Impaired Metabolic Flexibility to High-fat Overfeeding Predicts Future Weight Gain in Healthy Adults

The ability to switch fuels for oxidation in response to changes in macronutrient composition of diet (metabolic flexibility) may be informative of the individual susceptibility to weight gain. Seventy-nine healthy, weight-stable participants underwent 24-h assessments of energy expenditure and respiratory quotient (RQ) in a whole-room calorimeter during energy balance (EBL; 50% carbohydrate, 30% fat) and then during 24-h fasting and three 200% overfeeding diets in a crossover design. Metabolic flexibility was defined as the change in 24-h RQ from EBL during fasting and standard (STOF: 50% carbohydrate, 30% fat), high-fat (HFOF: 60% fat, 20% carbohydrate), and high-carbohydrate (HCOF: 75% carbohydrate, 5% fat) overfeeding diets. Free-living weight change was assessed after 6 and 12 months. Compared to EBL, RQ decreased on average by 9% during fasting and by 4% during HFOF, while increasing by 4% during STOF and by 8% during HCOF. Smaller decrease in RQ, reflecting smaller increase in lipid oxidation rate, during HFOF but not during other diets, predicted greater weight gain at both 6 and 12 months. An impaired metabolic flexibility to acute, high-fat overfeeding can identify individuals prone to gain weight, indicating that the individual capacity to oxidize dietary fat is a metabolic determinant of weight change.