Leptin resistance and the response to positive energy balance

Animals readily reduce food intake and normalize body weight following a period of involuntary overfeeding, suggesting that regulatory systems are engaged to defend against excess weight gain. However, these data exist in the background of an ongoing obesity epidemic, where the ready availability of palatable, energy dense foods often leads to obesity. Currently we know very little about the mechanisms underlying the normalization of body weight following involuntary overfeeding, nor do we fully understand why select individuals successfully remain lean despite living in an obesigenic environment. Recent progress in the study of leptin signaling indicates that manipulations which enhance leptin sensitivity reduce food intake and attenuate diet-induced obesity, while reductions in leptin signaling predispose to obesity. While it remains unclear whether a failure or insufficiency in the weight regulatory system contributes to obesity, this work highlights the importance of this system for the regulation of body weight and its potential value for the treatment of obesity. Nonetheless, it is necessary to more clearly identify those mechanisms that protect lean individuals from weight gain and mediate the normalization of body weight that follows involuntary overfeeding, because it is only with this knowledge that we can clearly determine whether obesity is dependent on, or independent of, a failure in the weight regulatory system.