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A1CR
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Joined: 18 Jan 2006
Posts: 559
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 Posted: Sun Feb 19, 2006 8:07 pm Post subject: Leptin biology |
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[posted on behalf of CRON4healthyfuture; 2002-07-18]
Leptin does so many things that it is becoming increasingly difficult to
figure out what its "primary role" is. Insulin, for example, has a nicely
defined primary role of shunting glucose out of the plasma and into
metabolically active tissues. But I have long since given up on the
concept of Leptin even having a primary role and now consider it to be one
of the multifunctional metabolic intermediaries I have ever tried to
understand.
Is there any aspect of metabolism it does not impact in some important
way?
In mice, there was that recent finding being published in Science [below] where
Leptin represses the expression of stearoyl-Coa desaturase-1 in the liver,
and that is critical for the observed effects of leptin on fat metabolism.
| Quote: |
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.
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 gene 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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