It soon became clear that there was a problem: obesity isn’t the result of a lack of leptin, but rather a lack of leptin response. In fact, obese individuals tend to have high levels of circulating leptin.
“They have enough, but it’s not doing its job,?Cowley said. “It’s an example of classic hormone resistance.?
Cowley’s group set out to show exactly where that breakdown occurs. The researchers fed mice a high-fat diet for 20 weeks, a long time for the mice, which live only for a couple of years. For reasons that remain unclear, some of the genetically identical mice became obese when fed such a diet, while others did not.
“On a high-fat diet, not all of the animals become fat,?Cowley said. “About 60 percent become fat, while others on the same diet, same calories, don’t gain weight, and leptin levels remain normal. Something else must protect them.?
The animals that did become obese maintained normal levels of the ARH brain receptors that respond to leptin, the researchers showed, while the level of SOCS-3 rose. Leptin hormone in those heavy animals failed to elicit “any element of the leptin signaling cascade.?The researchers demonstrated that those later players in the leptin pathway remained ready for action. Indeed, the downstream factors were actually found to be hypersensitive to stimulation.
“Previous studies have suggested that SOCS-3 is a negative regulator of leptin,?Cowley said. “As animals become bigger and fatter and leptin increases, SOCS-3 may rise to decrease the signal. It seems that in obesity, SOCS-3 might end up overriding the [leptin] signal completely.?
When the amount of fat in the animals?diets was reduced—even without any reduction in calories—the mice continuously lost weight until they reached a size comparable to control animals. Their brains?appetite control centers also regained sensitivity to leptin.