a, PPAR-δ is the most abundant PPAR family member in ISCs (Lgr5-GFPhi) and progenitors (Lgr5-GFPlow) based on RNA-seq data. b, Confirmation of PPAR family member mRNA expression levels in ISCs (Lgr5-GFPhi) and progenitors (Lgr5-GFPlow) by qRT–PCR (n = 5). c, Genes upregulated in HFD ISCs (Lgr5-GFPhi) versus control ISCs were enriched in PPAR and LXR/RXR motifs. d, GSEA of RNA-seq data identified enrichment of PPAR-δ targets in ISCs (Lgr5-GFPhi) and progenitors (Lgr5-GFPlow) with a HFD. e, Confirmation of induced PPAR-δ target gene expression in flow-sorted ISCs (Lgr5-GFPhi) and progenitors (Lgr5-GFPlow) by qRT–PCR (n = 5). All fold changes were significant, P < 0.05. f, g, Representative images of Olfm4+ (ISCs, f) and Crp4+ (Paneth cells, g) in situ hybridization from vehicle and GW501516-treated mice (f, n = 3; g, n = 4). h, Ex vivo exposure of organoids to palmitic acid, lipid mixture or GW501516 stimulated PPAR-δ and β-catenin target gene expression (n = 3, all fold changes were significant, P < 0.05). i, j, Injection with tamoxifen (4 injections on alternating days) in PpardL/L; Villin-CreERT2 mice led to efficient intestinal deletion (IKO) of Ppard (7 days after the last tamoxifen dose), as assessed by allele-specific deletion PCR (i, n = 3) and immunoblot analysis (j, n = 3) of crypts. For western blot source data, see Supplementary Fig. 1. k, Acute disruption of Ppard (8 days after the last tamoxifen dose) did not perturb ISC and progenitor proliferation, as determined 4-h after BrdU administration (n = 3). l, m, Acute Ppard deletion (8 days after the last tamoxifen dose) did not significantly alter Olfm4+ ISCs numbers (L/L: n = 5, IKO: n = 4) (l) or Crp4+ Paneth cell (n = 5) (m) numbers, as assessed by in situ hybridization. n, Loss of Ppard transcripts in Ppard IKO organoids was confirmed by qRT–PCR using deletion-specific primers (n = 3). o, PPAR-δ is required for the induction of PPAR-δ and β-catenin target gene expression in secondary organoids after ex vivo palmitic acid, lipid or GW501516 treatment (n = 5, all fold changes are significant, P < 0.05). p, Heat map of differentially expressed genes illustrated induction of a PPAR-δ program in HFD-derived ISCs and progenitors relative to controls. Unless otherwise indicated, data are mean ± s.d. from n independent experiments; *P < 0.05 (Student’s t-tests). Scale bars, 50 μm (f, g, k–m) and 20 μm (insets); 50 crypts per sample were analysed in each independent experiment (f, g, k–m).