Intestinal epithelial cell NCoR deficiency ameliorates obesity and metabolic syndrome

Obesity has emerged as a common disease worldwide. Risks of developing other metabolic diseases, such as Type 2 diabetes are also higher in obese population. However, current treatment options are limited. Here we discovered a new approach for mitigating obesity and metabolic disorders by targeting intestinal nuclear receptor corepressor (NCoR). In mice with diet-induced obesity, NCoR deficiency in intestinal epithelial cells (IECs) improved obesity, insulin resistance, and glucose intolerance, corrected atherogenic dyslipidemia, and reduced hepatic steatosis. These effects were mediated through regulation of energy expenditure, energy harvest, and gut hormone secretion. Mechanistically, NCoR deficiency in IECs stimulated peroxisome proliferator-activated receptor α (PPARα) signaling pathway-mediated succinate production and thermogenesis. Intestinal cholesterol excretion was induced by derepression of intestinal liver X receptor (LXR), and triglyceride and fatty acid absorption in the upper intestine was reduced by disrupted bile acid synthesis and altered bile acid composition. In the distal intestine, increased fatty acid uptake stimulated glucagon-like peptide-1 (GLP-1) secretion and improved glycemic control. To investigate the role of nuclear receptor corepressor (NCoR) in intestinal epithelial cells (IECs), wild type (WT) and IEC NCoR knock out (IKO) mice were fed with high fat diet for 15 weeks. After sacrifice, mucosa of ileum from WT and IKO mice was scraped and subjected to RNA sequencing. Each group includes 7 biological replicates.