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Impact of Diet-Induced Obesity on Intestinal Stem Cells: Hyperproliferation but Impaired Intrinsic Function That Requires Insulin/IGF1
Nutrient intake regulates intestinal epithelial mass and crypt proliferation. Recent findings in model organisms and rodents indicate nutrient restriction impacts intestinal stem cells (ISC). Little is known about the impact of diet-induced obesity (DIO), a model of excess nutrient intake on ISC. We...
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Published in: | Endocrinology (Philadelphia) 2014-09, Vol.155 (9), p.3302-3314 |
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description | Nutrient intake regulates intestinal epithelial mass and crypt proliferation. Recent findings in model organisms and rodents indicate nutrient restriction impacts intestinal stem cells (ISC). Little is known about the impact of diet-induced obesity (DIO), a model of excess nutrient intake on ISC. We used a Sox9-EGFP reporter mouse to test the hypothesis that an adaptive response to DIO or associated hyperinsulinemia involves expansion and hyperproliferation of ISC. The Sox9-EGFP reporter mouse allows study and isolation of ISC, progenitors, and differentiated lineages based on different Sox9-EGFP expression levels. Sox9-EGFP mice were fed a high-fat diet for 20 weeks to induce DIO and compared with littermates fed low-fat rodent chow. Histology, fluorescence activated cell sorting, and mRNA analyses measured impact of DIO on jejunal crypt-villus morphometry, numbers, and proliferation of different Sox9-EGFP cell populations and gene expression. An in vitro culture assay directly assessed functional capacity of isolated ISC. DIO mice exhibited significant increases in body weight, plasma glucose, insulin, and insulin-like growth factor 1 (IGF1) levels and intestinal Igf1 mRNA. DIO mice had increased villus height and crypt density but decreased intestinal length and decreased numbers of Paneth and goblet cells. In vivo, DIO resulted in a selective expansion of Sox9-EGFPLow ISC and percentage of ISC in S-phase. ISC expansion significantly correlated with plasma insulin levels. In vitro, isolated ISC from DIO mice formed fewer enteroids in standard 3D Matrigel culture compared to controls, indicating impaired ISC function. This decreased enteroid formation in isolated ISC from DIO mice was rescued by exogenous insulin, IGF1, or both. We conclude that DIO induces specific increases in ISC and ISC hyperproliferation in vivo. However, isolated ISC from DIO mice have impaired intrinsic survival and growth in vitro that can be rescued by exogenous insulin or IGF1. |
doi_str_mv | 10.1210/en.2014-1112 |
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Kay</creator><creatorcontrib>Mah, Amanda T ; Van Landeghem, Laurianne ; Gavin, Hannah E ; Magness, Scott T ; Lund, P. Kay</creatorcontrib><description>Nutrient intake regulates intestinal epithelial mass and crypt proliferation. Recent findings in model organisms and rodents indicate nutrient restriction impacts intestinal stem cells (ISC). Little is known about the impact of diet-induced obesity (DIO), a model of excess nutrient intake on ISC. We used a Sox9-EGFP reporter mouse to test the hypothesis that an adaptive response to DIO or associated hyperinsulinemia involves expansion and hyperproliferation of ISC. The Sox9-EGFP reporter mouse allows study and isolation of ISC, progenitors, and differentiated lineages based on different Sox9-EGFP expression levels. Sox9-EGFP mice were fed a high-fat diet for 20 weeks to induce DIO and compared with littermates fed low-fat rodent chow. Histology, fluorescence activated cell sorting, and mRNA analyses measured impact of DIO on jejunal crypt-villus morphometry, numbers, and proliferation of different Sox9-EGFP cell populations and gene expression. An in vitro culture assay directly assessed functional capacity of isolated ISC. DIO mice exhibited significant increases in body weight, plasma glucose, insulin, and insulin-like growth factor 1 (IGF1) levels and intestinal Igf1 mRNA. DIO mice had increased villus height and crypt density but decreased intestinal length and decreased numbers of Paneth and goblet cells. In vivo, DIO resulted in a selective expansion of Sox9-EGFPLow ISC and percentage of ISC in S-phase. ISC expansion significantly correlated with plasma insulin levels. In vitro, isolated ISC from DIO mice formed fewer enteroids in standard 3D Matrigel culture compared to controls, indicating impaired ISC function. This decreased enteroid formation in isolated ISC from DIO mice was rescued by exogenous insulin, IGF1, or both. We conclude that DIO induces specific increases in ISC and ISC hyperproliferation in vivo. However, isolated ISC from DIO mice have impaired intrinsic survival and growth in vitro that can be rescued by exogenous insulin or IGF1.</description><identifier>ISSN: 0013-7227</identifier><identifier>EISSN: 1945-7170</identifier><identifier>DOI: 10.1210/en.2014-1112</identifier><identifier>PMID: 24914941</identifier><language>eng</language><publisher>United States: Endocrine Society</publisher><subject>Animals ; Body weight ; Cell culture ; Cell Proliferation ; Crypts ; Diabetes-Insulin-Glucagon-Gastrointestinal ; Diet ; Diet, High-Fat - adverse effects ; Dietary restrictions ; Female ; Flow cytometry ; Food intake ; Gene expression ; Goblet cells ; Growth factors ; High fat diet ; Histology ; Humans ; Hyperinsulinemia ; Impact analysis ; In vivo methods and tests ; Insulin ; Insulin - metabolism ; Insulin-like growth factor I ; Insulin-Like Growth Factor I - metabolism ; Intestine ; Intestines - cytology ; Intestines - metabolism ; Low fat diet ; Male ; Mice ; Mice, Transgenic ; Morphometry ; Nutrient deficiency ; Nutrients ; Obesity ; Obesity - genetics ; Obesity - metabolism ; Obesity - physiopathology ; Quorum sensing ; Rodents ; Signal Transduction ; Sox9 protein ; Stem cells ; Stem Cells - cytology ; Stem Cells - metabolism ; Villus</subject><ispartof>Endocrinology (Philadelphia), 2014-09, Vol.155 (9), p.3302-3314</ispartof><rights>Copyright © 2014 by the Endocrine Society</rights><rights>Copyright © 2014 by the Endocrine Society 2014</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c488t-d3ba7332ace212abca28a565fa5d08906eaf707124867604cf92ed4a819c1bea3</citedby><cites>FETCH-LOGICAL-c488t-d3ba7332ace212abca28a565fa5d08906eaf707124867604cf92ed4a819c1bea3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24914941$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Mah, Amanda T</creatorcontrib><creatorcontrib>Van Landeghem, Laurianne</creatorcontrib><creatorcontrib>Gavin, Hannah E</creatorcontrib><creatorcontrib>Magness, Scott T</creatorcontrib><creatorcontrib>Lund, P. Kay</creatorcontrib><title>Impact of Diet-Induced Obesity on Intestinal Stem Cells: Hyperproliferation but Impaired Intrinsic Function That Requires Insulin/IGF1</title><title>Endocrinology (Philadelphia)</title><addtitle>Endocrinology</addtitle><description>Nutrient intake regulates intestinal epithelial mass and crypt proliferation. Recent findings in model organisms and rodents indicate nutrient restriction impacts intestinal stem cells (ISC). Little is known about the impact of diet-induced obesity (DIO), a model of excess nutrient intake on ISC. We used a Sox9-EGFP reporter mouse to test the hypothesis that an adaptive response to DIO or associated hyperinsulinemia involves expansion and hyperproliferation of ISC. The Sox9-EGFP reporter mouse allows study and isolation of ISC, progenitors, and differentiated lineages based on different Sox9-EGFP expression levels. Sox9-EGFP mice were fed a high-fat diet for 20 weeks to induce DIO and compared with littermates fed low-fat rodent chow. Histology, fluorescence activated cell sorting, and mRNA analyses measured impact of DIO on jejunal crypt-villus morphometry, numbers, and proliferation of different Sox9-EGFP cell populations and gene expression. An in vitro culture assay directly assessed functional capacity of isolated ISC. DIO mice exhibited significant increases in body weight, plasma glucose, insulin, and insulin-like growth factor 1 (IGF1) levels and intestinal Igf1 mRNA. DIO mice had increased villus height and crypt density but decreased intestinal length and decreased numbers of Paneth and goblet cells. In vivo, DIO resulted in a selective expansion of Sox9-EGFPLow ISC and percentage of ISC in S-phase. ISC expansion significantly correlated with plasma insulin levels. In vitro, isolated ISC from DIO mice formed fewer enteroids in standard 3D Matrigel culture compared to controls, indicating impaired ISC function. This decreased enteroid formation in isolated ISC from DIO mice was rescued by exogenous insulin, IGF1, or both. We conclude that DIO induces specific increases in ISC and ISC hyperproliferation in vivo. However, isolated ISC from DIO mice have impaired intrinsic survival and growth in vitro that can be rescued by exogenous insulin or IGF1.</description><subject>Animals</subject><subject>Body weight</subject><subject>Cell culture</subject><subject>Cell Proliferation</subject><subject>Crypts</subject><subject>Diabetes-Insulin-Glucagon-Gastrointestinal</subject><subject>Diet</subject><subject>Diet, High-Fat - adverse effects</subject><subject>Dietary restrictions</subject><subject>Female</subject><subject>Flow cytometry</subject><subject>Food intake</subject><subject>Gene expression</subject><subject>Goblet cells</subject><subject>Growth factors</subject><subject>High fat diet</subject><subject>Histology</subject><subject>Humans</subject><subject>Hyperinsulinemia</subject><subject>Impact analysis</subject><subject>In vivo methods and tests</subject><subject>Insulin</subject><subject>Insulin - metabolism</subject><subject>Insulin-like growth factor I</subject><subject>Insulin-Like Growth Factor I - metabolism</subject><subject>Intestine</subject><subject>Intestines - cytology</subject><subject>Intestines - metabolism</subject><subject>Low fat diet</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Transgenic</subject><subject>Morphometry</subject><subject>Nutrient deficiency</subject><subject>Nutrients</subject><subject>Obesity</subject><subject>Obesity - genetics</subject><subject>Obesity - metabolism</subject><subject>Obesity - physiopathology</subject><subject>Quorum sensing</subject><subject>Rodents</subject><subject>Signal Transduction</subject><subject>Sox9 protein</subject><subject>Stem cells</subject><subject>Stem Cells - cytology</subject><subject>Stem Cells - metabolism</subject><subject>Villus</subject><issn>0013-7227</issn><issn>1945-7170</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><recordid>eNp1kU1rFTEUhoMo9lrduZaAC104bU4m89WFIFdvO1AoaF2HTOaMTZmbTJOJcP-Av9uM91o_0FUI58nDm_MS8hzYCXBgp2hPOAORAQB_QFbQiCKroGIPyYoxyLOK8-qIPAnhNl2FEPljcsRFA6IRsCLf2u2k9EzdQN8bnLPW9lFjT686DGbeUWdpa2cMs7FqpJ9m3NI1jmM4oxe7Cf3k3WgG9Go2ieziTBef8cmQnnljg9F0E63-Mb--UTP9iHcxASEBIY7GnrbnG3hKHg1qDPjscB6Tz5sP1-uL7PLqvF2_u8y0qOs56_NOVXnOlUYOXHVa8VoVZTGoomd1w0pUQ8Uq4KIuq5IJPTQce6FqaDR0qPJj8nbvnWK3xV5jCqlGOXmzVX4nnTLyz4k1N_KL-yoF5HVRiiR4fRB4dxfTXuTWBJ02oiy6GCQURclrUXCe0Jd_obcu-rTGIHPIl5RMFIl6s6e0dyF4HO7DAJNLwRKtXAqWS8EJf_H7B-7hn40m4NUecHH6nyo7qPI9ibZ3OnWFU6ol_Er5zwDfAfb6v64</recordid><startdate>20140901</startdate><enddate>20140901</enddate><creator>Mah, Amanda T</creator><creator>Van Landeghem, Laurianne</creator><creator>Gavin, Hannah E</creator><creator>Magness, Scott T</creator><creator>Lund, P. 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Kay</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Impact of Diet-Induced Obesity on Intestinal Stem Cells: Hyperproliferation but Impaired Intrinsic Function That Requires Insulin/IGF1</atitle><jtitle>Endocrinology (Philadelphia)</jtitle><addtitle>Endocrinology</addtitle><date>2014-09-01</date><risdate>2014</risdate><volume>155</volume><issue>9</issue><spage>3302</spage><epage>3314</epage><pages>3302-3314</pages><issn>0013-7227</issn><eissn>1945-7170</eissn><abstract>Nutrient intake regulates intestinal epithelial mass and crypt proliferation. Recent findings in model organisms and rodents indicate nutrient restriction impacts intestinal stem cells (ISC). Little is known about the impact of diet-induced obesity (DIO), a model of excess nutrient intake on ISC. We used a Sox9-EGFP reporter mouse to test the hypothesis that an adaptive response to DIO or associated hyperinsulinemia involves expansion and hyperproliferation of ISC. The Sox9-EGFP reporter mouse allows study and isolation of ISC, progenitors, and differentiated lineages based on different Sox9-EGFP expression levels. Sox9-EGFP mice were fed a high-fat diet for 20 weeks to induce DIO and compared with littermates fed low-fat rodent chow. Histology, fluorescence activated cell sorting, and mRNA analyses measured impact of DIO on jejunal crypt-villus morphometry, numbers, and proliferation of different Sox9-EGFP cell populations and gene expression. An in vitro culture assay directly assessed functional capacity of isolated ISC. DIO mice exhibited significant increases in body weight, plasma glucose, insulin, and insulin-like growth factor 1 (IGF1) levels and intestinal Igf1 mRNA. DIO mice had increased villus height and crypt density but decreased intestinal length and decreased numbers of Paneth and goblet cells. In vivo, DIO resulted in a selective expansion of Sox9-EGFPLow ISC and percentage of ISC in S-phase. ISC expansion significantly correlated with plasma insulin levels. In vitro, isolated ISC from DIO mice formed fewer enteroids in standard 3D Matrigel culture compared to controls, indicating impaired ISC function. This decreased enteroid formation in isolated ISC from DIO mice was rescued by exogenous insulin, IGF1, or both. We conclude that DIO induces specific increases in ISC and ISC hyperproliferation in vivo. However, isolated ISC from DIO mice have impaired intrinsic survival and growth in vitro that can be rescued by exogenous insulin or IGF1.</abstract><cop>United States</cop><pub>Endocrine Society</pub><pmid>24914941</pmid><doi>10.1210/en.2014-1112</doi><tpages>13</tpages><oa>free_for_read</oa></addata></record> |
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subjects | Animals Body weight Cell culture Cell Proliferation Crypts Diabetes-Insulin-Glucagon-Gastrointestinal Diet Diet, High-Fat - adverse effects Dietary restrictions Female Flow cytometry Food intake Gene expression Goblet cells Growth factors High fat diet Histology Humans Hyperinsulinemia Impact analysis In vivo methods and tests Insulin Insulin - metabolism Insulin-like growth factor I Insulin-Like Growth Factor I - metabolism Intestine Intestines - cytology Intestines - metabolism Low fat diet Male Mice Mice, Transgenic Morphometry Nutrient deficiency Nutrients Obesity Obesity - genetics Obesity - metabolism Obesity - physiopathology Quorum sensing Rodents Signal Transduction Sox9 protein Stem cells Stem Cells - cytology Stem Cells - metabolism Villus |
title | Impact of Diet-Induced Obesity on Intestinal Stem Cells: Hyperproliferation but Impaired Intrinsic Function That Requires Insulin/IGF1 |
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