宫内微量元素铬（Ⅲ）缺乏对成年期糖脂代谢影响及机制研究

Chromium is an essential element required for normal carbohydrate and lipid metabolism. Relative chromium deficiency may be more common, because the average dietary chromium intake for adults is usually lower than the minimum recommended 50μg/d. Recent studies show chronic maternal chromium restriction induced insulin resistance, impaired glucose tolerance, increased body adiposity in offspring. But the exact mechanism is not clear. Maternal nutrient deficiencies are widely prevalent in the developing world. Robust evidence suggests that intrauterine nutritional status plays an important role in chronic diseases of adult life. There is increasing evidence that this effect is mediated biologically at the level of epigenetics, including DNA methylation. Our preliminary research show insulin signaling pathway, MAPK pathway and adipocytokine signaling pathways are involved in the regulation of intrauterine growth environment on glucose metabolism in the level of DNA methylation. Exposure of the foetus to maternal malnutrition (protein, energy, vitamin, trace elements) causes intrauterine growth retardation (IUGR) leading to low birth weight which is prevalent in China. Based on the available evidence, we hypothesize that chromium restriction intrauterine environment moderates the glucose and lipid metabolism in adult life through epigenetic mechanism. We will use mouse chromium restriction intrauterine environment model, apply whole genome methylation microarray, bisulfite sequencing PCR and immunochemistry technology to elucidate the associated mechanisms and key genes. These findings will provide important insights into the epigenetics of diabetes and the mechanisms of therapies.

铬（Ⅲ）是人体必须的微量元素。由于饮食结构不合理，人群中铬（Ⅲ）缺乏普遍存在。低铬（Ⅲ）饮食孕鼠所生子代小鼠成年期糖脂代谢紊乱。前期，本组发现中国人群不同出生体重（不同营养）下出生的婴儿在胎盘和脐血中胰岛素信号、脂肪因子信号和MAPK通路基因的甲基化程度均发生了显著变化。提示表观遗传学在宫内营养不良对成年期糖脂代谢机制中起重要作用。我们推测宫内铬（Ⅲ）缺乏导致了生命早期糖脂代谢通路基因产生了"甲基化编程"，从而为成年期糖脂代谢紊乱奠定了生物基础。为证实这一假说，我们将通过低铬（Ⅲ）饮食构建宫内铬（Ⅲ）缺乏模型，观察子代在成年期糖脂代谢相关指标，在出生后逐步转换为正常饮食，探讨早期干预的可能性，采用全基因组DNA甲基化芯片、亚硫酸盐测序、免疫组化等技术，从整体、组织、分子三个层次及新的视角，探讨宫内铬（Ⅲ）缺乏影响成年期糖脂代谢的关键表观遗传学通路，为糖尿病的防治提供新靶点和新思路。

铬（Ⅲ）是人体必须的微量元素。由于饮食结构不合理，人群中铬（Ⅲ）缺乏普遍存在。低铬（Ⅲ）饮食孕鼠所生子代小鼠成年期糖脂代谢紊乱。前期，本组发现中国人群不同出生体重（不同营养）下出生的婴儿在胎盘和脐血中胰岛素信号、脂肪因子信号和MAPK通路基因的甲基化程度均发生了显著变化。提示表观遗传学在宫内营养不良导致成年期糖脂代谢紊乱机制中起重要作用。我们推测宫内铬（Ⅲ）缺乏导致了生命早期糖脂代谢通路基因产生了 "甲基化编程"，从而为成年期糖脂代谢紊乱奠定了生物基础。为证实这一假说，我们通过低铬（Ⅲ）饮食构建宫内铬（Ⅲ）缺乏模型，观察子代在成年期糖脂代谢相关指标，在出生后逐步转换为正常饮食，探讨早期干预的可能性，采用全基因组DNA甲基化芯片、亚硫酸盐测序、免疫组化等技术，从整体、组织、分子三个层次及新的视角，探讨宫内铬（Ⅲ）缺乏影响成年期糖脂代谢的关键表观遗传学通路，为糖尿病的防治提供新靶点和新思路。研究结果发现，低铬宫内环境导致子代在老年期出现糖代谢异常，胰岛素抵抗，肥胖，体脂增加，血脂紊乱。本研究首次发现，这些现象的内在机制可能涉及低铬宫内环境诱导子代肝脏胰岛素信号通路上的基因高基因化，胰岛素信号通路上的基因表达抑制，肝糖输出增多；脂肪组织MAPK通路上的基因低甲基化，MAPK通路上的基因激活，PPAR激活，从而脂肪细胞生成增多。本研究将为宫内不良营养环境所致子代肥胖和糖尿病的早期防治提供新的表观遗传学靶点。