Intestinal Insulin Receptor Contributes to Elevated Cholesterol and Stem, Enteroendocrine, and Paneth Cell Adaptations to Obesity

Abstract

Background The insulin receptor (IR) regulates nutrient uptake and utilization in multiple organs, but its role in the intestinal epithelium is not defined. Methods: We generated and characterized lean and obese mice with intestinal epithelial cell (IEC)-specific IR deletion (IRΔIEC) and littermate controls (IRfl/fl) using chow or high-fat diet (HFD) feeding to test the hypothesis that loss of IEC-IR will alter intestinal growth, biomarkers of intestinal epithelial stem cells (IE­­­SC) or other lineages, and metabolic responses to HFD. Results: In lean IRΔIEC mice there was little effect on any parameter measured. During HFD-induced obesity, both IRfl/fl and IRΔIEC mice exhibited increased body mass, impaired glucose tolerance, and decreased Paneth cell number. Obese IRfl/fl mice exhibited increases in circulating cholesterol, numbers enteroendocrine cells (EEC), mRNAs encoding a cholesterol transporter and incretins glucose-dependent insulinotrophic peptide and glucagon, and IESC biomarkers. All these effects were significantly attenuated or lost in obese IRΔIEC mice. Conclusions Our findings provide novel evidence that although IEC-IR is not required for normal intestinal growth, during HFD-induced obesity, IEC-IR contributes to increases in plasma cholesterol, EEC number, and increased mRNAs marking IESC and encoding proteins involved cholesterol handing and insulin regulation. Grants: F31 AG040943 (SFA), NIH DK040247-19 (PKL).