母乳内源性多肽PDC89用于肥胖防治的应用基础研究

PDC89 is a breast milk-derived endogenous peptide with unknown functions identified by mass-spectrometric technique. We found that PDC89 inhibited the adipose-derived mesenchymal stem cells proliferation. Oral administration of PDC89 for ob/ob mouse had an obvious effect on losing weight, indicating that PDC89 may play a potential role in obesity prevention and treatment. It further revealed that its effects were associated with inhibition of JAK-STAT signal pathway. It has been reported that STAT3 is closely related to the proliferation of adipose-derived mesenchymal stem cells. This research intends to evaluate the consistency of the function of PDC89 in mesenchymal stem cell of different species and in different obese animal models and further evaluate its possibility in obesity prevention and control. This research systematically elucidates the molecular mechanism of how PDC89 regulating JAK-STAT signal pathway through JAK-STAT signal pathway activated agent OSM, the Pull-down experiment and Co-IP method. It is expected to provide new insights for obesity prevention and treatment.

PDC89是我们借助质谱技术发现的、功能未知的母乳内源性多肽。前期发现，PDC89具有抑制人脂肪源性间充质干细胞增殖的功能，给ob/ob小鼠饮水口服有显著的减重效果，提示PDC89具有潜在的肥胖防治作用；进一步揭示其作用与抑制JAK-STAT信号通路有关，已证实STAT3与人脂肪源性间充质干细胞增殖密切相关。研究拟评估PDC89在不同物种脂肪源性间充质干细胞、不同肥胖动物模型的功能一致性，论证其在肥胖防治中的可能性；借助JAK-STAT信号通路激动剂OSM、 Pull-down实验、Co-IP方法，系统阐明其调控JAK-STAT信号通路的分子机制。研究可望为肥胖防治提供新手段。

儿童肥胖不仅影响儿童时期的心理健康，更会增加儿童成年后患肥胖、高血压、心脏病等慢性疾病的风险。近年来，乳源性生物活性肽，作为母乳的重要成分之一，具有稳定性高、毒性低、不被胃肠道破坏、易被肠道吸收等特性，而受到研究者的密切关注。已发现，母乳来源的IPP、VPP三肽，不但能够促进脂肪细胞分化、抑制炎症分子分泌，而且还能改善高脂诱导小鼠的胰岛素抵抗，为解释母乳预防肥胖发生提供了新线索。PDC89是我们借助质谱技术发现的、功能未知的母乳内源性多肽。体外实验，PDC89多肽干预人脂肪源性及小鼠源性间充质干细胞，采用CCK-8、细胞实时监测系统及流式细胞仪检测，结果发现PDC89具有抑制人脂肪源性及小鼠源性间充质干细胞增殖的功能；采用油红O染色及甘油三酯检测技术，发现多肽PDC89对脂肪细胞成熟分化无影响。体内实验，采用ob/ob小鼠及db/db肥胖小鼠模型，多肽干预后，分别采用监测体重及DEXA体脂密度仪检测发现多肽具有显著的抑制肥胖的作用；同时进行GTT及ITT实验发现可以改善肥胖小鼠的糖耐量及胰岛素敏感性。血液检测，发现可以降低肥胖小鼠甘油三酯及胆固醇水平。进一步，机制方面采用OSM激动剂进行挽救实验，发现PDC89作用可能与抑制JAK-STAT信号通路有关。研究可望为肥胖防治提供新的手段。