Unlike previous clinical investigations which have focused on the role of leptin in treating obese individuals, this study looked at the hormone at the opposite end of the spectrum – when already lean individuals are put on a fasting regimen so that the body is in a state of "starvation."
Produced in the body's fat cells, leptin was first discovered in 1994 and identified as a "satiety signal," which let the brain know when the body had consumed enough food. It was initially thought that the hormone might have a place as a weight-loss therapy and indeed, leptin did prove effective in animal studies – obese rodents lost 30 percent of their body weight when the hormone was administered. However, subsequent clinical trials of leptin failed to produce any significant weight loss in human subjects.
Earlier animal research conducted in the laboratory of Jeffrey Flier, M.D., at Beth Israel Deaconess Medical Center (BIDMC) had demonstrated that during periods of "starvation," leptin levels markedly decline – presumably as a survival mechanism – and are linked to changes in neuroendocrine function, including reproduction.
In this new study, senior author Christos S. Mantzoros, M.D., clinical research overseer in the division of endocrinology at BIDMC, and clinical fellow Jean L. Chan, M.D., studied eight male subjects under fasting conditions during four separate 72-hour periods. The men were studied in the General Clinical Research Center at BIDMC.
"It would make sense that in an environment where food is unavailable, leptin levels would drop so that the body could survive," explains Mantzoros, who is also an assistant professor of medicine at Harvard Medical School. "Metabolism would decrease so that energy could be conserved and reproductive hormones would diminish to avoid procreation."
In the first study period, the subjects were observed in a "fed state," having been given enough calories in which to keep their body weights stable. In the second period, the subjects were studied during a "fasting state," at which time they received fluids and vitamins, but no food. During the final two portions of the study – both also conducted under the same fasting conditions – the subjects were first administered low doses of leptin, and then administered "replacement" doses which were high enough to bring leptin levels up to those of a "fed state."
"We found both important similarities and important differences between humans and animals when it comes to leptin response," notes Mantzoros of the study's results.
As predicted, the new findings demonstrated leptin's impact on reproductive hormones; during the fasting states, the men's testosterone levels dropped by approximately 40 percent. When leptin was administered, the levels "were normalized to the decimal point," he says.
"This proves that in humans, leptin is the signal that governs the reproductive axis, letting the body know exactly how much energy it needs in order to survive."
Also similar to the animal studies, the new findings showed that the men's levels of thyroid hormone (TSH) fell in response to dropping leptin levels, suggesting that metabolism slows during periods of starvation in order to save energy.
However, says Mantzoros, unlike the animal studies, this new study of men demonstrated that leptin did not influence the stress hormone cortisol. Nor was leptin found to have an effect on subjects' blood pressure. (The mineralocorticoid-blood pressure axis had not been previously tested in animals.)
"In Western countries, 'starvation' is often the result of dieting," explains Mantzoros. "But after a period of weight loss, many dieters find that they reach a 'plateau' whereby they stop losing weight and start regaining the lost pounds. Among other things, this study suggests that falling leptin levels may be to blame for this turn of events; by acting on the thyroid, leptin slows metabolism, thereby helping the body conserve energy and 'survive.'
"These findings help enhance our understanding of human physiology," Mantzoros further explains. "This study is of importance not only for what it's telling us now, but also for the avenues of investigation it offers us for the future. Moving forward, this gives us a much better picture of the body's reaction to states of fasting and may provide us with therapeutic opportunities for disease states such as anorexia nervosa."
Study coauthors include Kathleen Heist, B.S., of BIDMC; Alex M. DePaoli, M.D., of Amgen, Inc., Thousand Oaks, CA; and Johannes D. Veldhuis, M.D., of the Mayo Clinic, Rochester, MN.
This study was funded by grants from the National Institutes of Health, including the National Institute of Digestive and Kidney Diseases, and from Amgen, Inc.
Beth Israel Deaconess Medical Center is a major patient care, teaching and research affiliate of Harvard Medical School. BIDMC ranks third in NIH funding among independent hospitals nationwide.
Journal
Journal of Clinical Investigation