Universität zu Köln

Ostermann, A. L., Wunderlich, C. M., Schneiders, L., Vogt, M. C., Woeste, M. A., Belgardt, B. F., Niessen, C. M., Martiny, B., Schauss, A. C., Frommolt, P., Nikolaev, A., Hoevelmeyer, N., Sears, R. C., Koch, P. J., Guenzel, D., Bruening, J. C. and Wunderlich, F. T. (2019). Intestinal insulin/IGF1 signalling through FoxO1 regulates epithelial integrity and susceptibility to colon cancer. Nat. Metab., 1 (3). S. 371 - 390. LONDON: NATURE PUBLISHING GROUP. ISSN 2522-5812

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Abstract

Obesity promotes the development of insulin resistance and increases the incidence of colitis-associated cancer (CAC), but whether a blunted insulin action specifically in intestinal epithelial cells (IECs) affects CAC is unknown. Here, we show that obesity impairs insulin sensitivity in IECs and that mice with IEC-specific inactivation of the insulin and IGF1 receptors exhibit enhanced CAC development as a consequence of impaired restoration of gut barrier function. Blunted insulin signalling retains the transcription factor FOXO1 in the nucleus to inhibit expression of Dsc3, thereby impairing desmosome formation and epithelial integrity. Both IEC-specific nuclear FoxO1ADA expression and IEC-specific Dsc3 inactivation recapitulate the impaired intestinal integrity and increased CAC burden. Spontaneous colonic tumour formation and compromised intestinal integrity are also observed upon IEC-specific coexpression of FoxO1ADA and a stable Myc variant, thus suggesting a molecular mechanism through which impaired insulin action and nuclear FOXO1 in IECs promotes CAC.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Ostermann, A. L. UNSPECIFIED UNSPECIFIED UNSPECIFIED Wunderlich, C. M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Schneiders, L. UNSPECIFIED UNSPECIFIED UNSPECIFIED Vogt, M. C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Woeste, M. A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Belgardt, B. F. UNSPECIFIED UNSPECIFIED UNSPECIFIED Niessen, C. M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Martiny, B. UNSPECIFIED UNSPECIFIED UNSPECIFIED Schauss, A. C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Frommolt, P. UNSPECIFIED UNSPECIFIED UNSPECIFIED Nikolaev, A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Hoevelmeyer, N. UNSPECIFIED UNSPECIFIED UNSPECIFIED Sears, R. C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Koch, P. J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Guenzel, D. UNSPECIFIED UNSPECIFIED UNSPECIFIED Bruening, J. C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Wunderlich, F. T. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-154378
DOI:	10.1038/s42255-019-0037-8
Journal or Publication Title:	Nat. Metab.
Volume:	1
Number:	3
Page Range:	S. 371 - 390
Date:	2019
Publisher:	NATURE PUBLISHING GROUP
Place of Publication:	LONDON
ISSN:	2522-5812
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language HIGH-FAT-DIET; NECROSIS-FACTOR-ALPHA; STEM-CELLS; INDUCED OBESITY; GROWTH-FACTOR; BETA-CATENIN; MOUSE MODEL; TH17 CELLS; C-MYC; RECEPTOR Multiple languages Endocrinology & Metabolism Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/15437