Functional Impact of Obesity or Intermittent Feeding on Intestinal Stem Cells Public Deposited

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  • March 19, 2019
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  • Mah, Amanda
    • Affiliation: Gillings School of Global Public Health, Department of Nutrition
Abstract
  • Intestinal stem cells (ISCs) and progenitors constantly renew the intestinal epithelium. Effects of obesity or intermittent feeding specifically on ISCs versus progenitors are not defined. This dissertation used Sox9-EGFP reporter mice to test the hypothesis that obesity or intermittent feeding affects proliferation, numbers or intrinsic function of ISCs. Sox9-EGFP mice permit specific evaluation of ISCs or progenitors by histology or flow cytometry and intrinsic function in culture. High fat diet feeding induced obesity and hyperinsulinemia. ISC numbers and proliferation were selectively increased in obese mice. However, ISCs from obese mice exhibited impaired intrinsic function based on reduced ability to survive and generate enteroids in vitro. Excess insulin or IGF1 corrected this in vitro defect indicating that ISCs from obese mice develop acquired dependence on elevated insulin or IGF1 for survival or proliferation. Sox9-EGFP mice were subjected to 20 weeks of an intermittent fasting regimen involving alternating days of ad libitum access to food or fasting (ADF). ADF reportedly produces similar benefits to metabolism or health as calorie restriction. Total food intake and activity did not differ between ADF and ad libitum fed controls. Despite this, ADF mice did not gain body weight and displayed significantly lower fat mass and fasting plasma triglycerides. ADF did not alter ISC number, but affected numbers of intestinal progenitors. After a fast cycle, ADF animals displayed increased progenitors but decreased proliferation, relative to short-term fasted controls. This effect was reversed in ADF animals following a feed cycle suggesting that ADF leads to fasting-induced increases in progenitors that can be rapidly mobilized during feeding. After a fast cycle, ADF animals displayed decreased colonic epithelial cell proliferation associated with increased expression of an anti-proliferative insulin receptor isoform B implicated in protection against colon tumorigenesis. In summary, obesity and hyperinsulinemia promote ISC expansion and hyperproliferation but impaired ISC function, effects that may be relevant to obesity-associated intestinal dysfunction or tumorigenesis. ADF selectively affects small intestinal progenitors and not ISCs, leads to reduced proliferation of colonic epithelium, and promotes an insulin receptor isoform that may decrease cancer risk.
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  • In Copyright
Advisor
  • Makowski, Liza
  • Lund, Pauline Kay
  • Magness, Scott
  • Pomp, Daniel
  • Sethupathy, Praveen
Degree
  • Doctor of Philosophy
Degree granting institution
  • University of North Carolina at Chapel Hill Graduate School
Graduation year
  • 2015
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  • Chapel Hill, NC
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