顶叶皮层调控下丘脑参与棕色脂肪组织活化的机制研究

Brown adipose tissue (BAT) plays an important role in energy metabolism, and its activity is regulated by the brain. The preliminary study showed that while the BAT activity decreased after thermal intervention in BAT positive patients, the glucose metabolism of the parietal lobe BA7 and BA40 brain regions decreased and the level of serum neuropeptide Y (NPY) increased. The activation of the parietal lobe of mice could enhance BAT activity, but the central mechanism of BAT activation is not clear. Considering the relationship between hypothalamic NPY and BAT activity, we conclude that the parietal lobe BA7 and BA40 brain regions increase BAT activity by inhibiting the release of hypothalamic NPY and activating the sympathetic system. In this study, DREADD will be used to stimulate the BA7 and BA40 in the parietal lobe, and to verify that activating the parietal lobe could decrease NPY level in CSF and increase BAT activity. Furthermore, the fiber projection pathway from the parietal cortex to the NPY neurons of the hypothalamus will be traced by neural loop tracing method. Activation of this pathway by optogenetics technique will demonstrate that the parietal cortex increased BAT activity by modulating the release of hypothalamic NPY and activating the sympathetic system. This study will clarify the central mechanism of BAT activity regulation by the parietal lobe BA7 and BA40 brain regions, and provide a theoretical basis for clinical application of BAT activity regulation to prevent and treat obesity.

棕色脂肪组织(BAT)在机体能量代谢中起重要作用，其活性受大脑中枢的调控。前期研究发现BAT阳性者保暖干预后BAT活性下降的同时，顶叶BA7和BA40脑区葡萄糖代谢减低，且血神经肽Y(NPY)水平升高；而激活实验鼠该顶叶脑区可增强BAT活性，但其调控BAT活化的中枢机制尚不明确。鉴于已知下丘脑NPY与BAT活性调控相关，我们推断顶叶BA7和BA40脑区通过抑制下丘脑NPY释放，激活交感系统进而增加BAT活性。本研究将运用DREADD技术刺激顶叶BA7和BA40脑区，验证激活顶叶可降低脑脊液NPY水平，增加BAT活性；进一步用神经环路示踪法追踪顶叶皮层到下丘脑NPY神经元的纤维投射通路，通过光遗传学技术激活该通路验证顶叶皮层通过调控下丘脑NPY释放，兴奋交感进而增加BAT活性。本研究将明确顶叶BA7和BA40脑区调控BAT活性的中枢机制，为临床应用BAT的活性调控来防治肥胖症提供理论依据。

棕色脂肪组织(BAT)在机体能量代谢中起重要作用，其活性受大脑中枢的调控，但其具体的调控机制尚不明确。该课题按研究计划运用药理遗传学（DREADD）技术兴奋大鼠顶叶相关皮层，验证顶叶相关皮层对棕色脂肪组织（BAT）活性和神经肽Y（NPY）水平的影响作用；同时，通过PET-CT分析脑葡萄糖代谢和血浆NPY水平及BAT活性的相关性，探讨NPY是否参与人类BAT活性的中枢调节。结果显示在不同的大鼠干预组间NPY水平未见显著性差异，但多元线性回归模型分析提示BAT阳性组成人脑葡萄糖代谢与NPY水平之间呈负相关。进一步运用功能磁共振我们分别完成了寒冷刺激和β3肾上腺素受体激动剂引起大鼠BAT活化的相关脑功能研究，探讨了相关功能脑区通过交感神经系统对BAT活性的中枢调控机制，明确了与BAT活性调控可能相关的功能脑区。并在此研究过程中发现在实验组和对照组间老鼠肩胛间区棕色脂肪组织中检测到含衔接因子蛋白磷酸酪氨酸相互作用PH域亮氨酸拉链蛋白1(APPL1)的蛋白含量有显著性差异，故利用脂肪组织特异性敲除(ASKO)小鼠模型评价了APPL1在体内BAT产热中的作用。结果显示敲除脂肪组织APPL1会加重高脂饮食诱导的肥胖、损害能量消耗和适应性产热、减少棕色脂肪特异性基因表达和线粒体数量。同时，为进一步探索中枢对体脂含量的调控作用，我们利用大样本量数据分析了青少年睡眠时间和体脂含量变化的相关性，并比较了不同睡眠时间、运动强度对体重和身体成分的影响，阐明了不同身体成分指标在临床应用中的意义，为进一步探讨棕色脂肪组织活性的中枢调控机制提供了重要依据和研究方向。