Weight-independent effects of dietary carbohydrate-to-fat ratio on metabolomic profiles: secondary outcomes of a 5-month randomized controlled feeding trial
Journal article, 2026
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.
Author
Angeliki M. Angelidi
Harvard University
Broad Institute
Children's Hospital Boston
Eric Bartell
Children's Hospital Boston
Broad Institute
Harvard University
Yisong Huang
Broad Institute
Children's Hospital Boston
Oana Zeleznik
Brigham and Women's Hospital
Núria Estanyol-Torres
Chalmers, Life Sciences, Food and Nutrition Science
Michael Y. Mi
Beth Israel Deaconess Medical Center
Shilpa N. Bhupathiraju
Brigham and Women's Hospital
Rachel S. Kelly
Brigham and Women's Hospital
Clemens Wittenbecher
Chalmers, Life Sciences, Food and Nutrition Science
Jessica Lasky-Su
Brigham and Women's Hospital
Clary B. Clish
Broad Institute
David S. Ludwig
Children's Hospital Boston
Steno Diabetes Center
Harvard University
Cara B. Ebbeling
Children's Hospital Boston
Harvard University
J. N. Hirschhorn
Broad Institute
Children's Hospital Boston
Harvard University
Nature Communications
2041-1723 (ISSN) 20411723 (eISSN)
Vol. 17 1 1662Subject Categories (SSIF 2025)
Nutrition and Dietetics
DOI
10.1038/s41467-026-68353-z
PubMed
41547934