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

Sarah F. Andres, M. Agostina Santoro, Amanda T. Mah, J. Adeola Keku, Amy E. Bortvedt, R. Eric Blue, P. Kay Lund

Research output: Contribution to journalArticlepeer-review

18 Scopus citations

Abstract

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-IRΔ/Δ) and littermate controls with floxed, but intact, IR (IRfl/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-IRΔ/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, IRfl/fl and VC-IRΔ/Δmice 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 IRfl/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-IRΔ/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.

Original languageEnglish (US)
Pages (from-to)G100-G111
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Volume308
Issue number2
DOIs
StatePublished - Jan 15 2015
Externally publishedYes

Keywords

  • Cholesterol
  • Glucagon
  • Glucose-dependent insulinotrophic peptide
  • Hyperinsulinemia
  • Lysozyme
  • Obesity
  • Small intestine

ASJC Scopus subject areas

  • Physiology
  • Hepatology
  • Gastroenterology
  • Physiology (medical)

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