Cell Biology

Edited by: Stephen P. Hoffert D.S. Weigle, T.R. Buchowski, D.C. Foster, S. Holderman, J.M. Kramer, G. Lasser, C.E. Lofton-Day, D.E. Prunkard, C. Raymond, J.L. Kuijper, "Recombinant ob protein reduces feeding and body weight in the ob/ob mouse," Journal of Clinical Investigation, 96:2065-70, 1995. (Cited in more than 110 publications to date) Comments by D. Scott Weigle, department of medicine, University of Washington School of Medicine, Seattle A FULL FEELING: Washington's D. Scott Weigle demonstrated that leptin could bring about weight loss in mice. In the past, obesity often was considered a sign of weak willpower and a lack of self-restraint. But the discovery of the obese gene (ob gene) in 1994 by Jeffrey Friedman, a Howard Hughes Medical Institute investigator at Rockefeller University, has revolutionized the search for new therapies to treat this disorder, which afflicts one in three Americans. The demonstration by D. Scott Weigle, an associate professor of medicine at the University of Washington, and others that a protein byproduct of the ob gene induces satiety, or a feeling of fullness, represents a major step in understanding the process of body fat regulation. The body's tendency to restore fat mass to baseline levels after intentional or unintentional weight loss makes the treatment of obesity difficult. One important mechanism acting to stabilize body fat levels is the decrease in appetite and caloric intake that accompanies any increase in body fat. More than 40 years ago, researchers speculated the feeling of satiety, or fullness, that accompanies increases in body fat was due to signals transmitted from fat cells to the central nervous system (G.C. Kennedy, Proceedings of the Royal Society of London/Series B: Biological Sciences, 140:578-92, 1953). Some early studies provided evidence for such a genetic signal (G.R. Hervey, Journal of Physiology, 145: 336-52, 1959) and showed that defects in this signaling caused obesity in mice (D.L. Coleman, Diabetologia, 9:294-8, 1973). To show that leptin-the protein product of the ob gene-induced satiety in mice, Weigle's research team cloned and expressed the ob gene from fat tissue of a mouse homozygous for the diabetes gene. Leptin produced a dose-dependent suppression of 24-hour food consumption when administered intraperitoneally to obese ob/ob mice. Daily injections of leptin led to a sustained reduction in food consumption and progressive weight loss in ob/ob mice. Moreover, the mice experiencing weight loss showed normal levels of activity and appeared healthy. After the discontinuation of leptin injections, the weight of the mice returned to previously elevated levels. Dramatic decreases in circulating insulin and glucose levels accompanied the weight loss induced by leptin administration and suggest that leptin could be useful in the treatment of adult-onset diabetes. "The finding that a protein secreted by adipose tissue could affect eating behavior constituted a great advance in our understanding of body weight regulation," Weigle says, speculating on why the paper is highly cited. "This work, along with the work of many other groups, is significant because it established that body fat mass is regulated by a complex and interrelated series of hormones and feedback loops." To determine whether additional factors secreted by adipose tissue were required for leptin to exert its maximal satiety effect, the research team cultured adipose tissue fragments from obese mice in the presence and absence of recombinant leptin. The resulting media were administered to ob/ob mice. These experiments failed to demonstrate that adipocytes produce any cofactors for leptin action and demonstrated that leptin did not suppress the elevated ob gene mRNA levels detected in adipose tissue from ob/ob mice. These observations raise the possibility that leptin could be an independent signal of body fat mass to the central nervous system. The finding that leptin produced in bacterial and mammalian cells had equal satiety activity established that post-translational processing of the leptin molecule was not required for its biological action. Finally, Weigle's team demonstrated that modification of the amino-terminal of the leptin molecule by the addition of six histidine molecules can enhance its biological activity. This information could be helpful in designing more effective versions of leptin for use in vivo.

Cell Biology

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A FULL FEELING: Washington's D. Scott Weigle demonstrated that leptin could bring about weight loss in mice.