Anti-obesity effects of omega 3 fatty acids in brown adipose tissue

棕色脂肪组织中欧米伽 3 脂肪酸的抗肥胖作用

基本信息

批准号：
9171867
负责人：
Naima Moustaid-Moussa
金额：
$ 43.46万
依托单位：
TEXAS TECH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-01 至 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9171867
关键词：
Address Adipocytes Adipose tissue Animals Anti-Inflammatory Agents Anti-inflammatory Biogenesis Biological Body Composition Body Weight Body Weights and Measures Body fat Brown Fat Cardiovascular Diseases Cell Culture Techniques Cells Chronic Data Diabetes Mellitus Diet Dietary Component Dietary Factors Dietary Intervention Eating Eicosapentaenoic Acid Energy Metabolism Epidemic Exhibits Fatty Acids Fatty acid glycerol esters Food Energy Gene Expression Genes Genotype Genus Hippocampus Goals Health Health Benefit Healthcare Heating High Fat Diet Housing Human Inflammation Insulin Resistance Integrative Medicine Intervention Knock-out Knockout Mice Link Mediating Mesenchymal Stem Cells Metabolic Metabolic Diseases Mission Mitochondria Molecular Morbidity - disease rate Mus Nutrient Obesity Obesity associated disease Omega-3 Fatty Acids Outcomes Research Physiological Polyunsaturated Fatty Acids Prevention Prevention strategy Property Proteins Public Health Reducing diet Reporting Research Resistance Respiration Risk Role Safety Science Series Stem cells Strategic Planning Stress Temperature Testing Thermogenesis Tissues United States National Institutes of Health Up-Regulation abstracting base combat design dietary supplements energy balance evidence base extracellular feeding fibroblast growth factor 21 glucose tolerance improved in vivo innovation instrument insulin sensitivity knock-down mouse model natural hypothermia novel novel therapeutics obesity prevention obesity treatment prevent subcutaneous uncoupling protein 1

项目摘要

Abstract/Summary Obesity increases morbidity risks for several chronic metabolic disorders including diabetes and cardiovascular disease, and has been linked to both systemic and white adipose tissue inflammation. Brown adipose tissue (BAT), a fat tissue which protects against hypothermia, represents a novel target to reduce obesity-associated metabolic disorders. The goal of this proposal is to test whether dietary omega-3 fatty acids (namely eicosapentaenoic acid, EPA) with known anti-inflammatory effects potentially reduce high fat associated adiposity and metabolic alterations via activation of brown fat. We previously demonstrated that EPA-enriched high-fat diets significantly reduced diet-induced obesity, insulin resistance, and inflammation to levels comparable to those in low-fat-fed mice. Furthermore, our recent preliminary data show that these EPA-fed mice also manifest significantly higher brown fat UCP1 protein levels (i.e., uncoupling protein, a BAT-specific thermogenic marker) along with significant increases in gene expression for other markers of thermogenesis. Given the emerging role of BAT in human studies, it is critical to understand how bioactive dietary components such as EPA activate BAT. We hypothesize that the beneficial metabolic effects of EPA in obesity are in part mediated through increasing BAT thermogenic capacity (via upregulation of UCP1) and induction of master regulators of thermogenesis. This hypothesis will be tested in two specific aims through a series of integrated cellular, molecular and physiological studies using mouse models, cultured adipocytes (white and brown) and human mesenchymal stem cells. In aim 1 we will determine in vivo the mechanisms mediating beneficial effects of EPA in BAT and other depots in high-fat-fed wild type and UCP1 knockout mice. In aim 2, using white and brown adipose stem cells derived from animals in aim 1, and human mesenchymal stem cells treated with EPA, we will further dissect the molecular mechanisms by which EPA activates BAT and thermogenic markers (such as UCP1 and PGC1alpha). One of the major outcomes of this research is to provide science-based evidence for potential use of omega-3 fatty acids for improving metabolic health and possibly preventing and/or treating obesity. In addition, we will elucidate mechanisms mediating activation of brown fat by a safe dietary intervention with other proven health benefits. Our studies are consistent with the NIH Strategic Plan for Obesity Research and NCCIH mission emphasizing science-based information to support the usefulness and safety of complementary and integrative health interventions to improve health and health care. The proposed studies are highly innovative and are expected to impact obesity treatment and prevention strategies.

摘要/总结肥胖会增加多种慢性代谢性疾病的发病风险，包括糖尿病和心血管疾病，并与全身和白色脂肪组织炎症有关。棕色脂肪组织（BAT）是一种可以防止体温过低的脂肪组织，代表了一个新的目标减少与肥胖相关的代谢紊乱。该提案的目的是测试饮食是否具有已知抗炎作用的 omega-3 脂肪酸（即二十碳五烯酸，EPA）通过激活棕色脂肪，可能减少高脂肪相关的肥胖和代谢改变。我们先前证明富含 EPA 的高脂肪饮食可显着减少饮食引起的肥胖，胰岛素抵抗和炎症水平与低脂喂养的小鼠相当。此外，我们的最近的初步数据表明，这些 EPA 喂养的小鼠也表现出显着较高的棕色脂肪 UCP1 蛋白水平（即解偶联蛋白，一种 BAT 特异性生热标记）以及显着的其他产热标志物的基因表达增加。鉴于 BAT 在在人类研究中，了解 EPA 等生物活性膳食成分如何激活 BAT 至关重要。我们假设 EPA 对肥胖的有益代谢作用部分是通过介导的通过增加 BAT 产热能力（通过 UCP1 的上调）和诱导 master 产热调节剂。该假设将通过一系列的测试在两个特定目标上进行检验使用小鼠模型、培养脂肪细胞（白细胞）进行综合细胞、分子和生理学研究和棕色）和人类间充质干细胞。在目标 1 中，我们将确定体内机制在高脂肪喂养的野生型和 UCP1 敲除中介导 EPA 在 BAT 和其他储存库中的有益作用老鼠。在目标 2 中，使用目标 1 中源自动物的白色和棕色脂肪干细胞，以及源自人类的白色和棕色脂肪干细胞。经过EPA处理的间充质干细胞，我们将进一步剖析其分子机制 EPA 激活 BAT 和生热标记（例如 UCP1 和 PGC1alpha）。主要之一这项研究的成果是为 omega-3 脂肪酸的潜在用途提供基于科学的证据用于改善代谢健康并可能预防和/或治疗肥胖。此外，我们将通过安全饮食干预和其他已证实的方法阐明介导棕色脂肪激活的机制健康益处。我们的研究与 NIH 肥胖研究战略计划和 NCCIH 一致使命强调以科学为基础的信息，以支持补充性药物的有用性和安全性以及综合健康干预措施，以改善健康和保健。拟议的研究高度具有创新性，预计将影响肥胖的治疗和预防策略。