LSD1调控仔猪脂肪代谢/沉积的表观遗传机制

Morbidity and mortality of piglets before weaning contributes to large part of profit losses in swine industry. Emerging evidence shows fat mass of healthy weaned piglets is significantly higher than unhealthy ones, which suggests the pre-weaning survival rate of piglets is closely related to fat metabolism and accumulation. Studies show that LSD1, a histone demethylase, regulates fat metabolism in rodents, yet the molecular mechanism remains unclear. Our preliminary studies show LSD1 expression in adipose tissue of newborn piglets correlates with body weight and adipogenesis genes, which indicates LSD1 could potentially regulate fat metabolism and accumulation in piglets. In this study, we would investigate piglets of two well-defined pig breeds displaying distinct fat contents, Duroc breed and Laiwu breed. First, we would measure and compare the metabolic characteristics of piglets from two breeds as well as LSD1 expression. Secondly, we would genetically modify LSD1 to investigate the role of LSD1 regulation in piglet fat metabolism and accumulation. We would also investigate the enrichment of genes that directly interact with LSD1 by ChIP-Sequence to determine the target gene and epigenetic mechanism of LSD1 regulation. Meanwhile, we would explore the nutrients that could regulate fat metabolism and accumulation through LSD1 in order to improve preweaning piglets survival. Our results would provide not only better understanding of the epigenetic mechanism of LSD1 regulating fat metabolism and accumulation, but also nutritional strategies to improve preweaning piglets survival.

断奶仔猪存活率是影响养猪生产效率的重要因素。研究表明断奶前后存活的仔猪体脂含量显著高于死亡或淘汰的仔猪，提示断奶仔猪的存活率与其脂肪代谢/沉积密切相关。LSD1是一种组蛋白去甲基化酶，对模式动物脂肪代谢有重要调控作用，但分子机制尚未解析。申请人前期研究发现LSD1在初生仔猪脂肪组织的表达与初生重和脂肪沉积相关，提示LSD1可能参与调控仔猪脂肪代谢/沉积。本项目拟以杜洛克和莱芜猪两种不同沉脂能力的仔猪为模型，比较其脂代谢及LSD1表达的差异，采用基因编辑方法揭示LSD1在仔猪脂肪代谢/沉积中的调控作用，结合ChIP-Sequence高通量测序阐明LSD1的靶基因和表观遗传调控机制。同时探讨通过营养调控LSD1表达进而调节仔猪脂肪代谢/沉积和存活率。本项目研究结果不仅可阐明LSD1调控仔猪脂肪代谢/沉积的表观遗传机制，而且可为提高断奶仔猪的存活率提供营养调控思路，具有重要的学术价值和实践意义。

猪的体脂沉积是影响断奶存活率、胴体品质等的关键因素，对生猪生产效率有重要影响。研究显示，组蛋白去甲基化酶LSD1在模式动物的脂肪组织中参与能量代谢调控，并且我们的前期研究发现LSD1在初生仔猪脂肪组织中的表达与脂肪沉积相关，因此本项目研究了LSD1对猪脂肪组织代谢和沉积的调控作用和机制，并探索营养调控LSD1调节体脂沉积的方法。. 本项目以杜洛克猪和莱芜猪两种不同沉脂能力的仔猪为模型，比较其脂肪组织生理表型和分子表型，发现杜洛克和莱芜仔猪的脂肪组织在21日龄已存在显著区别：莱芜仔猪腹腔脂肪沉积显著高于杜洛克、皮下脂肪沉积在不同部位差异不同；转录组学分析显示莱芜仔猪脂肪组织中脂质代谢、氨基酸代谢、cAMP信号通路、钙离子信号通路等代谢、信号通路与杜洛克仔猪存在显著差异。同时，莱芜仔猪腹腔脂肪中的LSD1表达显著高于杜洛克；LSD1脂肪特异性敲除的模式动物脂肪沉积显著降低，结果显示LSD1是调控脂肪沉积的重要因子。进一步对敲除了LSD1的脂肪组织进行转录组学分析显示LSD1可能通过调节氨基酸代谢、炎症反应、激素合成分泌和作用等潜在机制对脂肪组织的脂质代谢和沉积产生影响。本项目还发现肠道微生物代谢产物丁酸可以调控脂肪组织内LSD1的表达，从而影响脂肪产热和体脂沉积。另外，本项目发现肠道微生物代谢产物丙酸可以调控模式动物肠道LSD1和脂质代谢从而影响体脂沉积。. 本项目的研究结果初步揭示了21日龄杜洛克和莱芜仔猪脂肪组织的生理表型差异和分子表型差异，为解析仔猪的脂肪发育与沉积、提高仔猪健康、促进地方猪种开发利用提供了新的理论基础。本项目通过结合猪和模式动物的结果深入研究了LSD1调控脂肪代谢和沉积的作用和机制，为阐明动物和人的代谢生理表观遗传调控提供新的科学依据。本项目还探索了肠道微生物代谢产物丁酸、丙酸通过调节LSD1调控体脂沉积的作用，可为解析肠道微生物调控机体代谢稳态提供新的理论依据，也可为改善猪的胴体品质和代谢健康，提高生猪养殖生产效率提供新的营养调控思路。