| First Author | Socha JJ | Year | 2026 |
| Journal | Mol Metab | Volume | 112 |
| Pages | 102429 | PubMed ID | 42595008 |
| Mgi Jnum | J:392936 | Mgi Id | MGI:8408542 |
| Doi | 10.1016/j.molmet.2026.102429 | Citation | Socha JJ, et al. (2026) Conditional overexpression of PPARalpha in intestinal epithelium diminishes GIP enteroendocrine cells and circulating hormone levels. Mol Metab 112:102429 |
| abstractText | Agonists of the lipid-sensing PPAR nuclear receptors, including PPARalpha, are being explored as therapies for metabolic disorders due to their roles in metabolic and anti-inflammatory processes. PPARalpha transcriptional programs have tissue-dependent features, yet there is a lack of genetic tools to study tissue-specific signaling activation without the addition of a systemic agonist. We aimed to investigate intestinal epithelial cell (IEC)-specific roles of PPARalpha signaling using a novel transgenic mouse that enables spatial and temporal control of Ppara overexpression. CAG-Ppara,-EGFP mice were bred to Villin-CreERT2 to establish the IEC-Ppara mouse, which was compared to littermate controls 2 weeks after tamoxifen exposure. IEC-Ppara mice had increased Ppara mRNA and PPARalpha protein in the intestinal epithelium. Transcriptional analysis of intestinal tissue from IEC-Ppara mice showed upregulation of PPARalpha target genes and functional enrichment for fatty acid catabolic processes. As expected, the enterocytes of IEC-Ppara mice were primed to absorb lipids following oral administration of an olive oil bolus. Unexpectedly, the enteroendocrine hormone Gip was among the most downregulated genes. GIP-positive cells were reduced in the intestines of IEC-Ppara mice and in mice treated with PPARalpha agonist WY-14643. Circulating GIP hormone was reduced in IEC-Ppara mice. GLP-1-positive cells and hormone were unchanged. Consistent with reduced GIP function, IEC-Ppara mice consumed more food. These findings reveal PPARalpha as a regulator of GIP and support a new framework in which PPARalpha signaling influences systemic energy balance via a gut hormone axis. This study could have future impact on understanding responses to therapies targeting PPAR or incretin signaling. |
