PRDM1在褐色及米色脂肪适应性产热中的作用和机制

Brown and beige fat are specialized tissues in mammals to expand energy through burning fat. Moderate cold exposure can recruit and activate these two types of fat, which become the hottest target tissues against obesity. However the cellular and molecular mechanisms governing their development and function are largely unknown. Our previous work demonstrated for the first time that alternatively activated macrophages coordinate animal adaptive thermogenesis by regulating brown and white adipose tissue function, and promote browning to further enhance animal thermogenic capacity. In contrast with cold challenge, thermoneutral acclimation decreases animal adaptive thermogenesis while animals still maintain basal thermogenic capacity to re-enter cold environment. In the preliminary study, we found that thermoneutral acclimation specifically upregulate PRDM1 expression (out of 15 PRDM family members) and PRDM1 is required for surviving cold exposure. In this proposal, we hypothesize that PRDM1 coordiates animal adaptive thermogenesis by promoting brown and beige fat thermogenesis, white fat lipolysis and alternative activation of macrophages. We will test this hypothesis through performing molecular, cellular, organic and systemic experiments. The knowledge generated through this project will further expand our understanding of how mammals maintain their thermogenic capacity, and provide novel strategy for treating obesity.

褐色和米色脂肪是哺乳动物中专门通过燃烧脂肪来消耗能量的组织，寒冷刺激可在成人体内招募和激活它们。这使它们成为当前最热门的减肥靶标组织。然而对它们发育及功能调控的细胞分子机制并不清楚。我们的前期工作首次证明：替代性活化巨噬细胞协调褐色和白色脂肪功能来维持动物的适应性产热，并可促进白色脂肪的褐色化来进一步增强产热能力。与寒冷刺激相反，热中性适应会降低动物的适应性产热，但仍保留一定的产热能力，以再次应对寒冷环境。在预实验中，我们发现PRDM1被热中性适应特异上调，并为热中性适应后再次激活产热所必需。在这份申请中，我们提出如下假说：PRDM1促进褐色和米色脂肪的产热、白色脂肪的脂解以及巨噬细胞的替代性活化，这些过程协同作用维持动物的适应性产热。我们将从分子、细胞、组织及动物水平来检验这一假说。如果该假说得以证实，将进一步拓展我们对哺乳动物如何维持它们的产热能力的了解，并为肥胖防治提供新的靶点。

褐色和米色脂肪是哺乳动物中专门通过燃烧脂肪来消耗能量的组织，寒冷刺激可在成人体内招募和激活它们。这使它们成为当前最热门的减肥靶标组织。然而对它们发育及功能调控的细胞分子机制并不清楚。我们的前期工作首次证明：替代性活化巨噬细胞协调褐色和白色脂肪功能来维持动物的适应性产热，并可促进白色脂肪的褐色化来进一步增强产热能力。与寒冷刺激相反，热中性适应会降低动物的适应性产热，但仍保留一定的产热能力，以再次应对寒冷环境。我们发现PRDM1被热中性特异上调，并为热中性适应后再次激活产热所必需。PRDM1既可以直接促进褐色脂肪产热，又可以调控白色脂肪脂解为褐色脂肪提供燃料而间接支持产热，还可以通过调控巨噬细胞的替代性活化，来促进产热、脂解及米色脂肪的生成而加强产热功能。该研究既拓展我们对哺乳动物维持产热机制的理解，又为肥胖防治提供新的潜在靶点。

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