Introduction and Objective: Metabolic flexibility (MetFlex) is the ability to match substrate oxidation to fuel availability. Metabolic inflexibility—failure to increase lipid oxidation during high-fat intake—may promote weight gain, ectopic fat, and insulin resistance. MetFlex is often quantified as absolute change in oxidation, but this approach ignores substrate availability and is biased by baseline oxidation, potentially misclassifying individuals with high baseline lipid oxidation. We tested a novel residual-based MetFlex approach and examined associations with follow-up weight and glucose tolerance.Methods: Forty-nine adults completed 24-h chamber stays during energy balance (EBL; 50%CHO/30%fat), fasting, and 200% overfeeding: standard (50%CHO/30%fat), high-fat (HFOF; 60%fat/20%CHO), and high-carbohydrate (HCOF; 75%CHO/5%fat). MetFlex was defined as residuals (measured-predicted) from regressions of oxidation during each condition on EBL oxidation. Participants were also classified by HFOF and HCOF residual responses (flexible to both, inflexible to both, HFOF-only, or HCOF-only). Weight and 2-h OGTT total and incremental AUC were assessed at baseline, 12, and 24 months.Results: Metabolic inflexibility to HFOF, indicated by higher-than-predicted carbohydrate oxidation (R²=0.09, p=0.03) and lower-than-predicted lipid oxidation (R²=0.08, p=0.04), predicted 12-month weight gain before and after adjustment for age, sex, and ethnicity. Participants inflexible to lipid oxidation during both HCOF and HFOF gained more weight over 24 months than those flexible to both (∼8kg; p=0.011; n=10). MetFlex was not associated with OGTT AUC or iAUC at 12 or 24 months.Conclusion: A 24-h HFOF challenge identified MetFlex phenotypes. Failure to increase lipid oxidation and suppress carbohydrate oxidation during HFOF predicted greater 12-month weight gain. Inflexibility to suppress lipid oxidation during HCOF and increase it during HFOF was linked to greater 24-month weight gain. These findings highlight lipid oxidation in long-term weight regulation.
M. Dote Montero: None. E.J. Stinson: None. S.B. Votruba: None. P. Piaggi: None.
This research was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) within the National Institutes of Health (NIH). The contributions of the NIH author(s) are considered Works of the United States Government. The findings and conclusions presented in this abstract are those of the author(s) and do not necessarily reflect the views of the NIH or the U.S. Department of Health and Human Services.
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