Short-term ketogenic diet induces systemic lipidomic remodeling associated with metabolic adaptation in humans

The ketogenic diet (KD) induces a shift in systemic energy metabolism toward fatty acid oxidation and ketone body production, but its impact on lipid species-level remodeling and insulin sensitivity in humans remains incompletely characterized. We aimed to characterize short-term KD-induced changes in circulating metabolites and lipid profiles and their relationships with insulin sensitivity in healthy adults. Fifteen participants (24-38 years) underwent a 3-day isocaloric KD (75% fat, 20% protein, 5% carbohydrate) under controlled conditions. Serum samples collected before and after the intervention were profiled using metabolomics and lipidomics. KD was associated with increased circulating acylcarnitines, acetyl-L-carnitine, and β-hydroxybutyrate, along with reduced lactate, consistent with enhanced fatty acid oxidation and ketogenesis. Lipidomics showed widespread changes across multiple classes, including lower total triglycerides and shifts toward species with longer acyl chains and higher unsaturation. Ether-linked phospholipids, including plasmalogens, tended to increase, whereas lysophospholipid-to-phospholipid ratios decreased, suggesting altered membrane turnover. Sphingolipid metabolism also appeared to be modulated, with higher sphingomyelin and hexosylceramide levels. Notably, specific lipid species, including phosphatidylethanolamine (16:0/20:5), were correlated with changes in insulin sensitivity indices (QUICKI, HOMA-IR, fasting insulin). Although these associations require validation in larger cohorts, they suggest that lipid species-level remodeling may be linked to short-term metabolic adaptation to KD. These findings highlight lipid species-level remodeling as a key feature of human KD responses and provide a basis for future mechanistic and validation studies.