Leptin-deficient mice before (left) and after (right) injections of leptin hormone.

Click above for a movie showing how Leptin helps to regulate body fat.

Is there a "magic bullet," a metabolic trick that might be used to "cure" chronic obesity? In the 1950s, researchers found a seriously obese laboratory mouse, and decided to see if the animal's weight problem had a genetic basis. It did. Several generations of crossbreeding led to the production of a genetically-obese mice, and before long a defective gene, called ob, responsible for the strain's obesity had been identified. In 1994 Jeffrey Friedman (at left) of the Rockefeller University identified a protein produced by the normal version of the ob gene, and called it "leptin," from the Greek word leptos, which means thin.

Almost immediately, researchers realized that leptin was a hormone, a chemical messenger. Mice produce leptin in their fatty tissues, where it enters the bloodstream and travels to a portion of the brain known as the hypothalamus. If leptin levels are high, the hypothalamus inhibits appetite and steps up metabolic activity. The more fat tissue in the body, the greater the amount of leptin in circulation. In effect, leptin in mice serves as a signal to tell the body how much fat it is carrying. The ob mice cannot make leptin, and their brains assume that the body has little or no fat, telling the rest of the body to eat and eat and eat. As a result, ob/ob mice eat almost continuously, weigh three times as much as normal mice, and suffer from diabetes.

In 1995, several research teams tried the obvious experiment - they injected leptin into ob/ob mice. The results were dramatic. Within a few weeks the genetically obese mice lost so much weight that they became indistinguishable from normal mice (see figure at left). Not surprisingly, biotech companies were interested, especially when a gene for leptin was also found in the human genome. One company paid almost $20 million for the patent rights to leptin, hoping, of course, that human leptin would be every bit as effective for seriously obese people as the mouse version had been.

Clinical trials for human leptin, unfortunately, have been disappointing. Although leptin has shown some promise in treating the very small numbers of people with defects in the ob gene, for most people, leptin treatment seems to have no effect. Why not? The reasons are only beginning to become clear, but it now looks as though the process of weight regulation in humans is more complex than in mice. Many obese people, recent research has shown, actually have high levels of leptin, but seem not to respond to the hormone.

Despite these disappointments, the discovery of leptin has opened a new window into the process of weight regulation. Researchers are more hopeful than ever that they will be able to discover exactly how the "set point" for body weight is determined and regulated.