Diet-induced alteration of intestinal stem cell function underlies obesity and prediabetes in mice.
Journal
Nature metabolism
ISSN: 2522-5812
Titre abrégé: Nat Metab
Pays: Germany
ID NLM: 101736592
Informations de publication
Date de publication:
09 2021
09 2021
Historique:
received:
27
03
2020
accepted:
13
08
2021
entrez:
23
9
2021
pubmed:
24
9
2021
medline:
15
12
2021
Statut:
ppublish
Résumé
Excess nutrient uptake and altered hormone secretion in the gut contribute to a systemic energy imbalance, which causes obesity and an increased risk of type 2 diabetes and colorectal cancer. This functional maladaptation is thought to emerge at the level of the intestinal stem cells (ISCs). However, it is not clear how an obesogenic diet affects ISC identity and fate. Here we show that an obesogenic diet induces ISC and progenitor hyperproliferation, enhances ISC differentiation and cell turnover and changes the regional identities of ISCs and enterocytes in mice. Single-cell resolution of the enteroendocrine lineage reveals an increase in progenitors and peptidergic enteroendocrine cell types and a decrease in serotonergic enteroendocrine cell types. Mechanistically, we link increased fatty acid synthesis, Ppar signaling and the Insr-Igf1r-Akt pathway to mucosal changes. This study describes molecular mechanisms of diet-induced intestinal maladaptation that promote obesity and therefore underlie the pathogenesis of the metabolic syndrome and associated complications.
Identifiants
pubmed: 34552271
doi: 10.1038/s42255-021-00458-9
pii: 10.1038/s42255-021-00458-9
pmc: PMC8458097
doi:
Substances chimiques
Fatty Acids
0
Peroxisome Proliferator-Activated Receptors
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1202-1216Informations de copyright
© 2021. The Author(s).
Références
Schauer, P. R. et al. Bariatric surgery versus intensive medical therapy in obese patients with diabetes. N. Engl. J. Med. 366, 1567–1576 (2012).
pubmed: 22449319
pmcid: 3372918
doi: 10.1056/NEJMoa1200225
Evers, S. S., Sandoval, D. A. & Seeley, R. J. The physiology and molecular underpinnings of the effects of bariatric surgery on obesity and diabetes. Annu. Rev. Physiol. 79, 313–334 (2017).
pubmed: 27912678
doi: 10.1146/annurev-physiol-022516-034423
Drucker, D. J. Mechanisms of action and therapeutic application of glucagon-like peptide-1. Cell Metab. 27, 740–756 (2018).
pubmed: 29617641
doi: 10.1016/j.cmet.2018.03.001
Gribble, F. M. & Reimann, F. Function and mechanisms of enteroendocrine cells and gut hormones in metabolism. Nat. Rev. Endocrinol. 15, 226–237 (2019).
pubmed: 30760847
doi: 10.1038/s41574-019-0168-8
Yilmaz, Ö. H. et al. MTORC1 in the Paneth cell niche couples intestinal stem-cell function to calorie intake. Nature 486, 490–495 (2012).
pubmed: 22722868
pmcid: 3387287
doi: 10.1038/nature11163
Beyaz, S. et al. High-fat diet enhances stemness and tumorigenicity of intestinal progenitors. Nature 531, 53–58 (2016).
pubmed: 26935695
pmcid: 4846772
doi: 10.1038/nature17173
Mihaylova, M. M. et al. Fasting activates fatty acid oxidation to enhance intestinal stem cell function during homeostasis and aging. Cell Stem Cell 22, 769–778 (2018).
pubmed: 29727683
pmcid: 5940005
doi: 10.1016/j.stem.2018.04.001
Le Gall, M. et al. Intestinal plasticity in response to nutrition and gastrointestinal surgery. Nutr. Rev. 77, 129–143 (2019).
pubmed: 30517714
doi: 10.1093/nutrit/nuy064
Lean, M. E. J. & Malkova, D. Altered gut and adipose tissue hormones in overweight and obese individuals: cause or consequence. Int. J. Obes. 40, 622–632 (2016).
doi: 10.1038/ijo.2015.220
Dailey, M. J. Nutrient-induced intestinal adaption and its effect in obesity. Physiol. Behav. 136, 74–78 (2014).
pubmed: 24704111
doi: 10.1016/j.physbeh.2014.03.026
Verdam, F. J. et al. Small intestinal alterations in severely obese hyperglycemic subjects. J. Clin. Endocrinol. Metab. 96, E379–E383 (2011).
pubmed: 21084402
doi: 10.1210/jc.2010-1333
Gehart, H. & Clevers, H. Tales from the crypt: new insights into intestinal stem cells. Nat. Rev. Gastroenterol. Hepatol. 16, 19–34 (2019).
pubmed: 30429586
doi: 10.1038/s41575-018-0081-y
Clevers, H. & Watt, F. M. Defining adult stem cells by function, not by phenotype. Annu. Rev. Biochem. 87, 1015–1027 (2018).
pubmed: 29494240
doi: 10.1146/annurev-biochem-062917-012341
Petit, V. et al. Chronic high-fat diet affects intestinal fat absorption and postprandial triglyceride levels in the mouse. J. Lipid Res. 48, 278–287 (2007).
pubmed: 17114807
doi: 10.1194/jlr.M600283-JLR200
Beuling, E. et al. GATA factors regulate proliferation, differentiation, and gene expression in small intestine of mature mice. Gastroenterology 140, 1219–1229 (2011).
pubmed: 21262227
doi: 10.1053/j.gastro.2011.01.033
Aronson, B. E., Stapleton, K. A. & Krasinski, S. D. Role of GATA factors in development, differentiation, and homeostasis of the small intestinal epithelium. Am. J. Physiol. Gastrointest. Liver Physiol. 306, G474–G490 (2014).
pubmed: 24436352
pmcid: 3949026
doi: 10.1152/ajpgi.00119.2013
Haber, A. L. et al. A single-cell survey of the small intestinal epithelium. Nature 551, 333–339 (2017).
pubmed: 29144463
pmcid: 6022292
doi: 10.1038/nature24489
Moor, A. E. et al. Spatial reconstruction of single enterocytes uncovers broad zonation along the intestinal villus axis. Cell 175, 1156–1167 (2018).
pubmed: 30270040
doi: 10.1016/j.cell.2018.08.063
Beumer, J. et al. Enteroendocrine cells switch hormone expression along the crypt-to-villus BMP signalling gradient. Nat. Cell Biol. 20, 909–916 (2018).
pubmed: 30038251
pmcid: 6276989
doi: 10.1038/s41556-018-0143-y
Kraiczy, J. et al. DNA methylation defines regional identity of human intestinal epithelial organoids and undergoes dynamic changes during development. Gut 68, 49–61 (2019).
pubmed: 29141958
doi: 10.1136/gutjnl-2017-314817
Middendorp, S. et al. Adult stem cells in the small intestine are intrinsically programmed with their location-specific function. Stem Cells 32, 1083–1091 (2014).
pubmed: 24496776
doi: 10.1002/stem.1655
Burtscher, I., Barkey, W. & Lickert, H. Foxa2-venus fusion reporter mouse line allows live-cell analysis of endoderm-derived organ formation. Genesis 51, 596–604 (2013).
pubmed: 23712942
doi: 10.1002/dvg.22404
Wolf, F. A. et al. PAGA: graph abstraction reconciles clustering with trajectory inference through a topology preserving map of single cells. Genome Biol. 20, 59 (2019).
pubmed: 30890159
pmcid: 6425583
doi: 10.1186/s13059-019-1663-x
Muzumdar, M. D., Tasic, B., Miyamichi, K., Li, N. & Luo, L. A global double-fluorescent cre reporter mouse. Genesis 45, 593–605 (2007).
pubmed: 17868096
doi: 10.1002/dvg.20335
Imuta, Y., Kiyonari, H., Jang, C. W., Behringer, R. R. & Sasaki, H. Generation of knock-in mice that express nuclear enhanced green fluorescent protein and tamoxifen-inducible Cre recombinase in the notochord from Foxa2 and T loci. Genesis 51, 210–218 (2013).
pubmed: 23359409
pmcid: 3632256
doi: 10.1002/dvg.22376
Parker, H. E., Gribble, F. M. & Reimann, F. The role of gut endocrine cells in control of metabolism and appetite. Exp. Physiol. 99, 1116–1120 (2014).
pubmed: 25210110
pmcid: 4405037
doi: 10.1113/expphysiol.2014.079764
Clemmensen, C. et al. Gut–brain cross-talk in metabolic control. Cell 168, 758–774 (2017).
pubmed: 28235194
pmcid: 5839146
doi: 10.1016/j.cell.2017.01.025
Gehart, H. et al. Identification of enteroendocrine regulators by real-time single-cell differentiation mapping. Cell 176, 1158–1173 (2019).
pubmed: 30712869
doi: 10.1016/j.cell.2018.12.029
Buczacki, S. J. A. et al. Intestinal label-retaining cells are secretory precursors expressing lgr5. Nature 495, 65–69 (2013).
pubmed: 23446353
doi: 10.1038/nature11965
La Manno, G. et al. RNA velocity of single cells. Nature 560, 494–498 (2018).
pubmed: 30089906
pmcid: 6130801
doi: 10.1038/s41586-018-0414-6
Piccand, J. et al. Rfx6 promotes the differentiation of peptide-secreting enteroendocrine cells while repressing genetic programs controlling serotonin production. Mol. Metab. 29, 24–39 (2019).
pubmed: 31668390
pmcid: 6728766
doi: 10.1016/j.molmet.2019.08.007
Martin, A. M. et al. The diverse metabolic roles of peripheral serotonin. Endocrinology 158, 1049–1063 (2017).
pubmed: 28323941
doi: 10.1210/en.2016-1839
Barker, N. et al. Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature 449, 1003–1007 (2007).
pubmed: 17934449
doi: 10.1038/nature06196
Chandel, N. S., Jasper, H., Ho, T. T. & Passegué, E. Metabolic regulation of stem cell function in tissue homeostasis and organismal ageing. Nat. Cell Biol. 18, 823–832 (2016).
pubmed: 27428307
doi: 10.1038/ncb3385
Ito, K., Bonora, M. & Ito, K. Metabolism as master of hematopoietic stem cell fate. Int. J. Hematol. 109, 18–27 (2019).
pubmed: 30219988
doi: 10.1007/s12185-018-2534-z
Dahly, E. M., Guo, Z. & Ney, D. M. Alterations in enterocyte proliferation and apoptosis accompany TPN-induced mucosal hypoplasia and IGF-I-induced hyperplasia in rats. J. Nutr. 132, 2010–2014 (2002).
pubmed: 12097684
doi: 10.1093/jn/132.7.2010
Mah, A. T. et al. Impact of diet-induced obesity on intestinal stem cells: hyperproliferation but impaired intrinsic function that requires insulin/IGF1. Endocrinology 155, 3302–3314 (2014).
pubmed: 24914941
pmcid: 4138564
doi: 10.1210/en.2014-1112
Mao, J. et al. Overnutrition stimulates intestinal epithelium proliferation through β-catenin signaling in obese mice. Diabetes 62, 3736–3746 (2013).
pubmed: 23884889
pmcid: 3806619
doi: 10.2337/db13-0035
Patel, P. & Woodgett, J. R. Glycogen synthase kinase 3: a kinase for all pathways? Curr. Top. Dev. Biol. 123, 277–302 (2017).
pubmed: 28236969
doi: 10.1016/bs.ctdb.2016.11.011
Fevr, T., Robine, S., Louvard, D. & Huelsken, J. Wnt/-catenin is essential for intestinal homeostasis and maintenance of intestinal stem cells. Mol. Cell. Biol. 27, 7551–7559 (2007).
pubmed: 17785439
pmcid: 2169070
doi: 10.1128/MCB.01034-07
Pinto, D., Gregorieff, A., Begthel, H. & Clevers, H. Canonical Wnt signals are essential for homeostasis of the intestinal epithelium. Genes Dev. 17, 1709–1713 (2003).
pubmed: 12865297
pmcid: 196179
doi: 10.1101/gad.267103
Aichler, M. et al. N-acyl taurines and acylcarnitines cause an imbalance in insulin synthesis and secretion provoking β cell dysfunction in type 2 diabetes. Cell Metab. 25, 1334–1347 (2017).
pubmed: 28591636
doi: 10.1016/j.cmet.2017.04.012
Shao, W. & Espenshade, P. J. Expanding roles for SREBP in metabolism. Cell Metab. 16, 414–419 (2012).
pubmed: 23000402
pmcid: 3466394
doi: 10.1016/j.cmet.2012.09.002
Mihaylova, M. M., Sabatini, D. M. & Yilmaz, Ö. H. Dietary and metabolic control of stem cell function in physiology and cancer. Cell Stem Cell 14, 292–305 (2014).
pubmed: 24607404
pmcid: 3992244
doi: 10.1016/j.stem.2014.02.008
Gao, Y. et al. LKB1 represses ATOH1 via PDK4 and energy metabolism and regulates intestinal stem cell fate. Gastroenterology 158, 1389–1401 (2020).
pubmed: 31930988
doi: 10.1053/j.gastro.2019.12.033
Kinzler, K. W. & Vogelstein, B. Lessons from hereditary colorectal cancer. Cell 87, 159–170 (1996).
pubmed: 8861899
doi: 10.1016/S0092-8674(00)81333-1
Nusse, R. & Clevers, H. Wnt/β-Catenin signaling, disease, and emerging therapeutic modalities. Cell 169, 985–999 (2017).
doi: 10.1016/j.cell.2017.05.016
pubmed: 28575679
Postic, C. & Girard, J. Contribution of de novo fatty acid synthesis to hepatic steatosis and insulin resistance: lessons from genetically engineered mice. J. Clin. Investig. 118, 829–838 (2008).
pubmed: 18317565
pmcid: 2254980
doi: 10.1172/JCI34275
Ipsen, D. H., Lykkesfeldt, J. & Tveden-Nyborg, P. Molecular mechanisms of hepatic lipid accumulation in non-alcoholic fatty liver disease. Cell. Mol. Life Sci. 75, 3313–3327 (2018).
pubmed: 29936596
pmcid: 6105174
doi: 10.1007/s00018-018-2860-6
Kawano, Y. & Cohen, D. E. Mechanisms of hepatic triglyceride accumulation in non-alcoholic fatty liver disease. J. Gastroenterol. 48, 434–441 (2013).
pubmed: 23397118
pmcid: 3633701
doi: 10.1007/s00535-013-0758-5
Namkung, J., Kim, H. & Park, S. Peripheral serotonin: a new player in systemic energy homeostasis. Molecules Cells 38, 1023–1028 (2015).
pubmed: 26628041
pmcid: 4696992
doi: 10.14348/molcells.2015.0258
Watanabe, H. et al. Serotonin improves high fat diet induced obesity in mice. PLoS ONE 11, e0147143 (2016).
pubmed: 26766570
pmcid: 4713156
doi: 10.1371/journal.pone.0147143
Poher, A. L., Tschöp, M. H. & Müller, T. D. Ghrelin regulation of glucose metabolism. Peptides 100, 236–242 (2018).
pubmed: 29412824
pmcid: 5805851
doi: 10.1016/j.peptides.2017.12.015
Tschöp, M. et al. Circulating ghrelin levels are decreased in human obesity. Diabetes 50, 707–709 (2001).
pubmed: 11289032
doi: 10.2337/diabetes.50.4.707
Papaetis, G. S. Incretin-based therapies in prediabetes: current evidence and future perspectives. World J. Diabetes 5, 817–834 (2014).
pubmed: 25512784
pmcid: 4265868
doi: 10.4239/wjd.v5.i6.817
Matthews, D. R. et al. Homeostasis model assessment: insulin resistance and β-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 28, 412–419 (1985).
pubmed: 3899825
doi: 10.1007/BF00280883
Nakajima, S., Hira, T. & Hara, H. Postprandial glucagon-like peptide-1 secretion is increased during the progression of glucose intolerance and obesity in high-fat/high-sucrose diet-fed rats. Br. J. Nutr. https://doi.org/10.1017/S0007114515000550 (2015).
Chambers, A. P. et al. Weight-independent changes in blood glucose homeostasis after gastric bypass or vertical sleeve gastrectomy in rats. Gastroenterology 141, 950–958 (2011).
pubmed: 21699789
doi: 10.1053/j.gastro.2011.05.050
Panaro, B. L. et al. Intestine-selective reduction of Gcg expression reveals the importance of the distal gut for GLP-1 secretion. Mol. Metab. 37, 100990 (2020).
pubmed: 32278655
pmcid: 7200938
doi: 10.1016/j.molmet.2020.100990
Andersson-Rolf, A., Fink, J., Mustata, R. C. & Koo, B. K. A video protocol of retroviral infection in primary intestinal Organoid culture. J. Vis. Exp. https://doi.org/10.3791/51765 (2014).
R Development Core Team, R. Lecture Notes in Physics, R: A Language and Environment for Statistical Computing. R Foundation for Statistical Computing https://doi.org/10.1007/978-3-540-74686-7 (2011).
Rainer, J., Sanchez-Cabo, F., Stocker, G., Sturn, A. & Trajanoski, Z. CARMAweb: Comprehensive R- and bioconductor-based web service for microarray data analysis. Nucleic Acids Res. 34, W498–W503 (2006).
pubmed: 16845058
pmcid: 1538903
doi: 10.1093/nar/gkl038
Mantini, D. et al. LIMPIC: a computational method for the separation of protein MALDI-TOF-MS signals from noise. BMC Bioinforma. 8, 101 (2007).
doi: 10.1186/1471-2105-8-101