese person obesity in children obesogenic probiotic therapy proglucagon response sex small hairpin RNA statistics treatment group

项目摘要

Significance. Exposure to traffic-generated particulate matter (PM), a significant source of ambient air pollution, is associated with adverse health outcomes, including metabolic disorder and obesity, rates of which are increasing in children and adults worldwide. However, the pathways involved in promoting an obese adipose phenotype resulting from PM exposure are not fully understood. An “unhealthy” gut microbiome and increased tissue-specific adipose renin-angiotensin system (RAS) signaling are both associated with obesity; however, the signaling pathways that link these two factors have not been fully characterized, especially related to environmental PM exposure. Thus, whether PM exposure mediates abnormal gut microbiota profiles that promote alterations in short-chain fatty acid (SCFA) and glucagon-like peptide (GLP)-1 signaling in the intestines will be determined. Elucidating the role of GLP-1 on tissue level RAS signaling in adipocytes may provide novel targets for future therapies for susceptible individuals living in regions with high urban air pollution levels. Innovation. The proposed experiments will analyze the cross-talk between SCFA, GLP-1, and RAS signaling in adipose tissue to determine whether inhalation exposure to diesel engine exhaust PM (DEP) results in altered gut microbiome profiles associated with deregulation of GLP-1-mediated RAS signaling and subsequent alterations in the adipose structure and metabolic/endocrine function associated with obesity. Importantly, these analyses will be conducted in tissues derived from male and female C57BL/6 mice, using characterized DEP, and appropriate pharmaceutical interventions (GLP-1 agonist, probiotics), to simulate exposure scenarios and underlying pathophysiologic states similar to that in the human population. Adipocyte cell culture will be used to further investigate the mechanism and 16S Next-Generation Sequencing, NanoString, and Multiplex methodologies to reveal alterations in the gut microbiome and metabolic/endocrine pathways involved in obesity. Specific Aims. The preliminary data shows that exposure to mixed vehicle engine emissions results in weight gain, adipocyte hypertrophy, and elevated adipose tissue level RAS in male C57BL/6 mice; however, the role of DEP has not been investigated as a contributing causative component in these outcomes. Thus, the hypothesis that inhalational DEP exposure promotes obesogenic profiles in adipose tissue through deregulation of GLP-1 – Ang II signaling will be investigated. In Aim 1, the outcome of inhaled DEP on gut microbiota profiles and SCFA signaling in regulating GLP-1 expression and RAS-mediated adipocyte hypertrophy and adipokine signaling will be analyzed C57BL/6 male and female mice using a probiotic treatment. DEP-mediated alterations in systemic metabolic and obesogenic gene expression pathways will also be assessed. In Aim 2, it will be determined whether DEP exposure mediates alterations in GLP-1 on adipocyte RAS signaling and subsequent lipid accumulation through GLP-1 agonist treatment (in vivo), and also GLP-1 agonist vs. siRNA knockdown of local GLP-1 receptor signaling (in vitro) in adipocyte cell culture treated with plasma from our study animals.

意义。暴露于交通生成的颗粒物（PM），这是环境空气污染的重要来源，与不良健康结果有关，包括代谢障碍和肥胖，其率是全球儿童和成人的增加。但是，促进肥胖脂肪涉及的途径 PM暴露引起的表型尚不完全了解。 “不健康”的肠道微生物组并增加组织特异性脂肪肾素 - 血管紧张素系统（RAS）信号传导都与肥胖有关。但是，连接这两个因素的信号通路尚未完全表征，尤其是与环境PM暴露。那，PM暴露是否介导异常的肠道菌群概况促进短链脂肪酸（SCFA）和胰高血糖素样肽（GLP）-1信号的改变将确定。阐明GLP-1对脂肪细胞中RAS信号传导的作用可能提供新颖的居住在城市空气污染水平较高的地区的易感人群的未来疗法的目标。创新。提出的实验将分析SCFA，GLP-1和RAS信号之间的串扰脂肪组织以确定吸入柴油发动机排气PM（DEP）是否导致变化肠道微生物组轮廓与GLP-1介导的RAS信号的放大管制有关与肥胖相关的脂肪结构和代谢/内分泌功能的改变。重要的是，这些分析将在源自男性和雌性C57BL/6小鼠的组织中进行，并使用表征的DEP，以及适当的药物干预措施（GLP-1激动剂，益生菌），以模拟暴露情况和与人口相似的基本病理生理状态。脂肪细胞细胞培养将用于进一步研究机制和16S下一代测序，纳米串和多重揭示肠道微生物组和代谢/内分泌途径涉及的方法的方法。具体目标。初步数据表明，接触混合发动机排放会导致重量雄性C57BL/6小鼠的增益，脂肪细胞肥大和脂肪组织水平升高；但是，在这些结果中，DEP尚未作为造成灾难性成分的研究。那是假设吸入DEP暴露通过放松glp-1 - ANG II信号将研究。在AIM 1中，对肠道微生物元素和SCFA的遗传DEP的结果调节GLP-1表达和RAS介导的脂肪细胞肥大和脂肪因子信号的信号传导将使用益生菌治疗对C57BL/6雄性和雌性小鼠进行分析。 DEP介导的全身性改变还将评估代谢和肥胖基因表达途径。在AIM 2中，它将确定 DEP暴露是否介导脂肪细胞RAS信号传导和随后的脂质上的GLP-1改变通过GLP-1激动剂治疗（体内）积累我们研究动物的血浆处理的脂肪细胞培养物中的GLP-1受体信号传导（体外）。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Exposure to diesel exhaust particles results in altered lung microbial profiles, associated with increased reactive oxygen species/reactive nitrogen species and inflammation, in C57Bl/6 wildtype mice on a high-fat diet.

DOI：
10.1186/s12989-020-00393-9
发表时间：
2021-01-08
期刊：
Particle and fibre toxicology
影响因子：
10
作者：
Daniel S;Phillippi D;Schneider LJ;Nguyen KN;Mirpuri J;Lund AK
通讯作者：
Lund AK

Inhaled diesel exhaust particles result in microbiome-related systemic inflammation and altered cardiovascular disease biomarkers in C57Bl/6 male mice.

DOI：
10.1186/s12989-022-00452-3
发表时间：
2022-02-09
期刊：
Particle and fibre toxicology
影响因子：
10
作者：
Phillippi DT;Daniel S;Pusadkar V;Youngblood VL;Nguyen KN;Azad RK;McFarlin BK;Lund AK
通讯作者：
Lund AK

Probiotics Function as Immunomodulators in the Intestine in C57Bl/6 Male Mice Exposed to Inhaled Diesel Exhaust Particles on a High-Fat Diet.

DOI：
10.3390/cells11091445
发表时间：
2022-04-25
期刊：
CELLS
影响因子：
6
作者：
Phillippi, Danielle T.;Daniel, Sarah;Nguyen, Kayla N.;Penaredondo, Bea Angella;Lund, Amie K.
通讯作者：
Lund, Amie K.

Mixed Vehicle Emissions Induces Angiotensin II and Cerebral Microvascular Angiotensin Receptor Expression in C57Bl/6 Mice and Promotes Alterations in Integrity in a Blood-Brain Barrier Coculture Model.

混合车辆排放诱导 C57Bl/6 小鼠血管紧张素 II 和脑微血管血管紧张素受体表达，并促进血脑屏障共培养模型完整性的改变。