高脂肪负荷对孕鼠后代的影响 -从炎症性脂肪细胞因子的角度解析DOHaD分子机制

The offspring of women with gestational diabetes mellitus is susceptible to diabetes, which is difficulty to explain with genetic factors. The developmental origins of health and disease (DOHaD) has become the social problems in China and the world. We had succeeded to establish a mice model fed high fat diet during pregnancy, which reflect the high fat energy dietary structure of women of childbearing age in our country, furthermore, demonstrated the fetal adipocyte hypertrophy. The adipocyte hypertrophy contributed to the insulin resistance. This study plans to investigate the prevalence and incidence of obesity, diabetes, high blood pressure after birth, so that to confirm the DOHaD theory. We analyze the adipocyte hypertrophy, chronic inflammatory changes in adipose tissue characterized as macrophage infiltration, and inflammatory adipocytokines (adipokines), to unveil the DOHaD the mechanism from adipokines single nucleotide polymorphisms (SNP). To interrupt the high fat load at neonatal period, explore the possibility of early intervention to reverse the adverse outcomes of offspring. The study will not only provide a theoretical basis for rational nutrition for clinical guidance during pregnancy, but also provide a new target spot on early intervention which may improve the prognosis of generations of the excessive nutrition during pregnancy.

糖尿病孕妇的后代易患糖尿病已不能单用遗传因素来诠释,the developmental origins of health and disease (DOHaD) 已引起中国乃至全球的广泛关注。本课题组已成功构建了反映我国生育年龄女性高脂肪能量比的孕鼠模型，并初步证实了胎鼠的脂肪细胞肥大。脂肪细胞肥大化与胰岛素抵抗的产生密切相关。本课题组拟监测孕期高脂负荷的仔鼠肥胖、糖尿病、高血压的患病率和发病时期，在验证DOHaD理论的同时，以脂肪细胞肥大、巨噬细胞浸润为特点的脂肪组织的慢性炎症性变化为中心，以炎症性脂肪细胞因子（adipokines）为代表，从adipokines 单核苷酸多态性(SNP)的角度揭示DOHaD的机制。通过在新生儿时期中断高脂负荷，探讨早期介入对逆转不良结局的可能性。不仅为临床指导孕期合理营养提供理论依据，也为改善孕期营养过剩的后代预后提供早期干预的新靶点。

孕期营养过剩导致巨大儿的增加、儿童肥胖等已成为中国乃至全球的社会问题。糖尿病孕妇的后代易患糖尿病已经不能单用遗传解释。胎儿期过低或者过高营养均可导致其后代肥胖、高血压、糖尿病的增加，这种现象被称作developmental origins of health and disease(DOHaD)，其作用机制不明。目前研究表明，孕妇高脂饮食可能引发一系列的代谢综合症疾病，将胎儿置于代谢紊乱及慢性炎症的高风险之中。已经发现并报导了高脂饮食对晚孕期的小鼠胎儿的危害，本研究主要探索中度高脂饮食的肥胖孕鼠，其后代在整个生命周期，即青少年，中年和老年的生理及病理状态的变化。取六周龄的雌性小鼠，分别喂食普通鼠粮或中度高脂鼠粮，整个孕期及哺乳期，还有子代小鼠的鼠粮不变，在子代小鼠达到8, 16, 24周龄时，测量其血压，葡萄糖及胰岛素耐受，疲劳测试，巨噬细胞脂肪组织浸润及巨噬细胞的亚型鉴定。结果发现，与对照组相比，中度高脂继承小鼠血压，葡萄糖敏感，胰岛素耐受等方面显著升高；脂肪细胞增大约4倍；青少年时期，肥胖小鼠运动耐力明显高于普通小鼠，但在中年及老年剧烈下降，老年期下降71%，有趣的是其运动协调及运动记忆没有明显变化。CD68，一种巨噬细胞表面标志物，在皮下脂肪细胞中，其表达量升高了2.48倍，证实了巨噬细胞大量招募并浸润。另外，血清中TNF-a的上升及IL-10的下降说明，浸润的巨噬细胞M1极化，并抵制了具有愈伤修复功能的M2型巨噬细胞。