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).