In animal trials, obese mice treated with these repurposed drugs began to slim down after a few days and continued to shed fat at a precipitous rate until they reached a normal body weight, usually about three weeks later. This process was associated with a dramatic decrease in food consumption. But unlike drugs that cause weight loss by reducing food intake, these compounds seemed to reduce food intake by causing weight loss. As the fat cells shrank, they released free fatty acids that acted as a source of energy for the body, seeming to partially supersede the need for food calories. As soon as the animals reached a healthy weight, their food consumption returned to normal or even elevated levels, even though they continued to receive the drug. Nonetheless, the mice retained their new lean physiques for the remainder of the study–about six months total.
Not only did the mice lose weight, but they also became healthier overall. Their metabolic rate increased, their insulin sensitivity improved, and the fat content of their livers diminished. Within the fat tissue itself, there was a marked change in the number and architecture of blood vessels. Hughes says that all of these changes were highly reminiscent of those seen with extreme calorie restriction, which has long been known to improve health and extend life span in rodents. That makes sense, he says, because while the mice are actively losing weight, their calorie consumption plummets by as much as 80 percent.
Zafgen plans to start clinical trials on an anti-angiogenic molecule later this year, to determine whether the weight loss and health improvements seen in mice will translate to humans. Meanwhile, the company is working to better understand why the drugs it has tested are so potent in mice, and to discover new molecules with similar effects.
The rodent studies suggest that the doses sufficient for fat loss are lower than that required for tumor suppression, which might reduce the potential for side effects.
Hughes emphasizes that Zafgen intends its drugs to be used by the morbidly obese, and not by those trying to shed a pesky 15 pounds. “It’s serious medicine,” he says–not a lifestyle drug.