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。

• 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
• 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

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.

接触交通产生的颗粒物 (PM)，这是环境空气污染的重要来源， 与不良健康结果相关，包括代谢紊乱和肥胖，其发生率 然而，导致肥胖的途径在全世界儿童和成人中不断增加。 PM 暴露导致的表型尚不完全清楚。“不健康”的肠道微生物组和增加。 然而，组织特异性脂肪肾素-血管紧张素系统 (RAS) 信号传导均与肥胖相关。 连接这两个因素的信号通路尚未得到充分表征，特别是与 因此，PM 暴露是否会介导异常的肠道微生物群分布？ 促进肠道内短链脂肪酸 (SCFA) 和胰高血糖素样肽 (GLP)-1 信号传导的改变 阐明 GLP-1 对脂肪细胞组织水平 RAS 信号传导的作用可能会提供新的思路。 未来区域针对生活在城市空气污染程度较高的易感人群的治疗目标。 创新性实验将分析 SCFA、GLP-1 和 RAS 信号传导之间的串扰。 脂肪组织以确定吸入暴露于柴油发动机废气 PM (DEP) 是否会导致脂肪组织改变 肠道微生物组谱与 GLP-1 介导的 RAS 信号传导失调及后续相关 重要的是，与肥胖相关的脂肪结构和代谢/内分泌功能的改变。 将使用特征化的 DEP 在雄性和雌性 C57BL/6 小鼠的组织中进行分析， 和适当的药物干预（GLP-1激动剂、益生菌），以模拟暴露场景和 与人类脂肪细胞细胞培养相似的潜在病理生理状态将被用于 进一步研究其机制和 16S 新一代测序、NanoString 和 Multiplex 揭示肠道微生物组和肥胖相关代谢/内分泌途径变化的方法。 具体目标 初步数据显示，接触混合车辆发动机排放物会导致重量增加。 然而，雄性 C57BL/6 小鼠的体重增加、脂肪细胞肥大和脂肪组织水平升高； 尚未将 DEP 作为这些结果的致病因素进行研究。因此，该假设是这样的。 吸入 DEP 暴露通过 GLP-1 的失调促进脂肪组织的肥胖特征 – 在目标 1 中，将研究吸入 DEP 对肠道微生物群谱和 SCFA 的影响。 调节 GLP-1 表达和 RAS 介导的脂肪细胞肥大和脂肪因子信号传导的信号传导将 使用益生菌治疗来分析 C57BL/6 雄性和雌性小鼠的全身变化。 代谢和肥胖基因表达途径也将在目标 2 中进行评估。 DEP 暴露是否介导 GLP-1 对脂肪细胞 RAS 信号传导和随后脂质的改变 通过 GLP-1 激动剂治疗（体内）进行的积累，以及 GLP-1 激动剂与 siRNA 局部敲低的比较 用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

Inhalation exposure to silver nanoparticles induces hepatic inflammation and oxidative stress, associated with altered renin-angiotensin system signaling, in Wistar rats.

Wistar 大鼠吸入银纳米粒子会诱发肝脏炎症和氧化应激，这与肾素-血管紧张素系统信号传导的改变有关。

• 发表时间: 2022-03
• 影响因子: 4.5
• 作者: Nayek, Subhayu;Lund, Amie K;Verbeck, Guido F
• 通讯作者: Verbeck, Guido F

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。

• 发表时间: 2019
• 作者: Suwannasual, Usa;Lucero, JoAnn;Davis, Griffith;McDonald, Jacob D;Lund, Amie K
• 通讯作者: Lund, Amie K

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.

在高脂肪饮食的 C57Bl/6 野生型小鼠中，暴露于柴油机尾气颗粒会导致肺部微生物特征改变，与活性氧/活性氮物种增加和炎症相关。

• 发表时间: 2021-01-08
• 作者: Daniel, Sarah;Phillippi, Danielle;Schneider, Leah J;Nguyen, Kayla N;Mirpuri, Julie;Lund, Amie K
• 通讯作者: Lund, Amie K

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

在高脂肪饮食中吸入柴油机尾气颗粒的 C57Bl/6 雄性小鼠中，益生菌在肠道中发挥免疫调节剂的作用。

• 发表时间: 2022-04-25
• 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

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

吸入柴油机尾气颗粒会导致 C57Bl/6 雄性小鼠与微生物组相关的全身炎症并改变心血管疾病生物标志物。

• 发表时间: 2022-02-09
• 作者: Phillippi, Danielle T;Daniel, Sarah;Pusadkar, Vaidehi;Youngblood, Victoria L;Nguyen, Kayla N;Azad, Rajeev K;McFarlin, Brian K;Lund, Amie K
• 通讯作者: Lund, Amie K