Reduction of intestinal RIPK1 ameliorates HFD-induced metabolic disorders in female mice

Background Metabolic disorders including obesity, impaired glucose tolerance, dyslipidemia, and insulin resistance constitute a global public health problem that increases the risk of cardiovascular and type 2 diabetes. In modern society, a major cause of metabolic disorder is excessive nutrient intake from food. Therefore, as the main site of nutrient absorption, the intestine plays an important role in diet-induced metabolic disorders. However, it is still largely unknown on how the intestine participates in such a process. Results Here we show that ileal jejunization is responsible for high-fat diet-induced metabolic disorders in female mice. Upon HFD-feeding, the transcriptional profile of the ileum was shifted towards that of jejunum which is characterized by increased expression of jejunal feature genes. Accordantly, the lipids uptake was increased in the ileum. Importantly, the HFD-induced ileal jejunization and metabolic disorders can be profoundly attenuated by intestinal-specific reduction of RIPK1. Interestingly, the HFD-induced increase in the expression of the jejunal feature genes in the ileum, and the effect of RIPK1 reduction were not observed in male mice. We generated receptor-interacting protein kinase 1 (Ripk1) intestine-specific heterozygous knockout mice (Ripk1IEC+/-) and analyzed the phenotypes and the transcriptional profile of Ripk1IEC+/- mice and their wild type (WT) littermates under normal chow diet (ND) and high-fat diet (HFD).研究背景 包括肥胖、糖耐量受损、血脂异常及胰岛素抵抗在内的代谢紊乱是一类全球性公共卫生问题，会增加心血管疾病与2型糖尿病的患病风险。在现代社会，代谢紊乱的主要诱因之一为膳食营养摄入过量。作为营养吸收的核心场所，肠道在膳食诱导的代谢紊乱进程中发挥着关键作用，但目前学界对肠道如何参与这一过程的认知仍较为有限。 研究结果 本研究证实，回肠空肠化（ileal jejunization）是雌性小鼠高脂饮食（high-fat diet, HFD）诱导代谢紊乱的核心机制。在HFD喂养条件下，回肠的转录组特征向空肠偏移，具体表现为空肠特征基因的表达水平显著上调；相应地，回肠的脂质摄取能力也随之增强。值得注意的是，通过肠道特异性下调受体相互作用蛋白激酶1（receptor-interacting protein kinase 1, RIPK1）的表达，可显著缓解HFD诱导的回肠空肠化与代谢紊乱表型。有趣的是，在雄性小鼠中既未观察到HFD诱导的回肠空肠特征基因表达上调，也未发现RIPK1表达下调所带来的保护效应。本研究构建了肠道特异性杂合敲除Ripk1基因的小鼠模型（Ripk1IEC+/-），并分别在普通饲料饮食（normal chow diet, ND）与HFD条件下，对该基因敲除小鼠及其野生型（wild type, WT）同窝对照小鼠的表型与转录组特征开展了分析。