Role of brown fat-derived specialized pro-resolving lipid mediators in inflammation and metabolism

棕色脂肪衍生的专门促溶解脂质介质在炎症和代谢中的作用

• 批准号: 10341149
• 负责人: Matthew R Spite
• 金额: $ 53.69万
• 依托单位: JOSLIN DIABETES CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10341149
• 关键词: Adipose tissue; Adrenergic Agents; Adrenergic Receptor; Adult; Agonist; Anabolism; Animal Model; Anti-Inflammatory Agents; Arachidonate 12-Lipoxygenase; Brown Fat; Chronic; Complement; Data; Development; Diabetes Mellitus; Diabetic mouse; Diet; Docosahexaenoic Acids; Energy Metabolism; Enzymes; Epoxide hydrolase; Etiology; Exposure to; Fatty Acids; Fatty acid glycerol esters; Genetic Models; Glucose; Health; Human; Immunosuppression; Impairment; In Vitro; Inflammasome; Inflammation; Inflammatory; Insulin; Insulin Resistance; Interruption; Knock-out; Knowledge; LOX gene; Lead; Link; Lipids; Liver; Mass Spectrum Analysis; Mediating; Mediator of activation protein; Metabolic; Metabolic Diseases; Metabolic syndrome; Metabolism; MicroRNAs; Molecular; Morbidity - disease rate; Mus; Non-Insulin-Dependent Diabetes Mellitus; Nuclear; Obese Mice; Obesity; Omega-3 Fatty Acids; Pathology; Peptides; Plasma; Process; Production; Research; Resolution; Role; Scheme; Signal Transduction; Testing; Therapeutic; Tissues; Translations; Transplantation; United States; base; combat; cytokine; improved; in vivo; inhibitor; insulin sensitivity; insulin sensitizing drugs; interest; lipid mediator; metabolome; mortality; mouse model; novel; obesity prevention; pathogen; prevent; release factor; response; side effect; success; tissue injury; tissue regeneration; uptake

Project Summary/Abstract Obesity and metabolic syndrome are rapidly growing worldwide, leading to high morbidity and mortality. Fundamental to these pathologies is adipose tissue. Chronic tissue inflammation, especially in adipose tissue, is a crucial feature of obesity and links to systemic insulin resistance and Type 2 diabetes (T2D). Although activation of brown adipose tissue (BAT) can increase energy expenditure and fuel utilization, leading to improvement of insulin sensitivity, little is known about whether the potential insulin-sensitizing effect of BAT is linked to resolution of inflammation. Specialized pro-resolving lipid mediators (SPM), such as the maresins, are novel mediators that resolve inflammation and trigger tissue regeneration. In work in progress, we discovered that activation of BAT by cold significantly reduces inflammation and improves systemic metabolism in obesity. Interestingly, we found that cold exposure selectively increases BAT production of maresins that are produced from ω-3 polyunsaturated fatty acid, docosahexaenoic acid (DHA). Based on these exciting findings, we hypothesize that the activation of BAT leads to increased production of maresins that act locally and systemically in resolving inflammation, leading to improved insulin sensitivity in obesity. The objectives of this proposal are to determine the role of maresins in the resolution of inflammation and improvement of insulin sensitivity in response to cold exposure and to investigate the molecular mechanisms mediating cold or β3- adrenergic stimulation-induced maresin biosynthesis. We will determine the role of a potential lipid transporter as well as key enzymes that regulate the maresin production. Completion of the proposed studies will lead to an entirely new understanding of the beneficial effects of BAT activation in obesity and could lead to novel biomimicry-based therapeutic approaches of obesity and T2D.

项目概要/摘要 肥胖和代谢综合征在全球范围内迅速增长，导致高发病率和死亡率。 这些病理学的基础是脂肪组织的慢性炎症，尤其是脂肪组织。 是肥胖的一个重要特征，与全身胰岛素抵抗和 2 型糖尿病 (T2D) 有关。 棕色脂肪组织（BAT）的激活可以增加能量消耗和燃料利用率，从而导致 改善胰岛素敏感性，但人们对 BAT 潜在的胰岛素增敏作用是否有效尚知之甚少。 与炎症消退相关的特殊促消退脂质介质 (SPM)，例如 maresins。 在正在进行的工作中，我们发现了能够解决炎症并引发组织再生的新型介质。 寒冷可显着激活 BAT，从而减少炎症并改善肥胖患者的全身代谢。 暗示，我们发现冷暴露选择性地增加了 Maresins 的 BAT 产量 来自 ω-3 多不饱和脂肪酸，二十二碳六烯酸 (DHA) 基于这些令人兴奋的发现，我们。 认为 BAT 的激活会导致 maresins 的产生增加，这些 maresins 会在局部发挥作用， 系统性地解决炎症，从而改善肥胖患者的胰岛素敏感性。 建议确定 maresins 在消除炎症和改善胰岛素方面的作用 对寒冷暴露的敏感性并研究介导寒冷或β3-的分子机制 我们将确定潜在脂质转运蛋白的作用。 以及调节 maresin 产生的关键酶。完成拟议的研究将导致 对 BAT 激活对肥胖的有益作用有了全新的认识，并可能带来新的发现 基于仿生学的肥胖和 T2D 治疗方法。