Leptin (part 2)

M.W. Schwartz, D.G. Baskin, T.R. Bukowski, J.L. Kuijper, D. Foster, G. Lasser, D.E. Prunkard, D. Porte Jr., S.C. Woods, R.J. Seeley, D.S. Weigle, "Specificity of Leptin Action on Elevated Blood Glucose Levels and Hypothalamic Neuropeptide Y Gene Expression in ob/ob Mice," Diabetes, 45 : 531-5, 1996. (Cited more than 150 times since publication) Comments by Michael W. Schwartz, professor of medicine, University of Washington and Puget Sound Health Care System. Few discoveries like that of the obese ( ob ) gene in 1994 have had such a sweeping effect on science. Traditionally regarded as an affliction due to the weak will of its sufferers, obesity is now considered a disease much like diabetes by many researchers and physicians. By 1995, scientists were discovering the enormous therapeutic potential of leptin, a protein encoded by the ob gene. Five research teams independently reported that doses of the protein normalized food intake, body weight, and blood glucose in obese mice with a leptin deficiency (D.S. Weigle, et al., Journal of Clinical Investigation, 96 :2065-70, 1995). But around this time, the emphasis of research on leptin was beginning to shift. "There was a race on to get studies on NPY and leptin to press." - Michael W. Schwartz Scientists saw that most forms of obesity were not caused by a leptin deficiency as was previously thought. Rather, blood leptin levels were found to be elevated in most obese animals and humans. Consequently, the focus turned to trying to understand the specific action of leptin in the brain. Researchers speculated that leptin controlled the activity of neuropeptide Y neurons (NPY) in the hypothalamus (T.W. Stephens et al., Nature, 377 :530-2, 1995). Previous studies suggested that high levels of NPY lowered energy expenditure, stimulated food intake, and ultimately caused obesity in rats. Moreover, NPY expression was increased in leptin-deficient ob/ob mice, which linked reduced leptin signaling to activation of the NPY system. This led to the question of whether leptin could act in the hypothalamus to lower levels of NPY; and if so, whether this effect was merely a result of the reversal of the obese state. Michael W. Schwartz By 1996, scientists had an answer. Michael W. Schwartz, an associate professor of medicine at the University of Washington and the Puget Sound Health Care System, led a team of investigators that proved that leptin and NPY played a direct role in the reversal of obesity in laboratory animals. The research team included University of Washington investigators Denis G. Baskin, Daniel Porte Jr., Randy J. Seely, Stephen C. Woods, and Zymogenetics Corp.'s D. Scott Weigle. Together, they showed that leptin inhibited hypothalamic NPY gene expression prior to reversal of obesity in ob/ob mice. Mice were given doses of leptin for five days. Controls did not receive the protein, and some were given restricted diets to match reduced food intake in mice receiving the protein. As expected, leptin dramatically reduced the weight and changed the feeding behavior of ob/ob mice. By the fifth day of experiments, those receiving doses of leptin had reduced food intake by more than 50 percent compared to controls and saw a 4.1 percent drop in body weight. Hybridization of NPY in the hypothalamus fell 42.3 percent compared to controls, and thus provided the research team with direct evidence that leptin suppressed NPY. Other observations gave support to the view that leptin played an active role in the reduction of NPY and reversal of the obese state. For example, major reduction of NPY mRNA was observed after only a 4.1 percent decrease in weight. Moreover, controls on a restricted diet had similar weight loss compared to leptin-treated mice, but did not have altered NPY mRNA levels. Similarly, db/db mice with a mutation of the leptin receptor had no response to leptin in terms of food intake or NPY expression. Thus, functional leptin receptors were necessary for leptin's effect on NPY. "Based on our own studies and the work of others, we were in an ideal position to come up with logical and critical experiments that would shed light on the action of leptin," Schwartz recalls. "But we weren't the only ones in this position. There was a race on to get studies on NPY and leptin to press." A team of investigators from Eli Lilly and Co. in Indianapolis won that race. They produced a related study in Nature that has been cited in more than 380 publications--one of the hottest papers in 1995 (T.W. Stephens et al., Nature, 377 :530-2, 1995). Science, which was still reviewing Schwartz's study at the time, deemed that the two studies were sufficiently similar and decided not to publish the study by Schwartz's research team. But Schwartz notes that their study still has gotten significant notice from other researchers because the experiments were well designed and highly controlled. "We carefully controlled our experiments so that it was apparent that leptin had specific effects on obese mice," he explains. "The animals in Lilly's study received leptin for three or four weeks. So, the researchers could not know for certain if effects were seen because you were making a fat mouse into a lean mouse or if the effects were something specific to leptin. Our study and Lilly's really turned out to be complementary. We answered questions that they didn't and they did the same for us."

Leptin (part 2)

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July 1998

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