Deletion of intestinal epithelial insulin receptor attenuates high-fat diet-induced elevations in cholesterol and stem, enteroendocrine, and Paneth cell mRNAs.
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.
Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; and.
Sarah F
SF
Andres
Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; and.
M Agostina
MA
Santoro
Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
Amanda T
AT
Mah
Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; and.
J Adeola
JA
Keku
Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; and.
Amy E
AE
Bortvedt
Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; and.
R Eric
RE
Blue
Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; and empk@med.unc.edu.
P Kay
PK
Lund
D000818:Animals; D002454:Cell Differentiation; D002784:Cholesterol / Q000378:metabolism*; D059305:Diet, High-Fat; D019858:Enteroendocrine Cells / Q000378:metabolism*; D005749:Gastric Inhibitory Polypeptide / Q000378:metabolism; D007328:Insulin / Q000097:blood; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D009765:Obesity / Q000378:metabolism; D019879:Paneth Cells / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D011972:Receptor, Insulin / Q000378:metabolism*; D013234:Stem Cells / Q000378:metabolism*
D007328:Insulin; D012333:RNA, Messenger; D005749:Gastric Inhibitory Polypeptide; D002784:Cholesterol; D011972:Receptor, Insulin
cholesterol; glucagon; glucose-dependent insulinotrophic peptide; hyperinsulinemia; lysozyme; obesity; small intestine