ω3多不饱和脂肪酸调控糖皮质激素转化酶改善早期营养程序化结局的机制研究

Neonatal overfed induced programming outcome including obesity and insulin resistance in adults, which associated with peripheral activative glucocorticoid (GC). Thus，we hypothesis that intervention with PUFA dietary after suckling has become the future strategy of prevention and treatment for obesity and related metabolic syndrome due to nutrition programming, and regualtion of glucocorticoid (GC) conversion enzymes programming which may underlie the molecular mechanism of this process. In this study, with small litter induced neonatal overfed rats, we will observe the intervention effect with dietary ω3 polyunsaturated fatty acids (ω3 PUFA) at postnatal different stage on obesity, and insulin resistance in adults and relationship with GC activate enzyme 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1), glucocorticoid receptor (GR), GC inactivate enzyme 5α reductase type 1 (5αR1) and 5β reductase (5βR) in adipose tissue and liver after weaning (before and after puberty respectively). Further, we investigated the effect and molecular pathway of ω3 PUFA on regulation of adipocyte 11βHSD1 expression and enzyme activity in primary adipocyte from rats and 3T3-L1 adipocyte by vitro study. Treatment with ω3 PUFA (eicosapentaenoic acid, docosahexaenoic acid ) in adipocyte at presence with or without PPARγantagonists or RNAi for C/EBPs, 11βHSD1、PPARγ and C/EBPs gene mRNA and protein expression are measured, and the relationship and the binding mode between them are determined to clarify if ω3 PUFA modulated adipocyte 11βHSD1 expression via a PPARγ-C/EBPs pathway. These result obtained are benefit for us to explore the molecular mechanism of dietary ω3 PUFA intervention nutrition programming development. Moreover, it may provide the molecular target and the window phase for obese intervention according on research findings. Therefore there is an important significance in science theoretical and clinical application.

哺乳期营养过度导致成年期肥胖和胰岛素抵抗的营养程序化结局与组织局部糖皮质激素活性密切相关。本研究假设，早期膳食脂肪酸干预可改变肥胖发生发展的轨迹，多不饱和脂肪酸对组织糖皮质激素代谢转化酶的调控是改变营养程序化发展的重要机制。应用哺乳期营养过度的动物模型，本研究将观察断乳后不同时期开始的ω3 PUFA膳食对成年期肥胖和胰岛素抵抗的影响以及与脂肪及肝脏组织糖皮质激素转化酶11β羟类固醇脱氢酶1型（11βHSD1）、糖皮质激素受体、5α还原酶1型及5β还原酶的关系；进一步，应用特异性拮抗剂和RNA干扰技术，探讨ω3 PUFA通过转录调节分子PPARγ、C/EBPs的调控进而影响脂肪细胞11βHSD1酶活性和脂肪细胞功能的分子机制。实验结果的获得有助于阐明ω3 PUFA干预对糖皮质激素转化酶调控的途径，并为肥胖靶点的选择和适时有效的干预提供科学依据，因而具有重要的临床价值。

哺乳期营养过度导致成年期肥胖和胰岛素抵抗的营养程序化结局与组织局部糖皮质激素活性密切相关。本研究假设，早期膳食脂肪酸干预可改变肥胖发生发展的轨迹，多不饱和脂肪酸（ω3 PUFA）对组织糖皮质激素代谢转化酶的调控是改变营养程序化发展的重要机制。我们应用小窝组喂养动物模型模拟人类婴儿期过度喂养，以及体外细胞培养研究11β羟类固醇脱氢酶 1 型（11βHSD1）代谢在早期营养程序化机制中的作用和膳食脂肪酸的调控机制。主要发现：（1）早期膳食脂肪酸干预可改变肥胖发生发展的轨迹：断乳后及早开始6%鱼油膳食干预能完全逆转成年期代谢紊乱、肥胖和脂肪肝的发生，而青春期前后开始的鱼油膳食干预仅部分改善糖脂代谢。断乳后高脂饮食则加剧肥胖及其代谢综合征的早龄化和严重程度。（2）小窝组喂养可持续增加脂肪组织和肝脏11βHSD1表达，鱼油膳食抑制脂肪组织和肝脏中11βHSD1表达和酶活性，但并不影响糖皮质激素受体、5α还原酶 1 型及 5β 还原酶。（3）PPAR γ、C/EBPs是调节脂肪细胞11βHSD1的重要分子，ω3 PUFA通过PPAR γ-C/EBPα途径抑制11βHSD1表达；（4）早期过度营养大鼠，不仅增加白色脂肪组织积聚，同时减少棕色脂肪，抑制其产热功能和UCP-1等相关产热基因的调控，而这些变化都可以通过早期鱼油膳食干预完全恢复正常。综上，实验结果不仅明确早期营养干预的时空理念，证实生后存在脂肪组织发育编程可干预的窗口期，也为加强儿童早期营养模式的管理，肥胖靶点的选择和适时有效的干预提供科学依据，因而具有重要的临床意义和学术价值。结果发表SCI论文5篇；中文核心期刊6篇，培养博士3名，硕士3名；获中国妇幼健康科技进步二等奖1项，江苏省医学会江苏医学科技二等奖1项。