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June 2006 Issue

mTOR signaling in the hypothalamus
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Brain 'Checkpoint' May Control Appetite

Published June 2006

A cell-signaling pathway in the brain that is linked to the development of cancer and diabetes is also a key part of networks that regulate food intake, say UC researchers.

The finding might one day lead to new ways of helping obese people lose weight, either with new drugs or by carefully designing diets that can activate this pathway.

Scientists from UC's Genome Research Institute demonstrated that the signaling pathway mTOR-activated by nutrient and hormonal signals-plays a role in the brain's ability to sense how much energy the body has available.

This finding, the researchers say, suggests that very specific micronutrients may drive these pathways in the brain and could lead to a more scientific approach to diet design to help regulate body weight.

The study, led by Randy Seeley, PhD, professor of psychiatry, appeared in the May 12 issue of the journal Science. Ingesting calories (energy in the form of nutrients) has two purposes, says Dr. Seeley.

"We take in calories to maintain levels of stored fuel (energy) and adequate available fuel," he says.

"The signals that tell our brain about both the stored and the available energy in our body can activate the mTOR pathway in key parts of the brain that control appetite."

Knowing that mTOR basically serves as a "checkpoint" for sensing energy changes, the researchers predicted that it could be manipulated to alter food intake.

The mTOR pathway is very sensitive to "branched-chain' amino acids, particularly leucine, Dr. Seeley explains. In laboratory studies, he and his team found that when they administered leucine directly to the hypothalamus, a brain region that controls a number of metabolic processes, animals ate less.

Other, similar amino acids did not give the same results. This animal study, says Dr. Seeley, could eventually have implications for human obesity.

"Rather than basing our diets only on macronutrients like fat or carbohydrates, we might one day be designing diets based on micronutrients like amino acids," he says.

But, Dr. Seeley adds, that certainly doesn't mean people should "run out and add more leucine to their diets.

"We still have a lot to learn about how these nutrients would act if simply ingested with other nutrients, in what form they could be most effective, and even if they are effective at all when not administered directly to the brain," he says.

The study was funded by the National Institutes of Health and is part of a major effort at the UC College of Medicine to understand the biology of weight regulation.

Coauthors include Daniela Cota, MD, Sara Kozma, PhD, Karine Proulx, Kathi Blake Smith, George Thomas, PhD, and Stephen Woods, PhD.

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