{"doi":"10.1016/j.celrep.2021.109212","title":"High-fat diet-activated fatty acid oxidation mediates intestinal stemness and tumorigenicity","abstract":"Obesity is an established risk factor for cancer in many tissues. In the mammalian intestine, a pro-obesity high-fat diet (HFD) promotes regeneration and tumorigenesis by enhancing intestinal stem cell (ISC) numbers, proliferation, and function. Although PPAR (peroxisome proliferator-activated receptor) nuclear receptor activity has been proposed to facilitate these effects, their exact role is unclear. Here we find that, in loss-of-function in vivo models, PPARα and PPARδ contribute to the HFD response in ISCs. Mechanistically, both PPARs do so by robustly inducing a downstream fatty acid oxidation (FAO) metabolic program. Pharmacologic and genetic disruption of CPT1A (the rate-controlling enzyme of mitochondrial FAO) blunts the HFD phenotype in ISCs. Furthermore, inhibition of CPT1A dampens the pro-tumorigenic consequences of a HFD on early tumor incidence and progression. 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.","journal":"Cell Reports","year":2021,"id":146681,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":203,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9508,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":624625,"name":"Amanda M. Hussey","orcid":null,"position":1,"is_corresponding":false},{"id":104320,"name":"Constantine N. Tzouanas","orcid":"0000-0002-7536-1156","position":2,"is_corresponding":false},{"id":62832,"name":"Shinya Imada","orcid":null,"position":3,"is_corresponding":false},{"id":624626,"name":"Yesenia Barrera Millan","orcid":null,"position":4,"is_corresponding":false},{"id":623508,"name":"Dorukhan Bahceci","orcid":"0000-0003-4020-3737","position":5,"is_corresponding":false},{"id":624627,"name":"Dominic R. Saiz","orcid":null,"position":6,"is_corresponding":false},{"id":623509,"name":"Anna Webb","orcid":"0000-0001-6045-415X","position":7,"is_corresponding":false},{"id":84822,"name":"Caroline A. Lewis","orcid":"0000-0003-1787-5084","position":8,"is_corresponding":false},{"id":287648,"name":"Peter Carmeliet","orcid":"0000-0001-7961-1821","position":9,"is_corresponding":false},{"id":62842,"name":"Maria M. Mihaylova","orcid":"0000-0002-2725-767X","position":10,"is_corresponding":false},{"id":1413,"name":"Alex K. Shalek","orcid":"0000-0001-5670-8778","position":11,"is_corresponding":false},{"id":39713,"name":"Ömer Yılmaz","orcid":"0000-0002-0962-2725","position":12,"is_corresponding":false},{"id":623507,"name":"Miyeko Mana","orcid":"0000-0002-5516-4008","position":0,"is_corresponding":true}],"reference_count":103,"raw_metadata":null,"created_at":"2026-07-18T23:42:24.567796Z","pmid":"34107251","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}