NEW YORK, July 12 - Using microarrays to probe gene expression in the liver, a team of biochemists and geneticists said it has gained new insight into how the hormone leptin regulates fat metabolism and body weight.
The team, led by Rockefeller University's Jeffrey Friedman, used knockout mice that lack the leptin gene to examine the hormone's effects on gene activity, and suggest that a particular gene may be a valuable target for drug therapy for obesity and fat metabolism disorders.
When Friedman's team discovered leptin in 1994, it was hailed as a key to understanding obesity and fat metabolism. Deprived of the weight-regulating effects of leptin, knockout ob/ob mice tend to get very fat very quickly.
In their new experiment, described in a paper in the July 12 Science, researchers gave a dose of the hormone to one group of these knockout mice and allowed the others to eat normally. The team then used Affymetrix mouse microarrays and an algorithm designed by Rockefeller's Nicholas Socci to compare liver gene expression in the two groups, identifying 15 gene clusters that are influenced by leptin.
Prominent among them was the gene SCD-1, which produces an enzyme that promotes fat storage through the synthesis of monounsaturated fatty acids. To cement the link between the gene and the hormone, the team, working with James Ntambi from the University of Wisconsin, conducted further experiments showing that leptin treatment of knockout mice reduced SCD-1 enzyme levels in the animals' livers.
Double-knockout mice that lacked both the leptin and the SCD-1 gene were much less obese than their ob/ob counterparts. Friedman and colleagues hypothesized that under normal conditions, leptin helps promotes fat burning by suppressing the SCD-1 enzyme.