#SfN14: How a fat metabolite lifts you up after exercise

Poster D40. Sleiman S et al. Epigenetic regulation of the BDNF gene in psychiatric diseases. Sunday Nov 16. New York University and NIH.

Aerobic exercise is an extremely potent antidepressant, and neuroscientists are just beginning to understand how a sweaty workout benefits the mind.

Part of the benefits of exercise comes down to increased levels of a protein called brain-derived neurotrophic factor (BDNF). BDNF is a nurturing protein: it promotes neuronal growth and survival, supports the formation of long-term memories, and crucially mediates the pharmacological effects of many popular anti-depressant drugs.

Yet how does the body alert the brain to start pumping out more BDNF after exercise? In a new study presented at the Society for Neuroscience conference, researchers from New York University identified beta-hydroxybutyrate (BHB), a fatty acid metabolite, as an important exercise-induced messenger to the brain.

The researchers started their search with some solid reasoning. The messenger has to satisfy several requirements: it should be produced in the body and be able to pass through the blood-brain barrier into the brain. It should also trigger BDNF gene expression, likely through an epigenetic mechanism. The latter deserves a bit more explanation.

Our DNA molecules are condensed and tightly wrapped around proteins called histones. Depending on environmental stimuli, small chemical groups can attach to (or detach from) both the DNA strands and histone proteins. The presence of these chemical groups strongly influence gene expression: for example, acetyl groups on histones greenlight the process, while methyl groups on genes clamps down gene expression. (For a more comprehensive explanation on why chemical modifications change gene expression, see this post. Hint: it has to do with proteins battling for space.)

BHB happens to satisfy all the above requirements: it's produced in the liver from fatty acids and readily diffuses into the brain. BHB also keeps gene expression going by inhibiting the action of a class of proteins called HDACs, the latter of which normally removes acetyl groups from histones and stops gene expression.

So is BHB the messenger molecule?

Researchers gave a group of male mice access to a running wheel. After a month of voluntary running, both BDNF and BHB were increased in the mice's hippocampi. When BHB was externally applied to isoloated hippocampus neurons and slices, BDNF levels also increased, suggesting that BHB is a cause of the observed BDNF increase after exercise.

Do epigenetic mechanisms underlie this effect? Researchers found that exercise inhibits HDAC activity, and that BHB treatment enhances histone acetylation in isolated neurons. Both chemical changes should promote gene expression. In a quick-and-dirty test, researchers directly inhibited HDAC activity with small molecule inhibitors, and found increased BDNF gene expression in the hippocampus.

It's not a lot of data, but enough to paint the beginnings of a story: exercise causes the liver to produce more BHB from fat, which travels through the bloodstream into the brain, where it inhibits HDAC activity and turns on BDNF gene expression. Increased BDNF, in turn, soothes depression.

BHB is far from the only messenger molecule that links exercise to enhanced BDNF expression, but it's an interesting one. For one, it seems to increase cellular energetics and decrease damage from oxidative stress in neurons. It's also a main metabolite produced during a metabolic state called ketosis, which is often used to control epilepsy in children.

Unfortunately BHB falls flat as a new anti-depressant drug. Just because it's natural doesn't mean it's completely safe, said the researcher. BHB rapidly changes the pH of the blood and tissue, which can lead to severe damage. "In our studies we had to implant skin patches to allow slow and steady release," said the researcher, "that way we can keep the mice alive."

Still, she continued, it's fascinating to see how exercise and metabolism are directly linked to how our genes are expressed in the brain.