“The Biggest Loser” weight-loss competition offered a unique opportunity to investigate human energy metabolism and body composition before, during, and after an extreme lifestyle intervention. Here, I reinterpret the results of “The Biggest Loser” study in the context of a constrained model of human energy expenditure. Specifically, “The Biggest Loser” contestants engaged in large, sustained increases in physical activity that may have caused compensatory metabolic adaptations to substantially decrease resting metabolic rate and thereby minimize changes in total energy expenditure. This interpretation helps explain why the magnitude of persistent metabolic adaptation was largest in contestants with the greatest increases in sustained physical activity and why weight-loss interventions involving lower levels of physical activity have not measured similarly large metabolic adaptations. Additional longitudinal studies quantifying the interrelationships between various components of energy expenditure and energy intake are needed to better understand the dynamics of human body weight regulation.