July 12, 2002
Research Identifies Enzyme Involved in Fat Storage
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.
“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.”
Jeffrey M. Friedman
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 —
so-called asebia mice obtained from The Jackson Laboratory —
the resulting double-knockout mice (which lacked both leptin and SCD-1)
were markedly less obese than ob/ob mice and showed increased
energy expenditure. The double-knockout mice also had an apparently
normal distribution of fat in the liver as compared to the enlarged,
fatty liver characteristic of ob/ob mice. They also found that
mice lacking SCD-1 were more lean than normal mice.
The results, said Friedman, demonstrate that SCD-1 is a key to
leptin-regulated fat metabolism in the liver. However, he said that
additional studies would be needed to understand how the enzyme is
regulated and whether it plays a role in other tissues and whether
there exist other leptin-regulates additional fat metabolism
pathways.
While SCD-1 could be a potential target for obesity drugs that would
promote fat-burning by reducing level of SCD-1, Friedman expressed
caution about the potential side effects of such drugs.
Friedman noted that there are many caveats. “Mice lacking the
enzyme have abnormalities of glands in the skin and eyes. A key
question is whether a partial reduction in SCD-1 activity — rather
than a complete loss of the enzyme’s activity, as in asebia
mice — could alter metabolism without incurring unwanted side
effects,” he said. “An SCD-1 deficiency produced by drugs
might affect metabolism and alter levels of free radicals in the body
in a way that would be harmful. So, while I believe that drugs to
target SCD-1 are worth exploring, as with any potential drug strategy,
there are no guarantees that the benefits would outweigh potential
unwanted side effects.”
Friedman is optimistic about information that may come from studies
of other genes identified through his team’s genomic screening.
“The fact that we developed criteria for ranking these genes and
found that the gene at the top of our list was biologically important
gives us confidence that the other genes (on the list) are also going
to be important,” he said. “This approach may provide an
opportunity to identify other components of the physiologic pathway
that regulates body weight and metabolism.”
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