Deletion of intestinal epithelial insulin receptor attenuates high-fat diet-induced elevations in cholesterol and stem, enteroendocrine, and Paneth cell mRNAs

Am J Physiol Gastrointest Liver Physiol. 2015 Jan 15;308(2):G100-11. doi: 10.1152/ajpgi.00287.2014. Epub 2014 Nov 13.


The insulin receptor (IR) regulates nutrient uptake and utilization in multiple organs, but its role in the intestinal epithelium is not defined. This study developed a mouse model with villin-Cre (VC) recombinase-mediated intestinal epithelial cell (IEC)-specific IR deletion (VC-IR(Δ/Δ)) and littermate controls with floxed, but intact, IR (IR(fl/fl)) to define in vivo roles of IEC-IR in mice fed chow or high-fat diet (HFD). We hypothesized that loss of IEC-IR would alter intestinal growth, biomarkers of intestinal epithelial stem cells (IESC) or other lineages, body weight, adiposity, and glucose or lipid handling. In lean, chow-fed mice, IEC-IR deletion did not affect body or fat mass, plasma glucose, or IEC proliferation. In chow-fed VC-IR(Δ/Δ) mice, mRNA levels of the Paneth cell marker lysozyme (Lyz) were decreased, but markers of other differentiated lineages were unchanged. During HFD-induced obesity, IR(fl/fl) and VC-IR(Δ/Δ) mice exhibited similar increases in body and fat mass, plasma insulin, mRNAs encoding several lipid-handling proteins, a decrease in Paneth cell number, and impaired glucose tolerance. In IR(fl/fl) mice, HFD-induced obesity increased circulating cholesterol; numbers of chromogranin A (CHGA)-positive enteroendocrine cells (EEC); and mRNAs encoding Chga, glucose-dependent insulinotrophic peptide (Gip), glucagon (Gcg), Lyz, IESC biomarkers, and the enterocyte cholesterol transporter Scarb1. All these effects were attenuated or lost in VC-IR(Δ/Δ) mice. These results demonstrate that IEC-IR is not required for normal growth of the intestinal epithelium in lean adult mice. However, our findings provide novel evidence that, during HFD-induced obesity, IEC-IR contributes to increases in EEC, plasma cholesterol, and increased expression of Scarb1 or IESC-, EEC-, and Paneth cell-derived mRNAs.

Keywords: cholesterol; glucagon; glucose-dependent insulinotrophic peptide; hyperinsulinemia; lysozyme; obesity; small intestine.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cell Differentiation
  • Cholesterol / metabolism*
  • Diet, High-Fat*
  • Enteroendocrine Cells / metabolism*
  • Gastric Inhibitory Polypeptide / metabolism
  • Insulin / blood
  • Intestinal Mucosa / metabolism
  • Intestines / pathology*
  • Mice
  • Mice, Transgenic
  • Obesity / metabolism
  • Paneth Cells / metabolism*
  • RNA, Messenger / metabolism
  • Receptor, Insulin / metabolism*
  • Stem Cells / metabolism*


  • Insulin
  • RNA, Messenger
  • Gastric Inhibitory Polypeptide
  • Cholesterol
  • Receptor, Insulin