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

项目总结/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， 是肥胖症的重要特征，并与全身性胰岛素抵抗和2型糖尿病（T2 D）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 尽管BAT具有改善胰岛素敏感性的作用，但关于BAT的潜在胰岛素增敏作用是否 与炎症消退有关。专门的促分解脂质介质（SPM），如maresins， 新的介质，解决炎症和触发组织再生。在进行中的工作中，我们发现 冷激活BAT可以显著减少炎症，改善肥胖患者的全身代谢。 有趣的是，我们发现冷暴露选择性地增加BAT产生的maresins， 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maresins的产生增加，这些maresins在局部起作用， 全身性地解决炎症，导致肥胖症中胰岛素敏感性的改善。这一目标 建议是确定maresins在解决炎症和改善胰岛素的作用 敏感性，并研究介导冷或β3- 肾上腺素能刺激诱导的marine生物合成。我们将确定一个潜在的脂质转运蛋白的作用 以及调节maresin生产的关键酶。完成拟议研究后， 对BAT激活在肥胖症中的有益作用有了全新的认识，并可能导致新的 肥胖和T2 D的仿生治疗方法。

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.