Obesity is a chronic metabolic disorder that affects half a billion people worldwide. Managing obesity is difficult, as many patients rebound to their pre-treatment weight. There is a hypothesis that chronic weight gain causes the body to adopt a state that supports excess weight. In a study published in the Journal of Clinical Investigation, researchers led by Malcolm Low at the University of Michigan challenged this hypothesis by developing a mouse model of obesity where the proopiomelanocortin (Pomc) gene in the hypothalamus can be turned on and off. With Pomc turned off, the mice ate heavily and became obese. Low and colleagues turned Pomc back on at different time points after the mice became obese and found that the effectiveness of this genetic rescue declined as the longer the mice stayed obese. In a companion commentary, Joel Elmquist of the University of Texas Southwestern Medical Center discusses the impact of this research on the development of strategies to halt the obesity epidemic.