Biological roles and developmental pathway of burn-induced beige fat in humans

项目总结/摘要 米色脂肪细胞是产热脂肪细胞的可诱导形式， 刺激，如慢性冷暴露和烧伤（即，白色脂肪的“布朗宁”），并有助于全身性 葡萄糖稳态鉴于其可诱导的性质和与成年人的相关性，米色脂肪细胞获得了 作为2型糖尿病的潜在治疗靶点备受关注。 该提议受到最近的发现的启发，该发现是人类皮下白色脂肪组织采用稳健的 严重烧伤后的布朗宁表型和人类米色脂肪具有高的能力， 氧化葡萄糖、脂肪酸和支链氨基酸（BCAA）。 目前的目标是扩大我们对生物学作用和发展途径的理解， 人米色脂肪细胞对烧伤的反应。在目标1中，我们将测试燃烧的假设- 诱导的米色脂肪不仅对葡萄糖、脂肪酸，而且对支链氨基酸起着“代谢库”的作用， 有助于预防烧伤后高血糖症。在目标2中，我们将表征 烧伤诱导的米色脂肪细胞在单细胞分辨率，并确定其发展途径。 我们的研究结果将产生重大影响，因为通过使用“燃烧模型”，我们将确定功能 WAT布朗宁在调节人体全身葡萄糖稳态和胰岛素抵抗中的作用。 我们的研究还将发展一个创新的概念，即BAT不仅是一个发热器官，而且还可以 作为葡萄糖、脂肪酸和支链氨基酸的代谢库。

Project Summary/Abstract Beige adipocytes are an inducible form of thermogenic adipocytes that emerge in response to certain extrinsic stimuli, such as chronic cold exposure and burn injury (i.e., “browning” of white fat), and contribute to systemic glucose homeostasis. Given its inducible nature and relevance to adult humans, beige adipocytes have gained much attention as a potential therapeutic target in type 2 diabetes. This proposal is inspired by the recent findings that human subcutaneous white adipose tissue adopts a robust browning phenotype following a severe burn injury and that human beige fat possesses high capacity to oxidize glucose, fatty acids, and branched-chain amino acids (BCAA). The current objective is to extend our understandings on the biological roles and developmental pathway of human beige adipocytes in response to burn injuries. In Aim 1, we will test the hypothesis that the burn- induced beige fat functions as a “metabolic sink” not only for glucose, fatty acids but also for BCAA, which contributes to the prevention of post-burn hyperglycemia. In Aim 2, we will characterize molecular signatures of the burn-induced beige adipocytes at single-cell resolution and determine its developmental pathway. Our findings will have a significant impact because by use of the “burn model” we will determine the functional roles of WAT browning in the regulation of systemic glucose homeostasis and insulin resistance in humans. Our study will also develop the innovative concept that BAT is not simply a heat-generating organ but can also function as a metabolic sink for glucose, fatty acid, and BCAA.