Don't cancel your gym membership yet, but a new study from Tufts University suggests that the hormone leptin may help people struggling with serious obesity.
Remember the obese mouse? The pudgy lab rodent got lean on leptin, making headlines and launching the quest for the next big thing in our national obsession with weight reduction.
Now, a six-month study shows that volunteers who received injections of genetically engineered human leptin shed about 16 pounds on the highest dose. People receiving placebo shots lost about four pounds.
So Leptin may be added to a dieter's tool kit as one more aid for the medical treatment of obesity. But it isn't going to replace diet and exercise as the cornerstones of sound weight management. And even if further studies confirm it is safe and effective, its initial use should focus mainly on the disease risks of obesity, not on esthetic slimming.
People are ready for some good news after a harrowing year of diet-drug debacles, with the withdrawal of Redux and Pondimin, also known as fenfluramine, the "fen" in the fen-phen combination therapy. This latest research news offers some hope for the intractably overweight. "There's no magic bullet, but these data are good," says John Foreyt, who treats obese patients at Baylor College of Medicine in Houston and is conducting future leptin trials.
Leptin's clinical tests included 46 obese dieters taking daily shots for half a year. That is too small and too short a study to reach definitive conclusions. More research is needed to prove long-term safety and efficacy, and to determine leptin's impact on diabetes. Expanded studies are now under way in 500 obese volunteers, as well as in overweight adults with noninsulin-dependent diabetes.
"I have guarded optimism," says study author Andrew Greenberg of Tufts University, who reported his results Sunday at the American Diabetes Association meeting in Chicago.
The leptin didn't work for everyone in the study. Some failed to lose weight and a few actually gained. Unfazed by the variation in individual responses, Dr. Greenberg says, "Obesity is multifactorial."
Some volunteers taking a high dose required their leptin in three shots daily -- an inconvenience that could hurt consumer acceptance. Amgen is working on a new formulation to address this problem.
Irritation -- bruising, redness or itching -- at the injection site was the most common side effect, says Dr. Greenberg. One volunteer experienced heart palpitations, which Dr. Greenberg says were "unlikely to be due to leptin."
Fears that leptin might cause insulin resistance, a prediabetic condition, weren't borne out by the Tufts study. Separately, Robert Considine of Indiana University School of Medicine reported test-tube studies suggesting leptin actually "enhances insulin action" in human fat cells.
Importantly, leptin showed a clear "dose-dependent effect," meaning its efficacy increased as the dose was escalated, indicating it has real biological activity, he says. Leptin's role in our growing understanding of human metabolism make this "the most exciting time in obesity research ever," he contends.
But leptin won't be a panacea. Moreover, the goal should be not merely weight loss but reduction of diseases, such as diabetes and hypertension, linked to obesity.
"The results are promising, but it's far too early to raise the public's hopes about this treatment," adds JoAnn Manson of the Harvard School of Public Health. Longer term, she cautions, efficacy may wane or unforeseen risks arise.
Leptin's mean 16-pound weight loss is comparable to other successful diet drugs, she notes. Still, Jeffrey Flier of Harvard labels the test results "significant but not extraordinary," and he says the variable responses make it essential to try to predict who will benefit most from leptin injections.
Leptin doesn't act alone. Appetite and satiety, energy output and fat storage are controlled by a complex cascade of natural chemicals -- including neuropeptide Y, melanocortins, orexins, and the newly discovered substance CART, says Jeffrey Friedman of the Howard Hughes Medical Institute of Rockefeller University in New York. He cloned the leptin gene in 1994. "Each is likely to be important as a piece in the puzzle."
Leptin's mystery, moreover, is far from solved. While we know leptin is secreted by fat cells to balance feeding and energy output, it works differently in hefty humans than in lab mice. While the obese mouse lacks leptin, most obese humans have high levels of the hormone. Thus, overweight people may grow resistant to leptin, much as type II diabetics become insulin-resistant. Future studies may clarify this conundrum. Another imponderable: Patients develop antibodies to leptin, which can prove troublesome over time.
Will consumers, in their quest to be thin, tolerate injections? Compared with stomach-stapling and other extreme interventions, daily needles might seem benign. But they are still more invasive than a pill. Proteins like leptin can't be given orally because they get destroyed in digestion.
"For cosmetic weight loss, I think people would be barking up the wrong tree," says a co-author of the leptin study, Steven Heymsfield of St. Luke's-Roosevelt Hospital in New York City. A potent biological agent, he says, it is too powerful -- and will likely be too expensive -- for casual use by lightweights.
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