Omega-3 PUFA suppress adipochemokines in human obesity

Omega-3 PUFA 抑制人类肥胖中的脂肪趋化因子

• 批准号: 8713988
• 负责人: Rachana Shah
• 金额: $ 14.53万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8713988
• 关键词: Address; Adhesions; Adipocytes; Adipose tissue; Adult; Advisory Committees; Age; Agonist; Animal Model; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Area; Attenuated; Bioinformatics; Biology; Blood; CCL2 gene; CX3CL1 gene; Cell model; Cells; Center for Translational Science Activities; Childhood; Clinical Research; Clinical Trials; Commit; Core Facility; Development; Development Plans; Diabetes Mellitus; Docosahexaenoic Acids; Dyslipidemias; Eicosapentaenoic Acid; Endocrinologist; Endocrinology; Ensure; Environment; Epidemic; Eragrostis; Fatty acid glycerol esters; Fish Oils; Flow Cytometry; Fractalkine; Functional disorder; Genetic; Genetic Polymorphism; Goals; Human; Immunology; In Vitro; Individual; Infiltration; Inflammation; Inflammatory; Insulin Resistance; Knowledge; Laboratories; Lead; Leukocytes; Link; Lipids; Mediating; Mentors; Mentorship; Messenger RNA; Metabolic; Modality; Modeling; Monocyte Chemoattractant Proteins; Mus; N-3 polyunsaturated fatty acid; NF-kappa B; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Obesity associated disease; Omega-3 Fatty Acids; Pathway interactions; Pediatric Hospitals; Pennsylvania; Philadelphia; Placebos; Plasma; Population; Prevention; Prevention strategy; Preventive; Process; Production; Proteins; Public Health; Relative (related person); Research; Research Personnel; Resources; Rodent; Rodent Model; Role; Signal Transduction; Stimulus; Supplementation; Surface; System; Testing; Therapeutic; Time; Tissues; Training; Translational Research; Translations; Universities; Visit; Weight; Work; career; career development; chemokine; chemokine receptor; cytokine; dietary supplements; experience; feeding; human data; human subject; human tissue; in vivo; insight; insulin sensitivity; interest; loss of function; macrophage; migration; monocyte; monocyte chemoattractant protein 1 receptor; mouse model; non-diabetic; novel; novel therapeutics; obesity risk; pediatric department; placebo controlled study; pre-clinical; prevent; programs; public health relevance; receptor; response; skills; small hairpin RNA; symposium; treatment strategy

DESCRIPTION (provided by applicant): Obesity and its resultant complications represent a major public health; further understanding of the underlying pathophysiology will aid the development of preventive and therapeutic modalities. As a pediatric endocrinologist, the P.I. Dr Shah has a committed interest in studying the early mechanistic processes involved in obesity-related metabolic dysregulation, with the hope of exploring novel preventive and treatment options. Her ultimate career goal is to become an independent translational researcher in the field of endocrinology, with a focus in obesity and adipose tissue biology across the pediatric and adult age spectrum. Through her current work with her mentor and training in the Masters in Translational Research program, she has developed essential skills and experience in clinical and translational research. This will allow her to perform the work proposed in this application, which integrates a human clinical trial with studies in human tissues and cells to explore novel pathways in obesity-related adipose inflammation. To acquire further expertise and knowledge as she transitions to independence, Dr Shah has devised a comprehensive career development plan that takes full advantage of the rich research, educational, and collaborative environment at the Children's Hospital of Philadelphia and the University of Pennsylvania. Dr Shah's career plan includes strong mentorship in translational research, didactic coursework in genetics, immunology, and bioinformatics, focused training in necessary laboratory skills and aspects of clinical research, scientific enrichment and professional development through attendance of intra- and extra-mural, seminars and conferences, and clearly delineated steps to independence. She has the full support of the Department of Pediatrics and Division of Endocrinology to ensure adequate time and resources for this training. Additionally, she will receive guidance through her mentors, Dr Muredach Reilly and Dr Karen Teff, and a carefully selected advisory committee of experts in critical areas of her proposed research. In order to complete her proposed studies, Dr Shah will have access to resources in the Penn/CHOP CTSA-sponsored Clinical and Translational Research Center (CTRC), Dr Reilly's laboratory, core facilities, and statistical expertise. Through the completion of the research and educational plans outlined in this application, Dr Shah will gain the experience necessary to establish an independent translational research program exploring mechanisms in obesity across the adult-pediatric spectrum. Murine long-chain omega-3 polyunsaturated fatty acids (LC n-3 PUFA) are used clinically to treat dyslipidemia and are demonstrated in pre-clinical cell and rodent models to decrease adipocyte and monocyte inflammation and prevent adipose leukocyte infiltration during high-fat feeding; in vivo human data, however, is lacking. A key driver of adipose inflammation and macrophage infiltration is adipochemokine signaling, including the CCL2-CCR2 and CX3CL1-CX3CR1 pathways. Whether LC n-3 PUFA anti-inflammatory actions in adipose are mediated via these chemokine systems is suggested by decreased CCL2 levels in mice fed n-3 PUFA but has not specifically been explored, The mechanisms by which LC n-3 PUFA exerts anti-inflammatory effects in adipose are also not clearly defined. Recently a LC n-3 PUFA receptor, GPR120, has been identified that in mouse and cell models appears to modulate n-3 PUFA inhibition of nuclear factor kappa beta (NF signaling to decrease inflammation in cells and adipose tissue. In humans, loss of function of GPR120 confers increased risk of obesity. Together these findings suggest a potential mechanism by which LC n-3 PUFA attenuates obesity- related adipose inflammation. We hypothesize that LC n-3 PUFA modulate adipocyte-macrophage chemokine signaling (CCL2-CCR2 and CX3CL1-CX3CR1) to decrease systemic and adipose inflammation via GPR120 inhibition of NF- B signaling. This application addresses the following hypotheses: 1) LC n-3 PUFA treatment of primary human adipocytes in vitro suppresses chemokine-induced adipocyte inflammation and adipocyte-monocyte interactions via GPR120 2) LC n-3 PUFA treatment of human monocytes and macrophages in vitro modifies CX3CL1-CX3CR1 and CCL2-CCR2 to reduce the inflammatory state of these leukocytes and resultant interactions with adipocytes in a GPR120-dependent manner and 3) treatment of obese human subjects with the n-3 PUFA supplement Lovaza, compared to placebo, regulates the CX3CL1-CX3CR1 and CCL2-CCR2 chemokine systems to reduce inflammatory leukocyte recruitment into human adipose. In vitro studies in primary human cells will assess effects of individual n-3 PUFAs and GPR120 agonists on baseline and inflammatory stimulated chemokine signaling, CX3CL1-CX3CR1 and CCL2-CCR2 induced monocyte-adipocyte adhesion and migration, and.NF activation. Knockdown of GPR120 and NFkB will be used to determine whether anti- inflammatory effects are modulated by these pathways. For the clinical trial, obese, non-diabetic subjects will be treated for 8 weeks with Lovaza or placebo; visits are planned at baseline and 8 weeks for assessment of insulin sensitivity, adipose and blood chemokine levels, NF signaling factors, and adipose and circulating CX3CR1- and CCR2-expressing macrophage and monocyte quantification via flow cytometry.

描述（由申请人提供）：肥胖及其由此产生的并发症代表了主要的公共卫生；进一步了解潜在的病理生理学将有助于预防和治疗方式的发展。作为儿科内分泌学家，P.I。 Shah博士致力于研究与肥胖相关的代谢失调涉及的早期机械过程，希望探索新颖的预防和治疗选择。她的最终职业目标是成为内分泌学领域的独立翻译研究员，重点是肥胖和脂肪组织生物学，整个小儿和成人年龄谱。通过与她的导师和翻译研究硕士学位培训的当前工作，她在临床和转化研究方面发展了基本技能和经验。这将使她能够在本应用中执行提出的工作，该工作将人类临床试验与人类组织和细胞的研究相结合，以探索与肥胖相关脂肪炎症的新途径。为了获得进一步的专业知识和知识，Shah博士设计了一项全面的职业发展计划，以充分利用费城儿童医院和宾夕法尼亚大学的丰富研究，教育和协作环境。 Shah博士的职业计划包括在翻译研究，遗传学，免疫学和生物信息学方面的教学课程方面的强大指导，将重点培训用于必要的实验室技能以及临床研究的各个方面，科学丰富和专业发展，通过参加内部和外交，研讨会，研讨会和研讨会，研讨会和研讨会和专业发展。会议，并明确描述了独立的步骤。她得到了儿科和内分泌学系的全部支持，以确保这项培训的足够时间和资源。此外，她将通过其导师Mudach Reilly博士和Karen Teff博士获得指导，以及她提议的研究的关键领域的精心选择的专家咨询委员会。为了完成她提出的研究，Shah博士将可以在Penn/Chop CTSA赞助的临床和转化研究中心（CTRC），Reilly博士的实验室，核心设施和统计专业知识中获得资源。通过完成本申请中概述的研究和教育计划，Shah博士将获得必要的经验，以建立一个独立的翻译研究计划，以探索整个成人培养基的肥胖机制。鼠长链omega-3多不饱和脂肪酸（LC N-3 PUFA）在临床上用于治疗血脂异常，并在临床前细胞和啮齿动物模型中得到证明，以减少脂肪细胞和单核细胞炎症并防止脂肪白细胞渗透率在高脂喂养过程中降低;但是，缺乏体内人类数据。脂肪炎症和巨噬细胞浸润的主要驱动力是脂肪动物信号传导，包括CCL2-CCR2和CX3CL1-CX3CR1途径。是否通过这些趋化因子系统介导LC N-3 PUFA抗炎作用是由饲养N-3 PUFA的小鼠中的CCL2水平降低提出的，但尚未特别探索，但尚未特别探索LC N-3 PUFA施加抗抗液的机制。脂肪中的炎症作用也未明确定义。最近，已经鉴定出一种LC N-3 PUFA受体GPR120，在小鼠和细胞模型中似乎调节了N-3 PUFA的核因子Kappa beta（NF信号传导减少细胞和脂肪组织的炎症。 GPR120的功能赋予了肥胖的风险。 -CX3CR1）通过GPR120抑制NF-B信号的抑制系统性和脂肪炎。通过GPR120 2）LC N-3 PUFA治疗人类单核细胞和巨噬细胞在体外修饰CX3CL1-CX3CR1和CCL2-CCR2，以减少这些白细胞的炎症状态，以及与GPR120依赖性治疗的炎症状态以及与脂肪的相互作用与安慰剂相比，具有N-3 PUFA补充剂Lovaza的人类受试者调节CX3CL1-CX3CR1和CCL2-CCR2趋化因子系统，以减少炎性白细胞募集到人类脂肪中。对原代人细胞的体外研究将评估单个N-3 PUFA和GPR120激动剂对基线和炎症刺激趋化因子信号传导，CX3CL1-CX3CR1和CCL2-CCR2诱导的单核细胞 - 脂肪细胞粘附和迁移的影响。 GPR120和NFKB的敲低将用于确定这些途径是否通过这些途径调节抗炎作用。对于临床试验，肥胖的非糖尿病患者将与洛夫萨或安慰剂治疗8周。计划在基线和8周内进行访问，以评估胰岛素敏感性，脂肪和血液趋化因子水平，NF信号传导因子以及脂肪以及通过流动细胞测定法进行循环的CX3CR1-和CCR2表达巨噬细胞的巨噬细胞和单核细胞定量。