title: Overnutrition stimulates intestinal epithelium proliferation through β-catenin signaling in obese mice.
abstract: Obesity is a major risk factor for type 2 diabetes and cardiovascular diseases. And overnutrition is a leading cause of obesity. After most nutrients are ingested, they are absorbed in the small intestine. Signals from β-catenin are essential to maintain development of the small intestine and homeostasis. In this study, we used a hyperphagia db/db obese mouse model and a high-fat diet (HFD)-induced obesity mouse model to investigate the effects of overnutrition on intestinal function and β-catenin signaling. The β-catenin protein was upregulated along with inactivation of glycogen synthase kinase (GSK)-3β in the intestines of both db/db and HFD mice. Proliferation of intestinal epithelial stem cells, villi length, nutrient absorption, and body weight also increased in both models. These changes were reversed by caloric restriction in db/db mice and by β-catenin inhibitor JW55 (a small molecule that increases β-catenin degradation) in HFD mice. Parallel, in vitro experiments showed that β-catenin accumulation and cell proliferation stimulated by glucose were blocked by the β-catenin inhibitor FH535. And the GSK-3 inhibitor CHIR98014 in an intestinal epithelial cell line increased β-catenin accumulation and cyclin D1 expression. These results suggested that, besides contribution to intestinal development and homeostasis, GSK-3β/β-catenin signaling plays a central role in intestinal morphological and functional changes in response to overnutrition. Manipulating the GSK-3β/β-catenin signaling pathway in intestinal epithelium might become a therapeutic intervention for obesity induced by overnutrition.
authors.affiliation: Institute of Molecular Medicine, Peking University, Beijing, China.
authors.forename: Jiaming
authors.initials: J
authors.lastname: Mao
authors.forename: Xiaomin
authors.initials: X
authors.lastname: Hu
authors.forename: Yao
authors.initials: Y
authors.lastname: Xiao
authors.forename: Chao
authors.initials: C
authors.lastname: Yang
authors.forename: Yi
authors.initials: Y
authors.lastname: Ding
authors.forename: Ning
authors.initials: N
authors.lastname: Hou
authors.forename: Jue
authors.initials: J
authors.lastname: Wang
authors.forename: Heping
authors.initials: H
authors.lastname: Cheng
authors.forename: Xiuqin
authors.initials: X
authors.lastname: Zhang
mesh_terms: D000818:Animals; D031204:Caloric Restriction; D049109:Cell Proliferation; D059305:Diet, High-Fat; D005947:Glucose / Q000008:administration & dosage; D038362:Glycogen Synthase Kinase 3 / Q000502:physiology; D000071679:Glycogen Synthase Kinase 3 beta; D007413:Intestinal Mucosa / Q000378:metabolism*; D007421:Intestine, Small / Q000196:embryology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D009765:Obesity / Q000503:physiopathology*; D044343:Overnutrition / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D051176:beta Catenin / Q000502:physiology*
chemical_list: D051176:beta Catenin; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3; D005947:Glucose