Diabetes：代谢疾病病从口的新机制

　　

北京大学分子医学研究所张秀琴研究组在糖尿病研究权威杂志《Diabetes》在线发表关于饮食刺激引起的肠道形态和功能变化与肥胖的关系的最新研究成果。

北京大学分子医学研究所张秀琴研究员是该论文的通讯作者，北京大学分子医学研究所博士生毛嘉明和胡晓敏为共同第一作者。

肥胖及由其引起的多种代谢和心血管疾病，已成为世界性的科学和社会问题。肥胖发生的主要原因是现代人们生活水平提高，食品种类极其丰富，营养物质摄取过多而导致，是现代‘病从口入’的典型范例。适当的饮食控制会减少肥胖的发生，而在日常生活中，每天面对美味佳肴，想要做到长期坚持饮食控制是非常艰难的。

肠道粘膜上皮是营养物质吸收的门户和场所，肠道粘膜上皮干细胞具有非常活跃的增殖能力，在一生中不断增殖、分化，以保证肠道上皮的新陈代谢和营养吸收面积。那么，营养物质经口摄入后是否会对肠道功能产生影响？这一影响是否与营养过剩及肥胖的发生相关联？而干扰这一关联过程，是否会对肥胖的发生产生影响？

在《Diabetes》论文中，毛嘉明等在小鼠模型中揭示了过多的营养物质的摄取，可通过激活小肠粘膜上皮细胞的GSK-3β/β-catenin信号通路，促进小肠粘膜上皮细胞增殖，小肠绒毛增长，扩大小肠粘膜的吸收面积，从而增加营养物质的吸收。而β-catenin的抑制剂JW55在不影响小鼠饮食量的情况下，可明显降低高脂饮食诱导的小鼠小肠粘膜上皮细胞的增殖，减少小肠粘膜的吸收面积，而起到抑制体重增加的作用。

这项发现提示了潜在的‘既饱口福，又可减肥’的肥胖预防治疗新机制。

原文摘要：

Overnutrition stimulates intestinal epithelium proliferation through β-catenin signaling in obese mice.

Obesity is a major risk factor for type 2 diabetes and cardiovascular diseases. And overnutrition is a leading cause of obesity. After most nutrients are ingested, they are absorbed in the small intestine. Signals from β-catenin are essential to maintain development of the small intestine and homeostasis. In this study, we employed a hyperphagia db/db obese mouse model and a high fat diet (HFD) induced obese mouse model to investigate the effects of overnutrition on intestinal function and β-catenin signaling. The β-catenin protein was upregulated along with inactivation of glycogen synthase kinase-3β (GSK-3β) in the intestines of both db/db and HFD mice. Proliferation of intestinal epithelial stem cells, villi length, nutrient absorption and body weight also increased in both models. These changes were reversed by caloric restriction in db/db mice and by β-catenin inhibitor JW55 (a small molecule that increase β-catenin degradation) in HFD mice. Parallel, in vitro experiments showed that β-catenin accumulation and cell proliferation stimulated by glucose were blocked by the β-catenin inhibitor FH535. And the GSK-3 inhibitor CHIR98014 in an intestinal epithelial cell line increased β-catenin accumulation and Cyclin D1 expression. These results suggested that, besides contribution to intestinal development and homeostasis, GSK-3β/β-catenin signaling plays a central role in intestinal morphological and functional changes in response to overnutrition. Manipulating the GSK-3β/β-catenin signaling pathway in intestinal epithelium might become a therapeutic intervention for obesity induced by overnutrition