白色脂肪米色化免疫调控新机制的研究

There has been a great interest over the past decade in understanding the mechanisms controlling the formation and function of brown adipose tissue (BAT) and the development of beige fat, because improving brown and beige fat function may have great metabolic benefits including prevention of over-nutrition-induced obesity and increasing insulin sensitivity. Our preliminary data showed that cold exposure greatly increased miR-182-5p levels. In addition, knockout of miR-182-5p suppressed cold exposure-induced beiging, IL-10 expression, and thermogenesis in mice, suggesting a novel mechanism regulating beige fat function and energy homeostasis. In this project, we will use unique knockout and overexpression cell and animal models to elucidate the mechanism by which miR-182-5p suppresses inflammation, promotes beiging, and improves metabolic homeostasis. Because reducing inflammation and improving beige fat function may have great metabolic benefits on obesity-induced insulin resistance and metabolic diseases, identification of new players in the immune-metabolic regulation of beige fat thermogenesis and their mechanisms of action would provide important information for developing novel therapeutic treatment of obesity and its metabolic diseases such as insulin resistance and type 2 diabetes.

近年来代谢研究领域的一个重要发现是白色脂肪的米色化 (Beiging)。米色脂肪具有和棕色脂肪类似的产热功能，它的形成对于降低营养过剩导致的肥胖，增加胰岛素敏感性，以及改善调节代谢平衡都具有重要作用。然而，白色脂肪细胞米色化的调控机制尚不十分清楚。我们前期研究的一个重要发现是冷刺激导致miRNA-182-5p显著升高且miRNA-182-5p的敲除能抑制冷刺激诱导的白色脂肪米色化。本研究将首次利用独特的基因敲除以及过表达的细胞和小鼠模型，从在体、细胞和分子三个不同层面系统研究miRNA-182-5p对白色脂肪米色化免疫调控抵抗肥胖的作用及其调控白色脂肪米色化的机制，为肥胖及肥胖诱导的代谢性疾病的预防和治疗提供新的靶点和思路。

脂肪组织微环境(ATME)是由脂肪细胞与邻近细胞(如驻留或浸润的巨噬细胞)之间的信号通路交互调节的，对脂肪组织功能和全身代谢稳态有重要影响。然而，脂肪组织中不同细胞间相互作用的机制和功能仍有待进一步阐明。我们的研究发现在人和小鼠脂肪组织中，miR-182-5p水平与肥胖呈负相关。冷暴露刺激小鼠脂肪细胞miR-182-5p表达，其缺失抑制了冷刺激诱导的产热基因的表达。另一方面，脂肪细胞中miR-182-5p的过表达促进了白色脂肪的米色化和产热，改善了能量稳态，并抵抗了饮食诱导的肥胖。脂肪miR-182-5p通过抑制核受体亚家族1组D成员1 (Nr1d1)，增加FGF21的表达和分泌，进而刺激巨噬细胞中乙酰胆碱的产生和分泌。乙酰胆碱增强了脂肪细胞中烟碱乙酰胆碱受体介导(nAChR-介导)的PKA信号通路激活，从而增加了产热基因的表达。我们的研究发现了一种潜在的新型miR-182-5p/FGF21/乙酰胆碱/PKA信号通路，该通路介导脂肪细胞和脂肪组织巨噬细胞之间的相互作用，以促进米色脂肪的发育并抵抗营养过剩引起的肥胖。因此，上调miR-182-5p/FGF21/乙酰胆碱/PKA轴可能是改善肥胖诱导的代谢性疾病的有效途径。