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.

项目摘要/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。 这些病理的基础是脂肪组织。慢性组织炎症，尤其是脂肪组织， 是肥胖的一个重要特征，并与全身性胰岛素抵抗和2型糖尿病(T2D)有关。虽然 棕色脂肪组织(BAT)的激活可以增加能量消耗和燃料利用，导致 改善胰岛素敏感性，关于BAT是否具有潜在的胰岛素增敏作用尚不清楚 与炎症的消退有关。专门化的促进分解的脂质介体(SPM)，如树脂，是 消炎和触发组织再生的新型介体。在工作进行中，我们发现 寒冷激活BAT显著减少炎症，改善肥胖患者的全身新陈代谢。 有趣的是，我们发现冷暴露会选择性地增加蝙蝠产生的松香。 来源于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 假设BAT的激活导致局部作用的松脂产量增加， 系统地消除炎症，从而改善肥胖症患者的胰岛素敏感性。这样做的目的是 建议确定乳脂素在消炎和改善胰岛素中的作用 对冷暴露的敏感性，并研究调节冷或β3的分子机制。 肾上腺素能刺激诱导大孔树脂生物合成。我们将确定潜在的脂类转运蛋白的作用 以及调节松脂生产的关键酶。建议的研究完成后，将导致 对激活BAT对肥胖的有益影响的全新理解，并可能导致新的 基于仿生学的肥胖和T2D治疗方法。