High-fat diet enhances stemness and tumorigenicity of intestinal progenitors
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE67324 | GEO | 2016/02/16
SECONDARY ACCESSION(S): PRJNA279509
REPOSITORIES: GEO
Similar Datasets
Project description:Little is known about how pro-obesity diets regulate tissue stem and progenitor cell function. Here we find that high fat diet (HFD)-induced obesity augments the numbers and function of Lgr5+ intestinal stem cells (ISCs) of the mammalian intestine. Like HFD, ex vivo treatment of intestinal organoid cultures with palmitic acid (PA), a constituent of the HFD, enhances the self-renewal potential of these organoid bodies. Mechanistically, HFD induces a robust peroxisome proliferator-activated receptor delta (PPAR-delta signature in intestinal stem and progenitor cells and pharmacologic activation of PPAR-delta recapitulates the effects that HFD has on these cells. Interestingly, HFD- and agonist-activated PPAR-delta signaling endows organoid-initiating capacity to non-stem cells and enforced PPAR-delta signaling permits these non-stem cells to form in vivo tumors upon loss of the tumor suppressor Apc. These findings highlight how diet-modulated PPAR-delta activation alters not only the function of intestinal stem and progenitor cells but also their capacity to initiate tumors. mRNA profiles of intestinal stem cells (GFP-Hi) and progenitors (GFP-Low) from WT or HFD fed mice were generated by deep sequencing using HiSeq 2000.
2016-02-16 | E-GEOD-67324 | biostudies-arrayexpress
Project description:Obesity is an established risk factor for cancer in many tissues such as the gastrointestinal tract. In the mammalian intestine, a pro-obesity high fat diet (HFD) promotes tumorigenesis in part by enhancing intestinal stem cell (ISC) numbers, proliferation and function. Although Ppar (Peroxisome proliferator-activated receptor) nuclear receptor activity has been proposed to mediate some of these effects in HFD ISCs, the exact role that different Ppar family members play in this process is unclear. Here, we find that in loss-of-function in vivo models, both Ppar family members alpha and delta contribute to the HFD response in ISCs. Mechanistically, both PPARs do so by robustly inducing a downstream fatty acid oxidation (FAO) metabolic program. Notably, pharmacologic and genetic disruption of CPT1a (the rate limiting enzyme of FAO) blunts the HFD phenotype in ISCs. Furthermore, just as HFD ISCs depend on CPT1a-mediated FAO, inhibition of CPT1a dampens the pro-tumorigenic consequences of a HFD on early tumor incidence and progression in the intestine. These findings demonstrate that inhibition of a HFD activated FAO program creates a therapeutic opportunity to counter the effects of a HFD on ISCs and intestinal tumorigenesis.
2021-06-01 | GSE167996 | GEO
Project description:Obesity is an established risk factor for cancer in many tissues such as the gastrointestinal tract. In the mammalian intestine, a pro-obesity high fat diet (HFD) promotes tumorigenesis in part by enhancing intestinal stem cell (ISC) numbers, proliferation and function. Although Ppar (Peroxisome proliferator-activated receptor) nuclear receptor activity has been proposed to mediate some of these effects in HFD ISCs, the exact role that different Ppar family members play in this process is unclear. Here, we find that in loss-of-function in vivo models, both Ppar family members alpha and delta contribute to the HFD response in ISCs. Mechanistically, both PPARs do so by robustly inducing a downstream fatty acid oxidation (FAO) metabolic program. Notably, pharmacologic and genetic disruption of CPT1a (the rate limiting enzyme of FAO) blunts the HFD phenotype in ISCs. Furthermore, just as HFD ISCs depend on CPT1a-mediated FAO, inhibition of CPT1a dampens the pro-tumorigenic consequences of a HFD on early tumor incidence and progression in the intestine. These findings demonstrate that inhibition of a HFD activated FAO program creates a therapeutic opportunity to counter the effects of a HFD on ISCs and intestinal tumorigenesis.
2021-06-01 | GSE151046 | GEO
Project description:Obesity is an established risk factor for cancer in many tissues such as the gastrointestinal tract. In the mammalian intestine, a pro-obesity high fat diet (HFD) promotes tumorigenesis in part by enhancing intestinal stem cell (ISC) numbers, proliferation and function. Although Ppar (Peroxisome proliferator-activated receptor) nuclear receptor activity has been proposed to mediate some of these effects in HFD ISCs, the exact role that different Ppar family members play in this process is unclear. Here, we find that in loss-of-function in vivo models, both Ppar family members alpha and delta contribute to the HFD response in ISCs. Mechanistically, both PPARs do so by robustly inducing a downstream fatty acid oxidation (FAO) metabolic program. Notably, pharmacologic and genetic disruption of CPT1a (the rate limiting enzyme of FAO) blunts the HFD phenotype in ISCs. Furthermore, just as HFD ISCs depend on CPT1a-mediated FAO, inhibition of CPT1a dampens the pro-tumorigenic consequences of a HFD on early tumor incidence and progression in the intestine. These findings demonstrate that inhibition of a HFD activated FAO program creates a therapeutic opportunity to counter the effects of a HFD on ISCs and intestinal tumorigenesis.
2021-06-01 | GSE151045 | GEO
Project description:Objective Recent evidence indicates that the adult hematopoietic system is susceptible to diet-induced lineage skewing. It is not known whether the developing hematopoietic system is subject to metabolic programming via in utero high fat diet (HFD) exposure, an established mechanism of adult disease in several organ systems. We previously reported substantial losses in offspring liver size with prenatal HFD. As the liver is the main hematopoietic organ in the fetus, we asked whether the developmental expansion of the hematopoietic stem and progenitor cell (HSPC) pool is compromised by prenatal HFD and/or maternal obesity. Methods We used quantitative assays, progenitor colony formation, flow cytometry, transplantation, and gene expression assays with a series of dietary manipulations to test the effects of gestational high fat diet and maternal obesity on the day 14.5 fetal liver hematopoietic system. Results Maternal obesity, particularly when paired with gestational HFD, restricts physiological expansion of fetal HSPCs while promoting the opposing cell fate of differentiation. Importantly, these effects are only partially ameliorated by gestational dietary adjustments for obese dams. Competitive transplantation reveals compromised repopulation and myeloid-biased differentiation of HFD-programmed HSPCs to be a niche-dependent defect, apparent in HFD-conditioned male recipients. Fetal HSPC deficiencies coincide with perturbations in genes regulating metabolism, immune and inflammatory processes, and stress response, along with downregulation of genes critical for hematopoietic stem cell self-renewal and activation of pathways regulating cell migration. Conclusions Our data reveal a previously unrecognized susceptibility to nutritional and metabolic developmental programming in the fetal HSPC compartment, which is a partially reversible and microenvironment-dependent defect perturbing stem and progenitor cell expansion and hematopoietic lineage commitment. Examination of differentially expressed genes between gestational day 15 (+/- 0.5 days) C57BL/6 mouse fetal livers from diet-induced (60% fat diet) obese or control female mice.
2014-10-25 | E-GEOD-62715 | biostudies-arrayexpress
Project description:Excess nutrient uptake and altered hormone secretion in the gut contribute to a systemic energy imbalance causing obesity and increased risk for type 2 diabetes (T2D) and colorectal cancer. This functional maladaptation is thought to emerge at the level of the intestinal stem cells (ISCs). But, how an obesogenic diet affects ISC identity and fate decisions is not well understood. Here, we study the intestinal responses to an obesogenic diet in mice by combining single-cell profiling of more than 27,000 small intestinal crypt cells with genetic lineage labelling and tracing of ISC fate decisions and in situ metabolomics. We find that an obesogenic diet induces ISC and progenitor hyperproliferation, but also enhances ISC differentiation and cell turnover. Furthermore, the regional identity of ISCs and enterocytes is reprogrammed from a distal to a proximal phenotype and enterocyte zonation is altered to adapt cell function to nutrient availability. Single-cell resolution of the enteroendocrine lineage shows an increase in endocrine progenitors and peptidergic enteroendocrine cell (EEC) types and a decrease in serotonergic EEC types. Mechanistically, we can link increased fatty acid synthesis, Ppar signalling and the Insr/Igf1r/Akt pathway to ISC dysfunction, hyperproliferation and impaired endocrine differentiation. In summary, our work describes key molecular mechanisms of diet-induced intestinal maladaptation in mice that promote obesity, and, thus, underlie the pathogenesis of the metabolic syndrome and associated complications.
2021-07-15 | GSE148227 | GEO
Project description:Objective Recent evidence indicates that the adult hematopoietic system is susceptible to diet-induced lineage skewing. It is not known whether the developing hematopoietic system is subject to metabolic programming via in utero high fat diet (HFD) exposure, an established mechanism of adult disease in several organ systems. We previously reported substantial losses in offspring liver size with prenatal HFD. As the liver is the main hematopoietic organ in the fetus, we asked whether the developmental expansion of the hematopoietic stem and progenitor cell (HSPC) pool is compromised by prenatal HFD and/or maternal obesity. Methods We used quantitative assays, progenitor colony formation, flow cytometry, transplantation, and gene expression assays with a series of dietary manipulations to test the effects of gestational high fat diet and maternal obesity on the day 14.5 fetal liver hematopoietic system. Results Maternal obesity, particularly when paired with gestational HFD, restricts physiological expansion of fetal HSPCs while promoting the opposing cell fate of differentiation. Importantly, these effects are only partially ameliorated by gestational dietary adjustments for obese dams. Competitive transplantation reveals compromised repopulation and myeloid-biased differentiation of HFD-programmed HSPCs to be a niche-dependent defect, apparent in HFD-conditioned male recipients. Fetal HSPC deficiencies coincide with perturbations in genes regulating metabolism, immune and inflammatory processes, and stress response, along with downregulation of genes critical for hematopoietic stem cell self-renewal and activation of pathways regulating cell migration. Conclusions Our data reveal a previously unrecognized susceptibility to nutritional and metabolic developmental programming in the fetal HSPC compartment, which is a partially reversible and microenvironment-dependent defect perturbing stem and progenitor cell expansion and hematopoietic lineage commitment.
2014-10-25 | GSE62715 | GEO
Project description:Carotenoids are naturally occurring pigments in plants responsible for the orange, yellow, and red color of fruits and vegetables. Carrots are one of the primary dietary sources of carotenoids. The biological activities of carotenoids in higher organisms are well documented in most tissues but not the large intestine. The gastrointestinal barrier acts as a line of defense against the systemic invasion of pathogenic bacteria, especially at the colonic level. Proteins involved in tight junction assembly between epithelial cells and mucus secretion from goblet cells are essential for maintaining intestinal barrier homeostasis. A high-fat diet can cause gut impairment by inducing barrier permeability, leading to low-grade chronic inflammation via metabolic endotoxemia. Our hypothesis for this study is that the dietary intake of carotenoid-rich foods can alleviate obesity-associated gut inflammation and strengthen the intestinal barrier function. Male C57BL/6J mice were randomized to one of four experimental diets for 20 weeks (n = 20 animals/group): Low-fat diet (LFD, 10% calories from fat), high-fat diet (HFD, 45% calories from fat), HFD with white carrot powder (HFD + WC), or HFD with orange carrot powder (HFD + OC). Colon tissues were harvested to analyze the biochemical effects of carotenoids in carrots. The distal sections were subjected to isobaric labeling-based quantitative proteomics in which tryptic peptides were labeled with tandem mass tags, followed by fractionation and LC-MS/MS analysis in an Orbitrap Eclipse Tribrid instrument. High-performance liquid chromatography results depicted that the HFD+WC pellets were carotenoid-deficient, and the HFD+OC pellets contained high concentrations of provitamin A carotenoids, specifically α-carotene and β-carotene. As a result of the quantitative proteomics, a total of 4410 differentially expressed proteins were identified. Intestinal barrier-associated proteins were highly upregulated in the HFD+OC group, particularly mucin-2 (MUC-2). Upon closer investigation into mucosal activity, other proteins related to MUC-2 functionality and tight junction management were upregulated by the HFD+OC dietary intervention. Carotenoid-rich foods may prevent high-fat diet-induced intestinal barrier disruption by promoting colonic mucus synthesis and secretion in mammalian organisms.
2024-11-04 | PXD054150 | Pride
Project description:Histone deacetylase 3 (Hdac3) regulates the expression of lipid metabolism genes in multiple tissues, however its role in regulating lipid metabolism in the intestinal epithelium is unknown. Here we demonstrate that intestine-specific deletion of Hdac3 (Hdac3IKO) protects mice from diet induced obesity. Intestinal epithelial cells (IECs) from Hdac3IKO mice display co-ordinate induction of genes and proteins involved in mitochondrial and peroxisomal b-oxidation, have an increased rate of fatty acid oxidation, and undergo marked remodelling of their lipidome, particularly a reduction in long chain triglycerides. Many HDAC3-regulated fatty oxidation genes are transcriptional targets of the PPAR family of nuclear receptors, Hdac3 deletion enhances their induction by PPAR-agonists, and pharmacological HDAC3 inhibition induces their expression in enterocytes. These findings establish a central role for HDAC3 in co-ordinating PPAR-regulated lipid oxidation in the intestinal epithelium, and identify intestinal HDAC3 as a potential therapeutic target for preventing obesity and related diseases.
2019-10-12 | GSE138775 | GEO
Project description:Obesity is a major risk factor for the development of insulin resistance and type II diabetes. The nuclear receptors PPAR delta and PPAR gamma play a central role in regulating metabolism in adipose tissue, as well as being targets for the treatment of insulin resistance. The metabolic effects of PPAR delta and PPAR gamma activation have been examined both in vivo in white adipose tissue from ob/ob mice and in vitro in cultured 3T3-L1 adipocytes using a combined 1H NMR spectroscopy and mass spectrometry metabolomic methodology to understand the contrasting roles of these receptors. These steady state measurements were supplemented with 13C-stable isotope substrate labeling to assess fluxes, respirometry and transcriptomic microarray analysis. The metabolic effects of the two receptors were readily distinguished, with PPAR gamma ?activation characterised by increased fat storage and fat synthesis/elongation, while activation of PPAR delta caused increased fatty acid beta-oxidation, TCA cycle rate and oxidation of extracellular branch chain amino acids. Stimulated glycolysis and increased desaturation of fatty acids were the only common pathways. PPAR delta has a role as an anti-obesity target as well as an anti-diabetic. Total RNA obtained from cultured 3T3-L1 cells treated for 48 hours with either DMSO control, GW610742 PPARd agonist or GW347845 PPARg agonist and compared.
2011-07-13 | E-GEOD-26207 | biostudies-arrayexpress