Su1776 Microvillus Structure and Function Modulated by Glucagon-like Peptide-2 and the Intestinal Epithelial Insulin-like Growth Factor-1 Receptor

Abstract Microvilli are tiny projections on the apical end of enterocytes, aiding in the digestion and absorption of nutrients. One of their key features is uniform length, but how this is regulated is poorly understood. Glucagon-like peptide-2 (GLP-2) has been shown to increase microvillus length but, the requirement of its downstream mediator, the intestinal epithelial insulin-like growth factor-1 receptor (IE-IGF-1R), and the microvillus proteins acted upon by GLP-2, remain unknown. Using IE-IGF-1R knockout (KO) mice, treated with either long-acting human (h) (GLY2)GLP-2 or vehicle for 11d, it was found that the h(GLY2)GLP-2-induced increase in microvillus length required the IE-IGF-1R. Furthermore, IE-IGF-1R KO alone resulted in a significant decrease in microvillus length. Examination of the brush border membrane proteome as well as of whole jejunal mucosa demonstrated that villin was increased with h(GLY2)GLP-2 treatment in an IE-IGF-1R-dependent manner. Under both basal conditions and with h(GLY2)GLP-2 treatment of the IE-IGF-1R KO mice, changes in villin, IRTKS-1, harmonin, β-actin, and myosin-1a did not explain the decrease in microvillus length, in either the brush border or jejunal mucosa of KO animals. Collectively, these studies define a new role for the IE-IGF-1R within the microvillus, in both the signaling cascade induced by GLP-2, as well as endogenously.

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The Intestinal Epithelial Insulin-Like Growth Factor-1 Receptor Links Glucagon-Like Peptide-2 Action to Gut Barrier Function

Endocrinology ◽

10.1210/en.2013-1871 ◽

2014 ◽

Vol 155 (2) ◽

pp. 370-379 ◽

Cited By ~ 52

Author(s):

Charlotte X. Dong ◽

Wen Zhao ◽

Chloe Solomon ◽

Katherine J. Rowland ◽

Cameron Ackerley ◽

...

Keyword(s):

Growth Factor ◽

Barrier Function ◽

Insulin Like Growth Factor ◽

Intestinal Epithelial ◽

Gut Barrier ◽

Gut Barrier Function ◽

Glucagon Like Peptide

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697 Role of the Intestinal Epithelial-Insulin-Like Growth Factor-1 Receptor in Glucagon-Like Peptide-2-Mediated Enhancement of Intestinal Barrier Function

Gastroenterology ◽

10.1016/s0016-5085(13)60464-3 ◽

2013 ◽

Vol 144 (5) ◽

pp. S-129

Author(s):

Charlotte X. Dong ◽

Chloe J. Solomon ◽

Wen Zhao ◽

Tanja Gonska ◽

Patricia L. Brubaker

Keyword(s):

Growth Factor ◽

Barrier Function ◽

Intestinal Barrier ◽

Intestinal Barrier Function ◽

Insulin Like Growth Factor ◽

Intestinal Epithelial ◽

Glucagon Like Peptide

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

Experimental Biology and Medicine ◽

10.1177/1535370218785152 ◽

2018 ◽

Vol 243 (11) ◽

pp. 911-916 ◽

Cited By ~ 3

Author(s):

Weinan Zhou ◽

Blair M Rowitz ◽

Megan J Dailey

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Growth Factor ◽

Insulin Like Growth Factor ◽

Intestinal Epithelial ◽

Receptor Signaling ◽

Epithelial Stem Cells ◽

Cell Niche ◽

And Function ◽

Abnormal Tissue

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.

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