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Small intestine and colon crypts differ in impact of obesity, hyperinsulinemia and insulin‐like growth factor 1 receptor (IGF1R) loss on DNA damage‐induced apoptosis
Author(s) -
Santoro Maria Agostina,
Blue R Eric,
Van Landeghem Laurianne,
McNaughton Kirk K,
Lund P Kay
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.834.11
Subject(s) - hyperinsulinemia , medicine , apoptosis , endocrinology , insulin like growth factor 1 receptor , small intestine , insulin , hyperinsulinism , crypt , insulin like growth factor , biology , insulin resistance , growth factor , receptor , biochemistry
Colorectal adenoma risk is linked to obesity, hyperinsulinemia and reduced apoptosis of normal colonocytes. We hypothesized that diet‐induced obesity (DIO)/hyperinsulinemia decreases apoptosis of genetically‐damaged intestinal stem cells (ISC) via IGF1R activation. Mice with villin‐cre mediated deletion of IGF1R in the intestinal epithelium and littermate controls with intact IGF1R were fed high fat diet (HFD) or low fat (LF) standard chow for 18 weeks, given 5 Gy abdominal radiation to induce DNA damage and euthanized 4 hours later, at the peak of apoptosis. HFD led to obesity, glucose intolerance and hyperinsulinemia, but no change in plasma IGF1. In small intestine of LF mice, IGF1R loss increased radiation‐induced apoptosis in the ISC zone. DIO also increased apoptosis in small intestine, but IGF1R loss had no additional effects. In colon, apoptosis was decreased in DIO group but unaffected by IGF1R loss. Plasma insulin levels significantly correlated with apoptosis in both small intestine and colon. Our studies provide novel evidence for region‐specific effects of DIO/hyperinsulinemia on apoptosis induced by DNA damage in small intestine vs . colon. DIO‐associated increases in apoptosis in small intestine are relevant to DIO‐associated intestinal dysfunction. DIO‐associated decreases in apoptosis of genetically damaged colonocytes may predispose to tumor initiation. Funding: NIH DK040247 ‐19