Molecular Genetics

Edited by: Steve Bunk WEIGHT CONTROL: Leptin might regulate body weight by signaling the size of the fatty tissue mass, research led by Jeffrey Friedman shows. M. Maffei, J. Haalas, E. Ravussin, R.E. Pratley, G.H. Lee, Y. Zhang, H. Fei, S. Kim, R. Lallone, S. Ranganathan, P.A. Kern, J.M. Friedman, "Leptin levels in human and rodent: Measurement of plasma leptin and ob RNA in obese and weight-reduced subjects," Nature Medicine, 1:1155-61, 1995. (Cited in 196 papers through August 1997) Comments by Jeffrey M. Friedman, Howard Hughes Medical Institute, Rockefeller University. "Leptin is assuming an increasingly prominent role in our understanding of how weight is regulated," says Jeffrey M. Friedman, a professor of molecular genetics in the Howard Hughes Medical Institute at Rockefeller University. "A lot of useful information can be gleaned quickly by measuring leptin levels." He should know, having led the research team that first cloned the obese (ob) gene in mice, which encodes for the production of leptin, a protein that helps to control weight by regulating appetite and energy expenditure (Y.R. Zhang et al., Nature, 372:425-32, 1994). That study sparked many subsequent experiments, including the work described in this paper, which is particularly significant in indicating how leptin might regulate body weight by signaling the size of the adipose or fatty tissue mass. Leptin serves as the signal in a "negative loop feedback": As the body mass index (BMI) rises, leptin levels correspondingly rise, telling the organism to stop or slow feeding. Conversely, a loss in weight causes a loss in leptin levels, prompting hunger. The authors established a connection between BMI and leptin levels by increasing leptin anywhere from twofold to tenfold in five strains of mice with mutant obese genes, as well as in mice with nongenetic obesity and in nonobese littermate controls. Food intake was then restricted, and declining leptin levels were noted as weight was progressively shed. In addition, leptin concentrations were measured in 87 lean and obese humans, and a strong correlation to BMI was observed. Leptin also was monitored in 14 of the human subjects before and after weight loss from dieting, and in two patients who subsequently regained weight. As with the mice, weight loss correlated to a decrease in leptin, suggesting that, in most cases, obesity is associated with "leptin resistance." However, some obese patients had absolute concentrations of leptin similar to others who were much less obese, indicating that, in those cases, there were differences in the secretion rate of leptin from fatty tissues. These findings imply the pathogenesis of obesity. "One possibility is that obesity results when the body is less responsive to leptin than normal," Friedman explains. "You might predict that the organism would think there's too little leptin, weight would increase, and the leptin would increase to reach equilibrium. The inference is a relative insensitivity to leptin. "An alternative cause for obesity would be that the fat makes too little leptin per kilogram of adipose tissue, so the organism gets fatter, but only until a normal leptin level is reached. So, if you see obesity with a normal leptin level, the problem might be expression of the leptin. Those are the two potential problems: Impaired sensitivity to leptin is one, and the other is how it's regulated." In general, the human subjects had higher leptin levels as they grew fatter, indicating resistance. About 5 percent were obese with normal leptin levels, suggesting misregulation of the gene. Among the individuals who lost weight by dieting, the decline in leptin relative to BMI reduction was variable. In other words, people lost varying percentages of leptin compared with the weight they lost. "If the fat is turning out relatively little leptin, as the patient loses fat, there will be less impact on the leptin plasma level," Friedman notes. "So there's variability in the leptin secretion levels." Studies haven't yet been done to determine if obese people with low leptin levels will respond to infusions of leptin by eating less, as would be expected. However, a recent paper of which Friedman was senior author has shown that this is the case with obese and lean mice (J.L. Haalas et al., Proceedings of the National Academy of Sciences, 94:8878-83, 1997). Much research also has been done recently on the leptin receptor, including another paper of which Friedman was senior author that located the receptor in the brain's hypothalamus (G. Lee et al., Nature, 379:632-5, 1996). "For the longest time, it has been thought that obese people are set that way by some unknown mechanism," Friedman muses. "Research now suggests that this may be the case, and the function of the leptin system could account for it."

Molecular Genetics

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