泛酸激活棕色脂肪的作用以及分子机制研究

With the worldwide spread of obesity, BAT has received more attentions. However, how to activate BAT safely and effectively to realize its function of regulating energy metabolism has always been the focus and difficulty in the research field. Aiming at Uncoupling protein 1 (UCP1), a key heat-producing protein of BAT, we screened pantothenic acid which can significantly increase the expression of UCP1, from the small molecule compound library of FDA. We further verified the effects that pantothenic acid can increase the content of UCP1 both in differentiated C3H10T1/2 cells (in vitro experiments), and in BAT of mice (in vivo experiments). Increasing of UCP1 content activated BAT indeed, the pantothenic acid treatment group mice were resistant to cold, and their oxygen consumption increased. From these preliminary experiments, it is predicted that pantothenic acid fed mice could maintain energy metabolism homeostasis and resist HFD induced obesity. This project will eventually explore the regulation process and specific molecular mechanism of pantothenic acid on glucose and lipid metabolism, in various obesity model mice. It will enrich the understanding of BAT and provide new therapeutic targets and ideas for the prevention and treatment of obesity, diabetes and other metabolic diseases.

随着肥胖在全世界范围的爆发，可调节能量代谢的棕色脂肪受到更多的关注。但是如何安全、有效地激活棕色脂肪，实现其调节机体能量代谢的功能，一直是领域内研究的重点和难点。我们以棕色脂肪产热关键蛋白解偶联蛋白-1（Uncoupling protein 1,UCP1）为切入点，在FDA的小分子化合物库中筛选出了能够显著增加UCP1表达的药物——泛酸。我们进一步验证了泛酸不但能增加分化后的C3H10T1/2细胞UCP1的含量（体外实验），也能增加小鼠体内棕色脂肪UCP1的含量（体内实验）。UCP1的增加激活了棕色脂肪的活性，小鼠抵抗寒冷的能力增强，机体的耗氧量也同样增加。因此可以预见泛酸饲喂小鼠能够抵抗高脂饮食诱导的肥胖，维持能量代谢稳态。本项目最终将在各肥胖模型小鼠上探究泛酸调控糖脂代谢的过程以及具体的分子机制，丰富领域内对于棕色脂肪的深入了解，为肥胖、糖尿病等代谢相关疾病的防治提供新的靶点以及思路。

棕色脂肪组织通过解偶联蛋白 1（UCP1, Uncoupling protein 1）将化学能转化为热能，这一过程对能量代谢有积极的影响，我们着手筛选能安全有效地激活棕色脂肪的小分子化合物。通过大规模的药物筛选，我们从 FDA 已批准的 635 个小分子化合物库中成功筛选出能上调人源棕色脂肪中 UCP1 的泛酸（维生素 B5）。泛酸在不改变运动量或摄食量，以及棕色脂肪中交感神经相关因子激活的同时，能够在机体水平上提高能量代谢水平，改善高脂饮食引起的脂肪堆积与胰岛素抵抗。值得强调的是，在热中性环境下，泛酸也能维持棕色脂肪的活性。这些结果说明，泛酸激活棕色脂肪不完全依赖交感神经。我们还发现泛酸以 UCP1 依赖的途径激活棕色脂肪，在 UCP1 敲除小鼠中泛酸无法发挥以上的有益作用。总之，这些结果揭示了泛酸-UCP1-棕色脂肪轴在肥胖处理中的关键机制，为开发泛酸作为肥胖等代谢疾病防治临床研究提供了理论支持，而且泛酸具备成为一种安全、有效的棕色脂肪激活剂的潜力，用于改善肥胖等代谢疾病，有望实现临床转化。