Leptin or 'Pubertin'?

For this article, Eugene Russo interviewed Philippe Froguel, a professor of genetics and nutrition at the Pasteur Institute in Paris. Data from the Web of Science (ISI, Philadelphia) show that Hot Papers are cited 50 to 100 times more often than the average paper of the same type and age. K. Clement, C. Vaisse, N. Lahlou, S. Cabrol, V. Pelloux, D. Cassuto, M. Gourmelen, C. Dina, J. Chambaz, J.M. Lacorte, A. Basdevant, P. Bougneres, Y. Lebouc, P. Froguel, B. Guy-Grand, "A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction," Nature, 392:398-401, March 26, 1998. (Cited in more than 200 papers since publication) In the last several years, leptin has proven to be quite complex. Initially touted as a key to alleviating chronic obesity, leptin is now known to play a more general part in a variety of hormonal processes. "The real name for leptin should be something like 'pubertin,'" suggests Philippe Froguel, a professor of genetics and nutrition at the Pasteur Institute in Paris and coauthor of this paper. "I don't think it's ... primarily regulating weight by itself. My feeling is that it's something controlling fecundity, puberty, and all the sexual life." Investigators now know that leptin by itself will help treat obesity in only a select few subjects; in both mice and humans, the more obese the animal, the more resistant it is to leptin. Any potential leptin treatments would therefore require unreasonably large amounts of the hormone. Research from Froguel and his colleagues at the Pasteur Institute and the French Institute of Health and Medical Research helped show just how manifold leptin function is. In the early 1990s, in an effort to find treatments for an epidemic of childhood, early-onset obesity in the United States and Europe, the researchers began tracing the condition's genetic origins. His team started tracking down families that appeared to be prone to early-onset obesity. Then, using a novel method, they screened hundreds of subjects to look for abnormally high levels of leptin, reasoning that any obese persons with copious amounts of the hormone might have a complete disruption of the leptin pathway or a mutation of the leptin receptor. Philippe Froguel That's exactly what they found, as reported in this paper, in one family whose leptin levels were 20-fold higher than expected. They then screened the associated gene and found that it contained a homozygous mutation present in some of the obese subjects. Apparently the mutation caused a truncation of the leptin receptor where it binds to the cytoplasmic membrane of neurons in the hypothalamus. Surprisingly, the mutation also had a dramatic effect on the onset of puberty. The group's work demonstrated that, as had been observed in mice, people need functional leptin receptors for pubertal development and for secretion of growth hormone and thyrotropin. In retrospect, says Froguel, the observation makes sense. "The control of adiposity and fat is highly linked to the control of fecundity of animals in general," he explains. "And there's a rationale for that. It's clear that it's important to avoid pregnancy if there is nothing to eat." Froguel's team also clarified the relationship between leptin and diabetes. Researchers had discovered previously that, in mice, a knockout of the leptin pathway would cause the disease; many assumed that the same would be true in humans. The group's findings proved otherwise--leptin is not a major regulator of glucose homeostasis in humans. Based on research first reported in Nature Genetics, 1,2 Froguel's group has begun to shift its focus away from leptin and toward, more specifically, a receptor called melanocortin 4 (MC4), which is initiated by leptin. In a paper soon to appear in the Journal of Clinical Investigation, his team reports that about 4 percent of obese children and teenagers exhibit a mutation in the MC4 receptor, a far greater percentage than those who have the leptin mutation. "Leptin and the leptin receptor were the beginning of molecular medicine in obesity," comments Froguel. MC4, he suggests, is in actuality the first major player in the genetics of obesity. Eugene Russo can be contacted at erusso@the-scientist.com. References 1. C. Vaisse et al., "A frameshift mutation in human MC4R is associated with a dominant form of obesity," Nature Genetics, 20:113-4, 1998. 2. G.S.H. Yeo et al., "A frameshift mutation in MC4R associated with dominantly inherited human obesity," Nature Genetics, 20:111-2, 1998.

Leptin or 'Pubertin'?

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Eugene Russo

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July 2000

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