Tudor-SN蛋白调控白色脂肪棕色化的分子机制研究

The pandemic rise in the prevalence of obesity, as well as its comorbidities, such as type-2 diabetes and cardiovascular diseases, has made it imperative to develop novel anti-obesity therapeutics. The browning of white adipocytes can significantly promote the energy consumption, improve glucose and lipid metabolism．Tudor-SN protein is a highly conserved and ubiquitously expressed multifunctional protein. Previous Studies showed that 1) Tudor-SN had a positive correlation with adipogenesis, once Tudor-SN had been knocked out in MEF cells, adipogenesis can be totally inhibited; 2) Tudor-SN and PPARγ combined with each other via the SN domain of Tudor-SN. Tudor-SN could combine to PPRE region of PPARγ target genes and promote the white fat gene expression (aP2 and adipsin); 3) Under cold exposure, the deficiency of Tudor-SN led to the appearance of brown fat gene expression, including UCP1, PGC-1a, PRDM16 and FGF21, as well as SIRT1 activation; 4) Tudor-SN could combines to PARP-1. It is reported that the deletion of the PARP-1 increases NAD+ content and SIRT1 activity in brown adipose tissue. Based on our previous study, we will establish an adipose-specific Tudor-SN knock-out mouse model (Tudor-SNaP2KO). By using cell model of adipocyte differentiation and Tudor-SNaP2KO mouse model, we will further study the potential function mechanism of Tudor-SN in browning of white adipocytes and investigate whether loss-of-function of Tudor-SN is involved in resistance to dietary obesity. This finding opens a new avenue to understand the molecular control of browning of white adipocytes and it might be the therapeutic target for obesity and its related metabolic disorders.

肥胖病逐渐成为一种全球性的流行病, 伴随它产生的各种代谢综合征已严重危及人类健康。白色脂肪棕色化能显著促进机体能量的消耗，有利于预防或治疗肥胖。本课题组一直从事多功能蛋白Tudor-SN的相关研究，前期研究发现:1.Tudor-SN的缺失可以抑制脂肪细胞分化;2.Tudor-SN与成脂关键蛋白PPARγ相互作用，并促进其下游白色脂肪标志基因的转录;3.冷暴露下Tudor-SN的敲除可导致棕色脂肪标志基因和PPARγ去乙酰化酶SIRT1的表达明显增高;4.Tudor-SN可以与影响SIRT1活性的PARP-1结合。本项目我们通过构建脂肪组织特异性Tudor-SN敲除小鼠模型，利用代谢组学结合分子生物学实验，研究Tudor-SN对白色脂肪棕色化的调控作用和机制，并探讨敲除Tudor-SN对高脂诱导的肥胖是否有抵抗作用，有助于为肥胖症及其相关代谢疾病的预防和治疗提供新的治疗靶点。

肥胖病逐渐成为一种全球性的流行病，伴随它产生的各种代谢综合征已严重危及人类健康。白色脂肪棕色化能显著促进机体能量的消耗，有利于预防或治疗肥胖。最近，我们构建了脂肪组织特异性Tudor-SN敲除小鼠模型aP2-cre/Tudor-SNflox/flox（Tudor-SNaP2KO）。我们发现给予寒冷刺激后，Tudor-SN的缺失可以减少白色脂肪生成并且促进一系列棕色脂肪标志基因的表达。同时，我们还观察到在冷暴露下Tudor-SN蛋白的敲除抵抗高脂诱导的肥胖，改善胰岛素敏感性和能量代谢。此外，我们组通过质谱及免疫共沉淀证实在冷暴露下，Tudor-SN蛋白与E3泛素连接酶SMURF2结合促进去乙酰化酶SIRT1的降解，进而影响PPARγ乙酰化和PRDM16的表达，影响白色脂肪棕色化的过程。从能量代谢的角度研究Tudor-SN蛋白的新功能，有助于揭示Tudor-SN在肥胖症及相关疾病的分子机制，可开拓肥胖症防治的新思路，并有助于发现新的治疗靶点。