Insulin/IGF-1 enhances intestinal epithelial crypt proliferation through PI3K/Akt, and not ERK signaling in obese humans

Abstract

The intestinal epithelium is 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 altered tissue growth and function. Obesity-induced high levels of insulin and insulin-like growth factor-1 in the stem cell niche are found to impact proliferation in rodents indicating that insulin and insulin-like growth factor-1 receptors may play a role in modulating intestinal epithelial stem cell proliferation. To determine whether insulin or insulin-like growth factor-1 can induce proliferation in human intestinal epithelial stem cells, and if two downstream insulin and insulin-like growth factor-1 receptor signaling pathways, PI3K/Akt and ERK, are involved, we used primary small intestinal epithelial crypts isolated from obese humans and investigated (1) the effect of insulin or insulin-like growth factor-1 on crypt proliferation, and (2) the effect of insulin and insulin-like growth factor-1 signaling inhibitors on insulin or insulin-like growth factor-1-induced proliferation. We found that insulin and insulin-like growth factor-1 enhanced the proliferation of crypt cells, including intestinal epithelial stem cells. Inhibition of the PI3K/Akt pathway attenuated insulin and insulin-like growth factor-1-induced proliferation, but inhibition of the ERK pathway had no effect. These results suggest that the classical metabolic PI3K pathway and not the canonical proliferation ERK pathway is involved in the insulin/insulin-like growth factor-1-induced increase in crypt proliferation in obese humans, which may contribute to abnormal tissue renewal and function. Impact statement This study investigates if insulin or insulin-like growth factor-1 (IGF-1) induces intestinal epithelial proliferation in humans, and if insulin and IGF-1 receptor signaling is involved in this process in obesity. Although obesity-induced high levels of insulin and IGF-1 in the stem cell niche are found to impact the proliferation of intestinal epithelial stem cells in rodents, we are the first to investigate this effect in humans. We found that insulin and IGF-1 enhanced the proliferation of intestinal crypts (including stem cells and other crypt cells) isolated from obese humans, and PI3K/Akt, and not ERK signaling was involved in insulin or IGF-1-induced proliferation. The imbalance in signaling between PI3K/Akt and ERK pathways may point to a pathway-specific impairment in insulin/IGF-1 receptor signaling. We propose that this may contribute to reciprocal relationships between insulin/IGF-1 receptor resistance and intestinal epithelial proliferation that leads to abnormal tissue renewal and function.

Hyodeoxycholic acid (HDCA) suppresses intestinal epithelial cell proliferation through FXR‐PI3K/AKT pathway, accompanied by alteration of bile acids metabolism profiles induced by gut bacteria

“…Numerous studies have shown that PI3K/AKT signaling pathway is involved in regulating the proliferation of intestinal epithelial cells 39‐41 . In agreement with previous reports, we found that inhibition of PI3K/AKT signaling pathway was accompanied with HDCA‐suppressed proliferation of IPEC‐J2 cells.…”

Protectin DX promotes epithelial injury repair and inhibits fibroproliferation partly via ALX/PI3K signalling pathway

“…We also found that PDX promoted the primary AT II cells proliferation in a dose‐dependent manner as well. PI3K/AKT is a classical signal pathway that controls cell proliferation and differentiation 30 . Furthermore, we also found that the mitogenic response of AT II cells to PDX is via the ALX/PI3K signalling pathway.…”

Obesity and intestinal stem cell susceptibility to carcinogenesis

“…It showed that the canonical ERK pathway was not involved in the increased proliferation. The authors suggested that the abnormal renewal of intestinal epithelial may be associated with inconsistency in signaling between PI3K/Akt and ERK pathways which caused insulin/IGF-1 resistance [ 104 ]. A role for PI3K pathway is suggested in regulation of cell cycle and apoptosis through inhibition of cell cycle inhibitors (e.g., phosphorylation of p21Cip1, and p27 kip1 ) and inactivation of apoptotic substrates (e.g., Bcl-2-associated death promoter (BAD), procaspase-9) [ 105 ], as well as modulating the activity of several transcription factors such as Forkhead family of transcription factors (FoxO), and mTOR [ 106 , 107 ].…”