Premium
Nutrient‐Induced Metabolism Dictates Intestinal Epithelial Crypt Proliferation
Author(s) -
Zhou Weinan,
Clara Rosmarie,
Mansouri Abdelhak,
Langhans Wolfgang,
Dailey Megan J.
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.lb695
Subject(s) - crypt , oligomycin , biology , microbiology and biotechnology , extracellular , carbohydrate metabolism , antimycin a , glycolysis , intestinal epithelium , metabolism , enterocyte , intestinal mucosa , biochemistry , mitochondrion , chemistry , epithelium , endocrinology , medicine , small intestine , enzyme , genetics , atpase
The intestinal epithelium plays an essential role in nutrient absorption, hormone release and barrier function. Maintenance of the epithelium is driven by continuous cell renewal by stem cells located in the intestinal crypts. The amount and type of diet influence this process and result in changes in the size and cellular make‐up of the tissue. We have found that glucose induces an increase in the rate of proliferation in intestinal epithelial crypts in a concentration dependent manner. The mechanism underlying this nutrient‐driven change in crypt proliferation is not known, but may involve a shift in intracellular metabolism that allows for more nutrients to be used to manufacture new cells. We hypothesized that nutrient availability drives changes in cellular energy metabolism of small intestinal epithelial crypts that could contribute to the increase in crypt proliferation. To test this hypothesis, we utilized primary small intestinal epithelial crypts from C57BL/6J mice to study the effect of glucose on crypt metabolism using a Seahorse XFe96 Extracellular Flux Analyzer for real‐time metabolic measurements. Glycolysis was determined by measuring the extracellular acidification rate (ECAR) in response to glucose and the glycolytic pathway inhibitor 2‐Deoxy‐D‐glucose (2‐DG). Glucose oxidation was determined by measuring oxygen consumption rate (OCR) in response to glucose and the glucose oxidation pathway inhibitor UK‐5099. Glucose‐induced mitochondrial respiration was determined by measuring OCR in response to glucose and modulators of mitochondrial respiration (i.e. ATP synthase inhibitor oligomycin, uncoupler FCCP, complex I inhibitor rotenone, complex III inhibitor antimycin A). The maximum respiration capacity (i.e. the capacity to oxidize any substrates present to meet metabolic challenges) was determined by measuring FCCP‐stimulated OCR. We found that glucose increased ECAR in a concentration dependent manner, and the glycolytic pathway inhibitor 2‐DG reduced glucose‐induced ECAR, indicating that glucose stimulates glycolysis of crypts. However, neither glucose nor the glucose oxidation pathway inhibitor UK‐5099 affected OCR, indicating that glucose oxidation is not active in crypts. Furthermore, glucose increased FCCP‐stimulated OCR, indicating that the presence of glucose is necessary for crypts to utilize substrates for oxidation. These data suggest that high nutrient availability drives metabolism towards utilization of glucose for glycolysis in crypts, and glucose might indirectly induce an increase in the oxidation of other nutrients (e.g. fatty acids, amino acids) in crypts. These metabolic changes may contribute to the nutrient‐induced crypt proliferation. Support or Funding Information USDA ILLU‐538‐926