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: 8581038
• 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/8581038
• 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）：肥胖及其引起的并发症是一项重大的公共卫生问题；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。作为一名儿科内分泌学家，P.I.沙阿博士对研究肥胖相关代谢失调的早期机制过程有着浓厚的兴趣，希望探索新的预防和治疗方案。她的最终职业目标是成为内分泌学领域的独立转化研究员，重点研究儿科和成人年龄段的肥胖和脂肪组织生物学。通过目前与导师的合作以及转化研究硕士项目的培训，她已经掌握了临床和转化研究方面的基本技能和经验。这将使她能够开展本申请中提出的工作，该工作将人体临床试验与人体组织和细胞研究相结合，探索肥胖相关脂肪炎症的新途径。为了在过渡到独立的过程中获得更多的专业知识和知识，沙阿博士设计了一个全面的职业发展计划，充分利用费城儿童医院和宾夕法尼亚大学丰富的研究、教育和合作环境。沙阿博士的职业规划包括转化研究方面的强有力的指导、遗传学、免疫学和生物信息学方面的教学课程、必要的实验室技能和临床研究方面的重点培训、通过参加校内和校外、研讨会和专业发展等方面的培训。会议，并明确规定了独立的步骤。她得到儿科和内分泌科的全力支持，确保本次培训有足够的时间和资源。此外，她还将获得导师 Muredach Reilly 博士和 Karen Teff 博士以及精心挑选的专家咨询委员会在她拟议研究的关键领域的指导。为了完成她提出的研究，Shah 博士将能够使用 Penn/CHOP CTSA 赞助的临床和转化研究中心 (CTRC) 的资源、Reilly 博士的实验室、核心设施和统计专业知识。通过完成本申请中概述的研究和教育计划，沙阿博士将获得建立独立转化研究项目所需的经验，探索成人-儿童肥胖的机制。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被证明可减少脂肪细胞和单核细胞炎症并预防高脂肪喂养期间的脂肪白细胞浸润;然而，缺乏人体体内数据。脂肪炎症和巨噬细胞浸润的关键驱动因素是脂肪趋化因子信号传导，包括 CCL2-CCR2 和 CX3CL1-CX3CR1 通路。喂食 n-3 PUFA 的小鼠中 CCL2 水平降低表明 LC n-3 PUFA 在脂肪中的抗炎作用是否是通过这些趋化因子系统介导的，但尚未具体探索。 LC n-3 PUFA 发挥抗炎作用的机制脂肪的炎症作用也没有明确定义。最近，在小鼠和细胞模型中发现了一种 LC n-3 PUFA 受体 GPR120，它似乎可以调节 n-3 PUFA 对核因子 kappa beta（NF 信号传导，以减少细胞和脂肪组织中的炎症）的抑制作用。在人类中， GPR120 的功能增加了肥胖的风险，这些发现表明了 LC n-3 PUFA 减轻肥胖相关脂肪炎症的潜在机制。调节脂肪细胞-巨噬细胞趋化因子信号传导（CCL2-CCR2 和 CX3CL1-CX3CR1），通过 GPR120 抑制 NF-B 信号传导来减少全身和脂肪炎症。本申请提出了以下假设：1) LC n-3 PUFA 处理原代人脂肪细胞。体外通过 GPR120 抑制趋化因子诱导的脂肪细胞炎症和脂肪细胞-单核细胞相互作用 2) LC n-3 PUFA 体外处理人单核细胞和巨噬细胞会修饰 CX3CL1-CX3CR1 和 CCL2-CCR2，以减少这些白细胞的炎症状态以及由此产生的以 GPR120 依赖性方式与脂肪细胞的相互作用，以及 3) 用 n-3 PUFA 治疗肥胖人类受试者-3 与安慰剂相比，PUFA 补充剂 Lovaza 调节 CX3CL1-CX3CR1 和 CCL2-CCR2趋化因子系统可减少炎症白细胞募集到人体脂肪中。原代人类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的趋化因子信号传导、CX3CL1-CX3CR1 和 CCL2-CCR2 诱导的单核细胞-脂肪细胞粘附和迁移以及 NF 激活的影响。 GPR120 和 NFkB 的敲低将用于确定抗炎作用是否由这些途径调节。对于临床试验，肥胖、非糖尿病受试者将接受 Lovaza 或安慰剂治疗 8 周；计划在基线和 8 周内进行访视，通过流式细胞术评估胰岛素敏感性、脂肪和血液趋化因子水平、NF 信号因子以及脂肪和循环表达 CX3CR1 和 CCR2 的巨噬细胞和单核细胞定量。