Fat Storage Enzyme Identified
Researchers pursuing the cause of leptin's ability to boost metabolism and shed fat have identified a metabolic switch that appears to tell the body to store or burn fat.
In an article published in the July 12, 2002, issue of the journal Science, Howard Hughes Medical Institute investigator Jeffrey M. Friedman and his colleagues reported that the hormone leptin represses a liver enzyme called stearoyl-CoA desaturase-1 (SCD-1). SCD-1 catalyzes the production of monounsaturated fats from fatty acids in the liver and other tissues. Genetically obese (ob/ob) mice are overweight and show low levels of fat metabolism. In the absence of leptin, the level of SCD-1 rises and more fat is stored in the liver.
Leptin is produced by fat tissue and secreted into the bloodstream, where it travels to the brain and other tissues, causing fat loss and decreased appetite. Friedman's research team cloned the ob gene in 1994 and discovered leptin in 1995. Since then, much of Friedman's research has focused on understanding how leptin exerts its effects on body weight, food intake and metabolism.
In their latest studies, Friedman, Paul Cohen and colleagues at The Rockefeller University and the University of Wisconsin, Madison, employed DNA microarrays to search for genes expressed in the liver that are specifically under the control of leptin.
"We concentrated on the effects of leptin on liver genes because the available evidence suggests that the liver is one of the tissues affected by leptin-triggered signals from the brain," said Friedman. "We wanted to learn more about what those signals are and what mechanisms they activate in the liver."
The scientists used DNA microarrays to compare the level of expression of liver genes in two groups of ob/ob mice that lack the leptin gene. One group of ob/ob mice was given leptin and the other "pair-fed" group was given only as much food as the leptin-treated mice ate voluntarily. Thus, the scientists knew that any genes they found to be activated only in the group of mice treated with leptin would be genes under leptin's influence and not merely those triggered by leptin's known effects on feeding.
To pinpoint the most important leptin-activated genes from the mass of data generated by the microarray screening, the researchers used a computer algorithm developed by co-author Nicholas D. Socci. The algorithm ranked activated genes based on three main criteria: the extent of gene activation in the livers of ob/ob mice; the extent of the genes' response to leptin treatment; and the difference in gene activity in the two groups of mice. These rankings led to the identification of several dozen major genes, of which SCD-1 was most prominent.
"Seeing SCD-1 at the top of the list didn't necessarily suggest a particularly compelling hypothesis to us in advance," said Friedman. "On the other hand, the gene does play a role in fat metabolism, which was the pathway we wanted to explore. And, there was already a mouse strain in which the gene for SCD-1 is knocked out, enabling us to explore its effects."
Co-author James M. Ntambi and his colleagues at the University of Wisconsin, Madison, determined that leptin treatment of ob/ob mice suppressed SCD-1 levels in the animals' livers. Furthermore, when the researchers bred ob/ob mice with an SCD-1-knockout