The effect of a leptin phenotype on weight change and energy expenditure responses to acute and prolonged energetic stressors

Leptin is a hormone produced by adipocytes that plays a crucial role in regulating energy homeostasis and body mass. Despite its close correlation with body fat, up to ∼40% of variation in plasma leptin concentration remains unexplained, allowing for the classification of a distinct "leptin phenotype." This leptin phenotype-characterized by either relatively high or relatively low leptin concentration relative to an individual's level of body fat-presents an intriguing opportunity to test whether relatively higher (compared with lower) leptin concentrations differentially affect energy expenditure, metabolic adaptation, and susceptibility to weight change in response to energy balance perturbations. To test this hypothesis, we characterized the energy expenditure and weight change response between the two leptin phenotypes (relatively high vs. low) using three distinct experimental contexts: a cross-sectional analysis (<i>n</i> = 104), acute (24-h) perturbations with fasting and overfeeding (<i>n</i> = 77), and chronic perturbations with 24-mo caloric restriction (<i>n</i> = 144) or 8-wk overfeeding (<i>n</i> = 28). Leptin phenotype did not explain variations in energy expenditure responses either in cross-sectional analyses or in response to acute or prolonged energetic stressors. Moreover, leptin phenotype was not a determinant of weight change in response to energy restriction or surplus, or subsequent weight recovery. These results suggest that classifying individuals based on a leptin phenotype does not allow to detect differential susceptibility to energy expenditure adaptations or weight change.<b>NEW & NOTEWORTHY</b> Leptin is linked to body fat, but unexplained variation remains. This study challenges the idea that distinct leptin phenotypes-characterized by relatively high or low leptin concentration for a given level of body fat-affects energy expenditure or weight change in response to acute or prolonged energy stressors. We found no association between leptin phenotypes and energy expenditure or weight change either cross-sectionally or in response to acute or prolonged over- or underfeeding.