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Most individuals with obesity or overweight have difficulty maintaining weight loss. The weight-reduced state induces changes in many physiological processes that appear to drive weight regain. Here, we review the use of cell biology, genetics, and imaging techniques that are being used to begin understanding why weight regain is the normal response to dieting. As with obesity itself, weight regain has both genetic and environmental drivers. Genetic drivers for "thinness" and "obesity" largely overlap, but there is evidence for specific ge