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

摘要/摘要 肥胖增加了几种慢性代谢紊乱的发病风险，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)，一种防止体温过低的脂肪组织，代表着一个新的靶点 减少肥胖相关的代谢紊乱。这项提案的目标是测试饮食是否 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，潜在地减少高脂肪相关的肥胖和代谢变化。我们 此前证明，富含EPA的高脂肪饮食显著减少了由饮食引起的肥胖， 胰岛素抵抗，炎症程度与低脂喂养的小鼠相当。此外，我们的 最近的初步数据显示，这些喂食EPA的小鼠也表现出明显更高的棕色脂肪 UCP1蛋白水平(即解偶联蛋白，蝙蝠特有的产热标志)以及显著的 产热的其他标志物的基因表达增加。鉴于英美烟草公司在 在人体研究中，了解生物活性饮食成分(如EPA)如何激活蝙蝠是至关重要的。 我们假设EPA对肥胖的有益代谢作用部分是由 通过增加BAT的产热能力(通过上调UCP1)和诱导MASTER 生热调节因子。这一假设将通过一系列的两个具体目标进行检验 利用小鼠模型进行细胞、分子和生理学的综合研究，培养的脂肪细胞(白色 和棕色)和人类间充质干细胞。在目标1中，我们将在体内确定这些机制 EPA在BAT等仓库对高脂饲喂野生型和UCP1基因敲除的有益影响 老鼠。在目标2中，使用来自目标1中动物和人类的白色和棕色脂肪干细胞 我们将进一步剖析EPA处理间充质干细胞的分子机制。 EPA激活BAT和产热标志物(如UCP1和PGC1pha)。其中一个主要的 这项研究的结果是为omega-3脂肪酸的潜在用途提供了科学依据 用于改善代谢健康，并可能预防和/或治疗肥胖症。此外，我们还将 通过一种安全的饮食干预与其他已证实的方法阐明介导棕色脂肪活化的机制 健康福利。我们的研究与NIH肥胖研究战略计划和NCCIH一致 强调以科学为基础的信息以支持互补性和安全性的使命 和综合卫生干预措施，以改善卫生和保健。拟议的研究具有很高的 具有创新性，预计将对肥胖治疗和预防战略产生影响。

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.