Nutrient-induced intestinal epithelial stem cell proliferation and its effect in obesity

Proper tissue function is maintained by continuous cell renewal of somatic stem cells that reside within many tissues. In addition to tissue homeostasis, somatic stem cells are also responsible for tissue regeneration after injury and growth during development or high nutrient availability. Although these processes occur in many tissues, some basic questions are still left unanswered. I investigated fundamental questions, including 1) how somatic stem cells function in response to nutrients under renewal versus growth conditions, 2) how overnutrition (i.e. obesity) modulates the nutrient-induced alterations in stem cell proliferation, and 3) whether there are sex differences in the proliferation and differentiation of stem cells under normal and disease states (i.e. obesity). I used intestinal epithelial stem cells (IESCs) as a model system due to their rapid proliferation ability and the availability for experimental measurement and manipulation. I found that 1) under high nutrient availability, IESCs increase proliferation by switching from using oxidative phosphorylation to glycolysis, that glycolysis is at least partially necessary for nutrient-induced proliferation to occur and that the protein kinase B/hypoxia inducible factor 1 subunit alpha (AKT/HIF1A) pathway is differentially involved in proliferation under low versus high nutrient availability, 2) it is the factors related to obesity and not the high fat diet that is driving an increase in proliferation in diet-induced obese mice compared with lean mice, 3) although obesity induces similar lasting effects in IESCs in males and females, the stem cells in females show an increase in proliferation compared with those from males whenever there is a change in their nutrient environment and that it takes them longer to adapt to a new nutrient environment, and 4) Phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT), and not the classical mitogenic mitogen activated protein kinase (MAPK) pathway, is necessary for obesity-induced IESC proliferation in obese humans. Taken together, these results indicate that nutrient availability enhances IESC proliferation by modulating energy metabolism, and diet-induced obesity, independent of the diet type, impacts IESCs and epithelial tissue without sex differences though sex difference in IESC proliferation exists when challenged with a new nutrient environment.

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Animal Sciences

Grantor

University of Illinois at Urbana-Champaign

Year dc:date

2018

Author dc:creator

• Zhou, Weinan

Contributors dc:contributor

• Dailey, Megan J.
• Gaskins, H. Rex
• Nakamura, Manabu T.
• Underhill, Gregory H.

• Intestinal epithelium
• Stem cells
• Proliferation
• Nutrient
• Obesity

Statement dc:rights

• Copyright 2018 Weinan Zhou

Language dc:language

en

Handle dc:identifier

http://hdl.handle.net/2142/101659

OAI record oai:identifier

https://www.ideals.illinois.edu/oai-pmh?verb=GetRecord&metadataPrefix=etdms&identifier=oai%3Awww.ideals.illinois.edu%3A2142%2F101659