n-3多不饱和脂肪酸基于“脂-肠道菌群-肝”轴促进脂肪米色化及调控糖稳态失衡的作用机制

Diabetes mellitus has become a major threat to public health problems of the health of residents in China. Studies regarding the ameliorative effect of nutrients on glucose homeostasis have raised extensive attention, but little is known about related crosstalk effect between dynamic regulation and signal pathways. The aim of currently proposed project is to investigate the effect of n-3 polyunsaturated fatty acids (PUFA) on promoting the white-to-beige process of adipose and regulating glucose homeostasis imbalance via adipose-gut microbiota-liver axis in cell, animal and human studies. We will first use primary subcutaneous adipose cells to (i) investigate the effect of n-3 PUFA on characterization change and gene regulation during the promotion of white-to-beige process; and (ii) unravel molecular pathways of white-to-beige process regulation by the activation of peroxisome proliferator-activated receptor γ (PPARγ) signal transduction pathway. Then, we will employ db/db type 2 diabetes mellitus mice to (i) validate the promotion effect of n-3 PUFA on the white-to-beige process and its synergic effect with cold stimuli; (ii) verify the molecular mechanism about the regulatory effect of n-3 PUFA on gut microbiota and hepatic glucose homeostasis; and (iii) reveal the crosstalk effect among signal pathways via adipose-gut microbiota-liver axis. Finally, we will conduct a randomized placebo-controlled trial to (i) demonstrate the ameliorative effect of n-3 PUFA on glycometabolism disturbance, gut microbiota imbalance and inflammatory reaction; and (ii) verify the correlation between white-to-beige process of human supraclavicular adipose tissues and glycometabolism improvement in the condition of n-3 PUFA intervention by advanced infrared thermal imaging and tissue biopsy techniques. The anticipated outcomes will be beneficial to (i) unraveling the role of white-to-beige process of adipose, a recent research hotspot, in the glucose homeostasis, and (ii) broadening a novel research orientation about the prevention and control of metabolic disorders by the use of nutrients.

糖尿病已成为威胁我国居民健康的重大公卫问题，有关营养素改善糖稳态的研究受到广泛关注，但对相关动态调控及信号通路交互对话作用知之甚少。本项目以n-3多不饱和脂肪酸为对象，在细胞、动物和人群水平研究其基于脂-肠道菌群-肝轴促进脂肪米色化和调控糖稳态失衡的机制。采用原代皮下脂肪细胞，研究其促米色化的表征变化与基因调控，阐明通过激活PPARγ通路调控米色化的分子途径；采用db/db小鼠，验证其促米色化效果及与冷刺激的协同作用，明确其调节肠道菌群和调控肝糖稳态的分子机制，揭示基于脂-肠道菌群-肝轴的信号通路交互对话机制；通过随机对照研究，论证n-3脂肪酸改善2型糖尿病患者糖代谢紊乱、肠道菌群失衡和炎症反应的效果，利用先进的红外热成像和组织活检技术，证实干预条件下锁骨脂肪米色化与糖代谢改善的关联性。预期成果有助于阐明新近热点白色脂肪米色化在糖稳态中发挥的作用机制，为营养素防治代谢疾病的研究拓展新方向。

糖尿病已成为威胁我国居民健康的重大公卫问题，有关营养素改善糖稳态的研究受到广泛关注，但对相关动态调控及信号通路交互对话作用知之甚少。本项目以n-3多不饱和脂肪酸（PUFA）为对象，在细胞、动物和人群水平研究其基于脂-肠道菌群-肝轴促进脂肪米色化和调控糖稳态失衡的机制。研究结果表明，n-3 PUFA能诱导脂肪细胞发生米色化从而改善糖脂代谢。在分子机制上，其通过激活PPARγ和去乙酰化以及维持PRDM16蛋白稳定性从而促进米色化进程，并且证实了n-3 PUFA调控此途径依赖于PRDM16。通过db/db糖尿病模型小鼠干预试验，剖析了n-3 PUFA对肠道菌群以及代谢产物的靶向调控作用，发现n-3 PUFA干预减少肠道中产内毒素（LPS）菌Enterobacteriaceae丰度而增加参与胆汁酸代谢的Barnesiella和Clostridium XlVa以及产短链脂肪酸菌的丰度，同时减少LPS水平、增加短链脂肪酸水平且改善胆汁酸谱，最终抑制肝糖异生而促进脂肪米色化和胰岛素信号转导，从而系统阐明了n-3 PUFA 基于“脂-肠道菌群-肝”轴改善糖稳态的分子机制，解释了其改善糖脂代谢紊乱的表型。最后，通过开展鱼油n-3 PUFA对2型糖尿病（T2DM）患者的营养干预试验，发现了鱼油n-3 PUFA补充改善T2DM 患者糖脂代谢紊乱状态，并且改善肠道菌群失调和促进锁骨米色脂肪产热。相关研究成果有助于阐明新近热点白色脂肪米色化在糖稳态中发挥的作用机制，为脂类营养素防治代谢疾病的研究拓展新方向。本项目执行期间共发表第一标注本基金资助的SCI论文12篇，其中IF(5-year)>10的论文3篇，参加国内外学术会议并作口头报告4次。本项目共培养博士研究生3名，硕士研究生5名。