Scientists at Johns Hopkins have discovered the first
direct evidence in mammals that a chemical intermediate in
the production of fatty acids is a key regulator of
appetite, according to a report in a recent issue of the
Proceedings of the National Academy of Sciences.
Scientists have long known that hunger causes
increases in some brain chemicals while lowering others.
However, the root cause of hunger's effects — the
initial chemical trigger of appetite — has been
In experiments with mice, the Johns Hopkins
researchers showed that appetite is immediately and
directly tied to amounts of a chemical called malonyl-CoA.
In hungry mice, malonyl-CoA was almost undetectable in the
brain. Once fasting mice were given food, however, amounts
of the chemical increased to high levels within two hours.
Furthermore, chemically reducing appetite by injecting a
compound called C75 into the brain brought levels of
malonyl-CoA up to those of mice given food, helping to
explain C75's effects.
"From this work, it appears as though malonyl-CoA
levels control appetite and levels of other brain chemicals
that we know go up and down with hunger and feeding," said
Dan Lane, professor of
chemistry in Johns Hopkins' Institute for Basic
Biomedical Sciences. "There may be other contributors, but
this is the first direct evidence that malonyl-CoA could be
the body's primary appetite controller."
In previous work, Lane and his colleagues had shown
that giving mice C75, which blocks conversion of
malonyl-CoA into fatty acids, dramatically reduced animals'
appetites. Subsequently, they found that C75 triggers
levels of several known appetite signals (NPY, AgRP, POMC
and others) to register "full" even when animals should
have been hungry.
However, the new experiments, during which C75 was
injected directly into the animals' brains, suggest that
increasing levels of malonyl-CoA, caused by "blocking the
dam" with C75, is the first step in the process that alters
levels of those appetite signals.
"Fully understanding how appetite is regulated by the
brain should reveal ways to control appetite," said Lane,
who was studying how fat cells develop when he and
colleagues discovered the appetite-suppressing effects of
C75 a few years ago. "Because C75 was injected into the
brain rather than into the abdomen as in earlier
experiments, we also now know that the compound's effects
on appetite stem primarily from its effects on chemicals in
the brain, not from effects it might have elsewhere in the
The scientists also discovered that preventing
formation of malonyl-CoA by injecting a different substance
(TOFA) into the brain partially reversed the
appetite-suppressing effect of C75. Lane suggests that a
better blocker of malonyl-CoA formation should more
completely counteract C75's effects.
The research was supported by the Yamanouchi
Pharmaceutical Co., in Tokyo. Authors on the paper are
Lane, Zhiyuan Hu and Seung Hun Cha of Johns Hopkins; and
Shigeru Chohnan, of Ibraki University, Japan.