Articles

In an article in the April 15 issue of the journal Genes & Development, Jeffrey M. Friedman, Howard Hughes Medical Institute investigator, and his colleagues at The Rockefeller University (New York) report that the "fat" hormone leptin alters gene expression in fat cells. Using expression arrays, the researchers found the pattern of expressed genes changed in fat cells following administration of leptin.

Leptin is produced by fat tissue and secreted into the bloodstream, sending a message to the hypothalamus and other tissues to stop eating and to burn more fat. Mice that lack leptin are obese, weighing as much as three times more than their normal counterparts. When these obese mice are given hormone treatments, they lose weight in part because they eat less, but there is another component to their weight loss that has not been characterized.

Both mice have a defect in a gene called obese (ob). The ob mouse on the left did not receive leptin, and weighed approximately 67 grams after x weeks, while the mouse on the right, which received daily injections of leptin, weighed 35 grams. Normal mice on the same diet weigh approximately 24 grams.

"We knew that an animal given leptin eats less and loses fat," said Friedman. "And while restricting food intake also causes weight loss, we had reason to believe that the two weight-loss responses are very different." For example, said Friedman, leptin triggers weight loss of fat stores alone, while food-restriction robs the body of both fat and muscle. Also, he said, human or animal on a restricted diet compensates for decreased caloric intake by lowering energy expenditure, while leptin treatment shows no such energy-robbing effect. Until now, however, no one had explored the molecular basis of such differences in detail, said Friedman.

To discover how exactly leptin causes weight loss, Friedman and colleagues took mRNA samples from the fat cells of normal mice and leptin minus mice given the hormone, and interrogated a chip array containing probes for thousands of genes. The researchers found that mice lacking leptin that were given the hormone had a different expression profile than those not given the hormone, indicating that at least some of leptin's effects are due to effects on transcription.

Analyzing data from many such experiments with the mice, the scientists were able to group the expressed genes into clusters that appeared to behave similarly—increasing or decreasing in expression in tandem—as the mice were subjected to different regimes of leptin treatment or food restriction.

"We were able to find at least half a dozen distinct clusters of genes that were specifically regulated by leptin and that were not regulated in the same way by food restriction," said Friedman. "So leptin is doing a lot more than just leading to food intake restriction."

Among the up-regulated genes were some known to be regulated by a protein named SREBP-1, including SREBP-1 itself, which plays a role in controlling fatty acid synthesis. In addition to SREBP-1, other genes involved in fatty acid synthesis were identified in the cohort of up-regulated genes.

The new findings open up new pathways for understanding the complexity of leptin's effects on different body tissues, according to Friedman. Although researchers know that leptin is produced by fat cells and suppresses appetite by affecting the hypothalamus, the hormone may also trigger metabolic changes in fat and other tissues. Learning how changes in gene regulation lead to these effects is a goal of future studies in Friedman's laboratory.

References

1. A Soukas, et al., "Leptin-specific patterns of gene expression in white adipose tissue," Genes & Development 14: 963–980, 2000.

For more information: Marion E. Glick, Rockefeller University, 120 York Ave., New York, NY 10021. Tel: 212-327-8967. Fax: 212-327-7876. Email: glickm@rockvax.rockefeller.edu.

Edited by Laura DeFrancesco

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