Conditional overexpression of PPARα in intestinal epithelium diminishes GIP enteroendocrine cells and circulating hormone levels
Abstract
Agonists of the lipid-sensing PPAR nuclear receptors, including PPARα, are being explored as therapies for metabolic disorders due to their roles in metabolic and anti-inflammatory processes. PPARα 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 PPARα 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 PPARα protein in the intestinal epithelium. Transcriptional analysis of intestinal tissue from IEC-Ppara mice showed upregulation of PPARα 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 PPARα 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.…
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