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ENDOCRINOLOGY Leptin Serves Body as Energy SignalStudy Confirms in Humans that the Hormone Helps Regulate Reproduction An interventional study in men demonstrates that leptin controls some neuroendocrine hormones--including those involved in reproduction--during periods of starvation. The research, published in the May 1 Journal of Clinical Investigation, confirms in humans what many animal models and observational studies have pointed to: leptin is needed for normal reproductive function and may be responsible for many of the hormonal changes that occur in periods of low food intake.
During brief periods of starvation, men experience a drop in testosterone. Jean Chan and Christos Mantzoros found that replacing leptin levels could block this effect. (Photo by Phil Farnsworth) "This proves that the brain uses leptin as a signal of energy availability and changes several neuroendocrine axes," said lead author Christos Mantzoros, HMS assistant professor of medicine at Beth Israel Deaconess Medical Center. The study also points to some important differences between leptin's effect in humans and in mouse models. Leptin and LibidoMuch leptin research in humans has focused on feasting rather than famine, but Mantzoros's team, led by Jean Chan, an HMS clinical fellow in medicine, took a different approach."We were not interested in obesity in the fed state," Mantzoros said. "We thought that a much more important role of leptin may be at the other end of the spectrum." Organisms respond to famine by lowering their metabolism and funneling their energy into survival and away from reproduction. Animal studies have shown that plummeting leptin levels caused by starvation have a critical role in regulating the hormonal responses to food deprivation.
During the brief periods of starvation, the men experienced a significant drop in testosterone levels as expected, along with a drop in leptin. But replacing leptin to physiologically normal levels during fasting fully restored testosterone to baseline, indicating that leptin regulates the hypothalamic-pituitary- gonadal axis that controls the release of testosterone and estrogen. The study also suggests that leptin may regulate thyroid hormone. "Leptin clearly has some effect on the thyroid hormone axis," said Chan, including thyroid-stimulating hormone and the free-circulating form of thyroid hormone. But the exact effects are difficult to discern from a short-term study. Replacing leptin also had a mild effect on insulin-like growth hormone. However, leptin did not alter some hormones affected in mouse models, including human growth hormone and the stress hormone cortisol, and it also had no impact on axes that have not been addressed in animals. The Proof in PeopleSince its discovery nearly 10 years ago, leptin has slowly secured its place in the pantheon of hormones as a molecule that holds sway over many functions in the body, even as its role in obesity--the characteristic that first won it fame--remains muddy. Part of the confusion results from the many studies accumulating over the decade that have been performed in animals. The false hopes for an obesity cure were based on mouse models, so the need to bring leptin research from the lab to the clinic has been especially pressing.Jeffrey Flier, the George C. Reisman professor of medicine at HMS and BID, said that in the mid-90s, his team, which then included Mantzoros, performed a series of experiments in mice that suggested leptin's role was to control the neuroendocrine response to starvation. "The one thing we hadn't done was to test this hypothesis in humans," said Flier. This study, he said, provides "the critical test of the experiments in mice." The notion that body fat and reproductive function are inextricably linked predates leptin research. In the late 1970s, Rose Frisch, now an associate professor emerita of population sciences at HSPH, proposed the idea that girls need a certain level of body fat to go through puberty and hypothesized that some signal, whether from food intake or fat deposits, must govern the process. "A crucial amount of fat is necessary," said Frisch. A body mass index between 20 and 25 is now considered necessary for normal reproductive ability. And women who are anorexic or highly athletic often lose their menstrual periods and fertility. The discovery of leptin as an indicator of fat stores offered a hormonal link between body fat and the reproductive system. Evidence for leptin's role in reproduction also came from genetic studies; three sisters in a family that carried a mutation in the leptin receptor, for instance, failed to mature sexually and became obese. Mantzoros said this latest study "proves definitively that leptin is not a marker, but the real signal that goes from the fat to the brain and activates the gonadal axis." Are leptin's clinical applications moot? Since finding that most obese people are leptin-resistant, obesity researchers have been scrambling to locate downstream targets of leptin that might offer better therapeutic potential. But Mantzoros is hoping that leptin's real therapeutic benefit lies in people whose leptin levels are dangerously low. He explained that women who have undergone hypothalamic amenorrhea because they are athletes or have eating disorders have essentially regressed to a prepubertal stage because their fat stores are so depleted. George Blackburn, the S. Daniel Abraham associate professor of nutrition at BID, said that recombinant leptin may be a boon to these women by restoring some of their normal endocrine functions, without the need to take several different hormones. "The potential exists to restore not only fertility, but thyroid status and hormone abnormalities responsible for osteoporosis in these individuals," he said. --Courtney Humphries |
