Leptin, the Master Regulator of Body Weight
The discovery of leptin 25 years ago opened a new chapter in our understanding of the biological mechanisms of obesity, and the possibility of developing a treatment for obesity. Leptin is a hormone produced by fat cells that mediates body weight by telling the brain whether to eat more or less and how much energy to expend. Leptin is produced in proportion to body fat stores – increased body fat leads to greater circulating leptin levels.
When the leptin system is functioning properly, higher levels of leptin signal the brain to reduce food intake and increase energy expenditure, thus preventing a subject from gaining weight above a certain “set point range.” Similarly, lower levels of leptin signal the brain to increase food intake and decrease energy expenditure, thus maintaining an individual’s weight in a healthy range. To early researchers, this suggested that leptin could be a key to treating obesity.
Leptin Resistance and Sensitization
Research in animal models of obesity and in obese humans has shown that exogenous administration of leptin as a treatment is ineffective in creating a sense of fullness or suppressing food intake and fails to lead directly to body weight loss in the majority of the population. These findings led to the notion that obesity in the general population, which generally has high circulating leptin levels, is a condition not of leptin deficiency, but rather one of leptin resistance.
Therefore, a leptin sensitizer, which would sensitize the body to the effects of leptin in circulation, could have great potential to treat obesity and related diseases in humans. This approach carries similarities to insulin sensitizers in the treatment of diabetes, in which patients with type 2 diabetes have high circulating levels of insulin, but a limited or dysregulated response to the available insulin.