Insulin/IGF‐1 Enhances Intestinal Epithelial Crypt Proliferation through PI3K/Akt, and Not ERK Signaling in Obese Humans

Abstract

The intestinal epithelium plays important roles in nutrient absorption, satiety hormone release and immune barrier function. In order to ensure proper tissue actions are maintained, the cells are continuously regenerated through proliferation and differentiation of stem cells located in the intestinal crypts. Obesity affects this process and results in greater stem cell proliferation and abnormal tissue growth and function. Obesity‐induced high levels of insulin/insulin‐like growth factor‐1 (IGF‐1) in the stem cell niche are found to impact the changes in proliferation in rodents indicating that insulin/IGF‐1 receptors may play a role in modulating intestinal epithelial stem cell proliferation. Insulin receptor resistance is a hallmark of obesity that can be driven by an imbalance between or abnormal signaling within two downstream signaling pathways, PI3K and ERK, in non‐intestinal epithelial tissues. To determine whether insulin/IGF‐1 can induce proliferation in human intestinal epithelial stem cells and if PI3K or ERK pathways are involved, we used primary small intestinal epithelial crypts and investigated 1) the effect of insulin/IGF‐1 on crypt proliferation, and 2) the effect of insulin/IGF‐1 signaling inhibitors (i.e. PI3K/Akt pathway inhibitor Wortmannin and ERK pathway inhibitor PD98059) on insulin/IGF‐1‐induced crypt proliferation. We found that insulin/IGF‐1 enhanced crypt proliferation in obese humans. Inhibition of PI3K/Akt pathway attenuated insulin/IGF‐1‐induced crypt proliferation, but inhibition of ERK pathway had no effect. These results suggest that the classical metabolic PI3K pathway and not the canonical proliferation ERK pathway is involved in insulin/IGF‐1‐induced increase in crypt proliferation in obese humans. Pathway‐specific impairments in insulin/IGF‐1 signaling may contribute to reciprocal relationships between insulin/IGF‐1 resistance and intestinal epithelial stem cell proliferation and differentiation that fosters tissue dysfunction.Support or Funding InformationThis work was supported by USDA Hatch (to MJD) ILLU‐538‐926.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.