December 21, 2003
Fatty Acid Metabolite Plays Key Role In Regulating Appetite

Fatty acid intermediate metabolite malonyl-CoA appears to play a key role in regulating appetite and its synthesis and breakdown can be controlled by drugs.

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 elusive.

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," says Dan Lane, Ph.D., professor of biological chemistry in 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," says 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 body."

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.

My guess is that C75 binds and blocks the activity of an enzyme that converts malonyl-CoA into something else. By preventing malonyl-CoA from being further metabolized the C75 compound causes a rise in the level of malonyl-CoA in brain cells and that, in turn, probably causes malonyl-CoA to bind in places that cause other signals to be sent that cause the brain to feel sated. If hunger can be increased by blocking malonyl-CoA formation and if hunger can be decreased by slowing the breakdown or usage of malonyl-CoA then it might turn out be fairly easy to control appetite and weight.

A safe and effective pair of drugs for increasing and decreasing appetite would give humans easy conscious control of body weight. The development of the means to take conscious control of appetite is one element in a larger toolset which humans need to develop in order to better adapt ourselves to the lifestyles most common in industrialized societies to which our evolutionary past currently leaves us poorly adapted. We also still need to develop the means to adapt ourselves to lower levels of exercise, less need for fear and anger, and other changes we have made in our environments for which we are not well adapted.

Share |      Randall Parker, 2003 December 21 07:56 PM  Biological Mind

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