Can blocking a single protein tackle depression, obesity, and pain?

Depression, obesity, and chronic pain are some of the most pressing global health concerns. New research may have found a drug that could one day tackle all of these three conditions.

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Almost 40 percent of adults in the United States were living with obesity in 2015–2016. Worldwide, nearly 40 percent of adults are overweight, and 13 percent of them have obesity.

According to the World Health Organization (WHO), Depression is the leading cause of disability across the globe. In the U.S., over 17 million adults have experienced at least one episode of major depression in their lives.

Finally, alarming reports from the Centers for Disease Control and Prevention (CDC) have placed the number of U.S. adults living with chronic pain at 50 million. Studies have linked chronic pain with depression, anxiety, and opioid addiction.

All of these severe conditions are taking their toll on U.S. adults. But could there be a silver bullet that could tackle all of them at once?

New research suggests that there might be. Felix Hausch, Ph.D., from the Technical University of Darmstadt, in Germany, led a new investigation into the effects of blocking a single protein that has links with all three conditions.

The protein is called FK506-binding protein 51, or FKBP51. Hausch and colleagues developed a compound that can block the activity of this protein in mice. The drug relieved chronic pain, improved mood, and reduced diet-induced obesity in the rodents.

The researchers presented their findings at the American Chemical Society (ACS) Spring 2019 National Meeting & Exposition in Orlando, FL.

Why study the FKBP51 protein?

Hausch explains, "The FKBP51 protein plays an important role in depression, obesity, diabetes, and chronic pain states."

He goes on to share the motivation for the research, saying that some previous studies had piqued his interest.

"I was intrigued by the peculiar regulatory role [FKBP51] seemed to play in cells [...] [a]nd there was a known natural product that could serve as a starting point. Collectively, this looked like an interesting protein to work on."

Indeed, previous studies have suggested that FKBP51 may regulate stress and metabolism, mediating the relationship between diet-induced obesity, chronic stress, and stress-related psychiatric conditions.

Several parts of the human body, such as the brain, muscles, and fat tissue, contain FKBP51. The protein serves many functions, including limiting the uptake of sugar and restricting how much fat is turning into brown fat — the good type of fat that helps transform nutrients into energy.

Therefore, the protein FKBP51 can make us store fat instead of burning it, which may lead to obesity. The protein is also involved in how our body responds to stress.

FKBP51 inhibitor affects stress, mood, weight

However, targeting the FKBP51 protein has proven difficult in the past, mainly because it looks very similar to another protein it is close to, called FKBP52.

"These two proteins are very similar in structure, but they are doing opposing things in cells," explains Hausch.

"We have this yin-yang situation. Selectivity between these two proteins is thought to be crucial, but this is hard to achieve since the two proteins are so similar."

"We discovered that FKBP51 can change its shape in a way that FKBP52 can't, and this allowed the development of highly selective inhibitors," continues the researcher. The scientists used nuclear magnetic resonance techniques to discover a new binding site in FKBP51.

As a result, they developed a "highly selective inhibitor," which they called SAFit2. Tests in mice revealed its benefits. "It indeed helps mice cope better in stressful situations," says Hausch.

In fact, SAFit2 lowered stress hormone levels and promoted stress-coping mechanisms in the rodents. "Furthermore, SAFit2 ameliorated inflammatory pain-induced disabilities and diet-induced obesity," report the scientists.

"Inhibition of FKBP51 could thus be a new therapeutic option to treat [depression, obesity, diabetes, and chronic pain states.]"
- Felix Hausch

Finally, however, the researchers caution that they need to do much more work before they can test the drug in humans.

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