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1st appeared
16 November
1999 Contradictory News Accounts Highlight Obesity Research Two conflicting news "spins" on the potential appetite-curbing and fat-fighting hormone, leptin, appeared on the same day recently in the San Francisco Chronicle -- "Hormone Study Offers Hope," and in the New York Times -- "Hormone that Slimmed Fat Mice Disappoints as Panacea in People." Naturally, readers who read both accounts were left wondering what it all meant. The articles reported on a leptin study funded in part by Amgen, which paid $48 million for rights to commercially use the hormone and its receptor. The Amgen researchers and their university and contract laboratory collaborators measured weight loss in participants who injected themselves daily with either a placebo or with leptin. The preliminary study, published in the October 27 issue of JAMA, was "double-blinded," meaning that neither the researchers nor the participants knew who received the drug until after the data was collected. The Los Angeles Times article that ran in the Chronicle emphasized that study participants lost an average of 15 pounds over six months. The New York Times story emphasized that 10 of 18 obese participants on the highest leptin dose dropped out of the study, not wanting to inject themselves repeatedly. In addition, the newspaper article noted that the hormone had "little effect" except on two participants. The weight loss in the eight obese subjects who injected the highest leptin dose appeared statistically significant, almost 19 pounds on average, but it ranged widely. Two individuals lost about 35 pounds, while one patient gained nearly 20 pounds. Fortunately, UCSF now is home to a small but growing number of basic researchers who are making their own contributions to science’s growing understanding of how body weight is regulated, and who keep up with the research. Among them is Christian Vaisse, who in the past has studied leptin’s mechanism of action at the molecular level and who now is interested in identifying genetic variations among individuals that may play a role in obesity. After leptin was identified in 1994 and scientists showed that mice lacking the hormone got fat, Vaisse, as part of a research team that helped to confirm that leptin is essential for body weight regulation in humans, described obese patients with a rare mutation in the leptin receptor gene. Fat cells make leptin, and in general, obese people have more leptin in their bloodstreams. Experiments with mice show that leptin injections can reduce food intake. When the injections are halted, the mice eat more again. Recently, in a study pubished in the New England Journal of Medicine, a British research team led by Stephen O’Rahilly found that a very obese girl with an extremely rare complete leptin deficiency-- due to a mutation in the leptin gene--dramatically lost weight when O’Rahilly began giving her injections of the hormone. But single-gene mutations that cause obesity may be an exception to the rule. Vaisse suspects that mutations in numerous genes may have an influence on an individual’s tendency to become fat. Considering that obese mouse strains with different defects in the leptin signaling pathways respond differently to leptin, it is not unreasonable to think humans may differ in their ability to lose weight with supplemental leptin, according to Vaisse. "It’s logical to think that some will respond and some will not, depending on the underlying defect in the body weight regulating pathway," he says. But the new clinical study does not seem to indicate that leptin will be a good obesity treatment for the average overweight person, he adds. Vaisse leans more toward the New York Times spin on the JAMA study. The high dropout rate in the study may have been due in part to the discomfort caused by the injections, as the New York Times reported. But in addition, Vaisse points out, participants in either the placebo or leptin-receiving groups who did not lose weight at the beginning of the study also may have been the most likely to become discouraged and to drop out, introducing a bias to the study in favor of those who lost weight. Similarly, all obese subjects were prescribed a weight-loss diet. Given the relatively small numbers of patients in each group, the individual adherence to the diet could also be a confounding effect in the study, Vaisse points out. In fact, the authors reported that the placebo group lost less weight than expected (about four pounds on average), which suggested that they did not stick to the diet. Even if leptin proves disappointing as a general obesity treatment, its discovery has opened the doors for researchers such as Vaisse to explore new biochemical pathways implicated in body weight regulation. These research efforts may ultimately lead to the characterization of gene defects in those pathways that might cause obesity. This research could also lead to the discovery of new drugs that target more common biochemical contributors to obesity. And as Vaisse points out, "For a small number of individuals, leptin itself may be life-saving." Links: Weighed Down with Obesity, Nation Grows Nostalgic over Diets JAMA (Oct. 27)
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