Impaired Metabolic Flexibility to High-Fat Overfeeding Predicts Future Weight Gain

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 subjects 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 (SOF: 50% carbohydrate, 30% fat), high-fat (FNP: 60% fat, 20% carbohydrate), and high-carbohydrate (CNP: 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 FNP, while increasing by 4% during SOF and by 8% during CNP. Smaller decrease in RQ, reflecting smaller increase in lipid oxidation rate, during FNP but not during other diets, predicted greater weight gain at both 6 and 12 months. An impaired metabolic flexibility to acute, high-fat overfeeding identify individuals prone to gain weight, indicating that the individual capacity to oxidize dietary fat is a metabolic predictor of weight change.