Ketogenic diets induce pro-inflammatory macrophage accumulation through long-chain saturated fatty acids driving cGAS-STING signaling

ABSTRACT: Ketogenic diets (KDs) have demonstrated both pro- and anti-inflammatory effects; however, the mechanisms underlying divergent outcomes on a KD are unclear. Here, we show that a KD promotes the accumulation of pro-inflammatory macrophages in multiple mouse tissues, using immunoblotting, immunohistochemistry, single-cell immunofluorescence multiplex staining, flow cytometry, and RNA-sequencing. In both murine and human macrophage tissue cultures, we demonstrate that long-chain saturated fatty acids (LC-SFA) promote M1-like polarization, while no effect was observed with medium-chain fatty acids or unsaturated fatty acids. Metabolomics analysis of primary macrophages from mice on a KD revealed enrichment for pro-inflammatory ceramides and hexosylceramides. Transcriptomics showed multiple upregulated pro-inflammatory pathways, including inflammasome activation and cGAS-STING signaling. Myeloid-lineage specific Sting knockout mice demonstrated that cGAS-STING is required for the observed pro-inflammatory effects of a KD. This data suggests that elevated LC-SFA on a KD may induce pro-inflammatory macrophage accumulation in multiple tissues, a finding with significant clinical importance.

ORGANISM(S): Mus musculus

PROVIDER: GSE341597 | GEO | 2026/10/06

REPOSITORIES: GEO