Dec. 25, 1997 Leptin leapt into the headlines when it was identified in 1995 as a protein that triggers weight loss in mice. But the appetite-taming hormone lost some luster as the ultimate diet drug when scientists found last year that obese people already have high levels of leptin in their blood. This finding suggested that overweight people may become unable to respond to leptin, though little is known about leptin's interactions in the body.
Now investigators at Washington University School of Medicine in St. Louis have identified the first factor to significantly boost human leptin concentrations. And surprisingly, this substance also boosted leptin levels in some overweight individuals.
In the study conducted by endocrinologist Samuel Dagogo-Jack, M.D., assistant professor of medicine, and by John W. Newcomer, M.D., assistant professor of psychiatry and of psychology, oral administration of a steroid hormone for four days doubled the amount of circulating leptin in 52 patients. Levels of leptin, a product of fat cells, climbed even higher in obese subjects. The results were published in the October 1997 issue of the Journal of Clinical Endocrinology and Metabolism.
Dagogo-Jack says the findings suggest that overweight people still have leptin reserves. "Because their supplies are not exhausted," he notes, "future leptin therapy may require the use of high doses of leptin to make a dent in obese people's weight."
A similar approach works well in people with adult-onset, or type 2, diabetes, who are resistant to their own insulin. "If we treat these diabetics with insulin to increase their circulating insulin levels, their blood glucose concentrations come down, and their diabetes is controlled."
Heavier People Respond Better
The study, which was funded by grants from the National Institute of Mental Health, the American Diabetes Association and the U.S. Public Health Service, involved 20 healthy men and 32 healthy women ranging from 19 to 84 years in age. Of the 31 receiving steroid treatment, 11 were considered obese based on their body-mass-index (BMI), which relates weight to height. For instance, a 5-foot-10-inch person who weighs 193 pounds would have a BMI of 28. A BMI of 27.3 or higher for men or 27.8 or higher for women was considered obese in the study.
To test leptin levels, Dagogo-Jack, Newcomer and colleagues analyzed the pattern of leptin secretion in volunteers treated with increasing doses of the steroid dexamethasone or a placebo. Dexamethasone, which mimics the hormone cortisol, is commonly used to treat arthritis and other inflammatory conditions.
The researchers tested blood samples taken before, during and after a four-day treatment period for concentrations of insulin and other hormones as well as leptin. By the third day of dexamethasone treatment, obese patients' leptin levels had doubled from an average of 24.3 ng/ml to a peak of 47.7 ng/ml. In their lean counterparts, they increased from 11.3 ng/ml to 20.1 ng/ml. A follow-up study by the researchers showed that results were similar when cortisol was used to stimulate leptin release.
Although the heavier patients responded to dexamethasone treatment, most were moderately obese. Dagogo-Jack notes that the findings may not apply to people who are morbidly obese, defined as having a BMI of 35 or above.
"The ability to keep increasing leptin production may fail at some point of massive obesity," he says. Future studies with dexamethasone and other steroid hormones as stimulants will include this weight group to try and determine if some obese people lose the ability to respond to the stimulants.
Men and women responded equally well to dexamethasone treatment, however. This was a surprise because women generally have higher levels of leptin in their blood, possibly because their bodies contain a greater percentage of fat. The different concentrations of sex hormones in men and women also may play a role. Some long-term studies have suggested that insulin elevates leptin levels slightly. Insulin affects energy supplies by triggering cells to take up glucose as an energy source. But no jump in insulin levels coincided with the increases in circulating leptin documented during this four-day study.
Weight Loss Link Suggested
Besides identifying a leptin regulator, the findings also may help explain how stress can trigger weight loss. Cortisol is called the "stress hormone" because its levels increase during stress and long-term illnesses such as chronic depression and AIDS. But no one has understood how cortisol causes weight loss. "Our study suggests that leptin might be one link between cortisol action and weight loss," Dagogo-Jack says.
Dagogo-Jack notes that the dexamethasone finding serves as only one piece in an unfinished jigsaw puzzle depicting the pathways regulating body weight. "This one piece of the puzzle should lead to other areas worthy of examination," he says.
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