Can Leptin Responsiveness Be Restored in Common Human Obesity?

In 1994, leptin was identified as a hormone that signals the brain to reduce food intake and increase energy expenditure. Leptin was initially considered a breakthrough therapy for obesity. This was largely based on animal studies, showing that leptin reversed obesity in individuals with congenital leptin deficiency and normal leptin receptor sensitivity. However, due to leptin resistance, leptin therapy failed to reduce weight in common human obesity. Consequently, interest in leptin waned for many years. However, recent studies in animal models of common obesity show that combining leptin with other weight-loss-stimulating agents, can restore hypothalamic leptin sensitivity and induce a greater reduction of body weight than after single drug treatment. Moreover, after initially reducing weight by combination therapy, leptin monotherapy proved enough to maintain reduced body weight. The strongest evidence for restoring leptin’s weight-lowering actions in common obesity to date comes from mouse studies in which leptin was combined with other pharmacotherapies. However, it is unclear at this moment whether this strategy also can be used to treat common human obesity successfully. Overcoming leptin resistance, by combining leptin with other pharmacotherapies, is a promising strategy that needs to be further investigated in humans with obesity.