Weight-independent effects of dietary carbohydrate-to-fat ratio on metabolomic profiles: secondary outcomes of a 5-month randomized controlled feeding trial

Diet plays a crucial role in health, with low-carbohydrate diets often proposed to exert metabolic benefits. We aim to investigate metabolomic adaptations in 164 adults with overweight or obesity who were randomly assigned to high- (n = 54), moderate- (n = 53), or low-carbohydrate (n = 57) diets during a 20-week weight-loss maintenance phase of the Framingham State Food Study [(FS)2], a controlled, parallel feeding trial (ClinicalTrials.gov: NCT02068885). We measure fasting plasma metabolites by liquid chromatography-tandem mass spectrometry using samples from 147 participants who completed the study (n = 45, 48, and 54 in the high-, moderate-, and low-carbohydrate diet groups, respectively). Significant associations (False Discovery Rate<0.05) are identified between carbohydrate-to-fat ratio (CFR) and diet-induced changes in 148 of 479 metabolites at 20 weeks, with nearly all showing consistent trends at 10 and 20 weeks. Phosphatidylcholines plasmanyls/plasmalogens, phosphatidylethanolamines plasmanyls/plasmalogens, and sphingomyelins generally decrease with higher CFR, whereas lysophosphatidylcholines, lysophosphatidylethanolamines, and triglycerides generally increase. Our findings are largely reproducible in an independent feeding trial involving diets with similar CFR (Popular Diets Study, ClinicalTrials.gov: NCT00315354). Eleven triglyceride species (≤3 double bonds), linked to type 2 diabetes risk, increase with higher CFR. Our findings demonstrate metabolomic changes caused by varying CFR dietary patterns, offering potential insights into mechanisms that could guide targeted dietary intervention strategies.